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Introduction

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Currently marketed antidepressants are poorly efficacious, requiring weeks of chronic dosing for symptomatic relief, and many of those who suffer from major depressive disorder fail to achieve complete remission. (1,2) First-line pharmacotherapies, frequently selective serotonin reuptake inhibitors, are poorly efficacious, and nonpharmacological approaches such as bright light therapy actually may have a greater antidepressant effect. (3) Alternative pharmacotherapies such as tricyclic antidepressants are associated with greater risk of adverse effects, including weight gain, gastrointestinal and urinary retention, sexual dysfunction, and cardiovascular problems. Furthermore, no currently available antidepressants produce long-term antidepressant effects without chronic administration.

Recently, ketamine has been shown to have extremely rapid antidepressant effects. (4−7) Ketamine is an NMDA receptor antagonist used as a sedative and anesthetic in human and veterinary medicine. Ketamine infusion can produce symptomatic relief for major depression and suicidal ideation within minutes, (6) and it has been used off-label and in clinics across the country to treat depression. Unfortunately, for patients with treatment-resistant depression, ketamine is an efficacious antidepressant only for approximately half of the people infused, and the mean time to relapse of another depressive episode is only 17 days. (8) To prolong the antidepressant effect, ketamine requires repeated clinical visits (typically 6 visits over 12 days), (6) but symptomatic relief lasts only for about 5 weeks before another round of infusion therapy is needed.

Significantly, in March 2019, the U.S. Food and Drug Administration (FDA) approved clinical administration of intranasal esketamine (the S-(+) enantiomer of ketamine) through a restricted distribution system, and in conjunction with standard antidepressants, for treatment-resistant depression. (9) Although shown to be efficacious for treatment-resistant depression, intranasal administration is similar to intravenous infusion in that it requires repeated clinical administration. Regardless, ketamine has provided a powerful context in which to study pharmacological mechanisms that contribute to rapid antidepressant effects of drugs.

Ketamine's antidepressant effects are associated with increased synaptic density in the hippocampus (7) and medial prefrontal cortex of rats (7,10) and in rat cortical cell culture. (11) These effects are consistent with neuroproliferation observed with traditional antidepressants (12−14) that has been associated with antidepressant effects. Additional recent studies indicate that ketamine-related neuroproliferation and plasticity are dependent on the mammalian target of rapamycin (mTOR) signaling cascade, (15,16) which is dysfunctional in humans suffering from major depressive disorder. (17) Like ketamine, certain psychedelic compounds such as lysergic acid diethylamide (LSD) (18) and N,N-dimethyltryptamine (DMT) (19) have been reported to have some antidepressant-like behavioral effects in rodents, as well as to promote neuroplasticity in rat cortical cell culture via a tropomyosin receptor kinase B (TrkB) and mTOR-dependent mechanism. (11) All classic psychedelic compounds activate the serotonin 5-HT_2A receptor, (20) several of which have been shown to activate the Akt/mTOR pathway. (21)

Psilocybin, a psychedelic prodrug long excluded from biomedical research due to legal restrictions and social stigma, has been shown in multiple clinical trials to have rapid, long lasting antidepressant (22,23) and anxiolytic (22,24,25) effects in humans after only one or two acute treatment sessions. These trials included strictly controlled and highly supervised sensory environments incorporating several psychotherapy sessions post drug administration to "integrate" the subjective experience. There has been significant debate in the field as to whether the therapeutic effects of psilocybin to treat depression and anxiety are purely dependent on the individuals' subjective "peak" experience, (26,27) or are physiological in nature with the peak experience merely serving as a biomarker for antidepressant efficacy. (28)

With psilocybin recently achieving Breakthrough Status by the FDA for human Phase III clinical trials in the United States, it is imperative that we gain a better understanding of the mechanisms through which psychedelics can, after only one or two treatments, produce positive and long lasting antidepressant and anxiolytic effects persisting for six or more months in patient populations. Further, in light of the recent approval of esketamine to treat major depression, it is unknown how the rapid and long lasting therapeutic effects of psilocybin directly compare with ketamine. Ketamine also has significant abuse liability, and there are certain safety issues associated with its long-term use. Therefore, it is important to determine comparative efficacy of psilocybin and ketamine toward developing safe and effective therapeutic strategies in the clinic for the treatment of depression.

In order to investigate these issues, we have tested the ability of psilocybin, LSD, and ketamine to alleviate depressive-like symptoms and anxiety in a rat model for depression. Importantly, developing an animal model where psilocybin and LSD have therapeutic effects similar to the human demographic provides a context in which to investigate fundamental biological mechanism(s) to elucidate the robust and long lasting antidepressant and anxiolytic effects of psilocybin and related drugs.

Results and Discussion

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Psilocybin, LSD, and Ketamine Do Not Cause Persistent Stimulant or Sedative Effects

No differences in overt locomotor activity (LCA) were observed between treatment and control rats (Supplementary Figure S1).

Psychedelics Have Persistent Antidepressant-like Effects

We performed a number of experiments in which we administered intraperitoneal (IP) psilocybin (1 mg/kg), LSD (0.15 mg/kg), ketamine (5.0, 20, or 100 mg/kg), or saline, followed by evaluation for depressive-like behaviors at various intervals between 1 and 5 weeks following injection (Figure 1). Both psilocybin and LSD significantly reduced depressive-like behaviors 5 weeks after administration, although psilocybin's effect size (d = 4.985) was far greater than LSD's (d = 0.863) (Figure 2A–C,G) at the doses we used. Further, there was no indication of the effects decreasing over time, suggesting that the therapeutic effects of a single administration of psilocybin likely last far beyond the 5 weeks we tested. In our first experiment, a nonsignificant trend of reduced immobility by repeat measures psilocybin (rPSI, n = 8) rats in the forced swim test (FST) was observed 2 and 3 weeks following psilocybin administration, and rPSI rats were significantly less immobile in the FST than saline (SAL, n = 8) rats 4 weeks (p < 0.05) and 5 weeks (p < 0.05) following psilocybin administration (Figure 2A). Interval psilocybin (iPSI, n = 8) rats were significantly less immobile (p < 0.0001) 5 weeks following psilocybin treatment when compared to SAL rats in their first FST analysis (Figure 2B). Immobility reductions observed in iPSI rats were due to significantly increased swimming (p < 0.0001) and climbing (p < 0.0001) (Figure 2B). Consistent results were observed in our final experiment, where psilocybin (PSI, n = 6) rats were significantly less immobile than saline (SAL, n = 6) rats at 1 week (p < 0.0001) and 5 weeks (p < 0.001) following psilocybin administration, due to increased swimming (p < 0.05 both weeks) (Figure 2G). LSD (n = 6) rats were significantly less immobile in the FST 5 weeks following LSD (p < 0.05) treatment, due to increased swimming (p < 0.05) and climbing (p < 0.05) when compared to saline (SAL, n = 6) rats (Figure 2C).

Figure 1

Figure 1. Experimental design. (A) Rats were injected with IP saline or 1.0 mg/kg psilocybin (PSI) on day 0. Locomotor activity (LCA) and forced swim test (FST) behaviors were assessed in SAL (n = 8) and rPSI (n = 8) rats on days 7, 14, 21, 28, and 35, and elevated plus maze (EPM) behaviors were assessed on day 41. (B) iPSI (n = 8) rats were injected with 1.0 mg/kg PSI on day 0. LCA and FST behaviors were assessed on day 35, and EPM behaviors were assessed on Day 41. The iPSI group was concurrent with SAL and rPSI shown above. (C) Rats were injected with IP saline (n = 6) or LSD (n = 6) on day 0. LCA and FST behaviors were assessed on day 35, and EPM behaviors were assessed on day 40. (D) Rats were injected with IP saline, 5.0 mg/kg ketamine, or 1.0 mg/kg PSI on day 0. LCA and FST behaviors were assessed on days 7 and 35, and EPM behaviors were assessed on day 41.

Figure 2

Figure 2. Forced swim test. (A) Immobility in the FST by SAL (n = 8) and rPSI (n = 8) did not change significantly over time. However, t tests found rPSI rats were less immobile than SAL rats on days 28 (p < 0.05) and 35 (p < 0.05). (B) iPSI (n = 8) rats were significantly less immobile than SAL rats during their first FST session (p < 0.0001) and significantly more likely to swim (p < 0.0001) and climb (p < 0.0001) than SAL rats. (C) LSD (n = 6) rats were significantly less immobile than SAL (n = 6, p < 0.05) rats, and significantly more likely to swim (p < 0.05) and climb (p < 0.05). (D) Group 1 (n = 6) rats were given saline on day 0, and LCA and FST behaviors were assessed day 1 to establish control behaviors for groups 1 and 2 (shown in E). 5.0 mg/kg KET did not alter immobility in the FST 1 day after injection (day 7), but it significantly reduced immobility in the FST 1 week (p < 0.001) and 2 weeks (p < 0.01) after injection (days 21 and 28). No differences in immobility were observed 3, 4, or 5 weeks after injection when compared to saline (day 1). (E) Group 2 (n = 6) was studied concurrently with group 1 (shown in D) and compared with group 1 saline (day 1) as control behaviors. No significant differences were observed within group 2 at 20 or 100 mg/kg, or between group 2 and group 1 saline (day 1). (F) 5.0 mg/kg IP KET (n = 6) significantly reduced immobility (p < 0.0001), and increased swimming (p < 0.05) but not climbing in the FST 1 week after injection vs SAL (n = 6). 1.0 mg/kg IP PSI (n = 6) significantly reduced immobility (p < 0.0001), and increased swimming (p < 0.05) but not climbing in the FST 1 week after injection vs SAL. (G) PSI significantly reduced immobility (p < 0.001), and increased swimming (p < 0.05) but not climbing in the FST 5 weeks (day 35) after injection vs SAL. No significant differences were observed between PSI day 7 (shown in F) and PSI day 35. KET day 35 was not different from SAL days 7 or 35.

The reduced effect size of LSD may simply be due to nonoptimization of dose size or to pharmacological differences between these two drugs. We selected the psilocybin dose (1.0 mg/kg) using guidance from previously published literature, (29) in which male rats given 1.0 mg/kg psilocybin displayed the greatest behavioral changes without impaired locomotor activity. Further, the results of a small pilot study we performed in male Sprague–Dawley rats supported the antidepressant-like efficacy of this dose. Our LSD dose (0.15 mg/kg) was determined by estimations of relative potency at the target receptor (5-HT_2A), and potential off-target effects of LSD at higher levels, with no pilot validating studies. All rats given psilocybin or LSD displayed acute behavioral changes within 30 min of administration, such as limb abduction and forepaw treading, that persisted less than 2 h. Both drugs elicited substantial reduction of depressive-like behavior in the FST several weeks after complete biological clearance of the drugs (Figure 2A–C,G).

Low-Dose Ketamine Has a Transient Antidepressant-like Effect

When comparing the antidepressant-like and anxiolytic effects of psilocybin with the established antidepressant ketamine in a dose–response experiment, we found only the lowest dose of ketamine (5.0 mg/kg) was efficacious in our experimental system (Figure 2D), as 5.0 mg/kg, but not 20 or 100 mg/kg, ketamine significantly reduced immobility in the FST 1 week (p < 0.001) and 2 weeks (p < 0.01) following ketamine administration (Figure 2E). These results are consistent with the human demographic, (30) correlate to generic allometric scaling of drug administration to rats, (31) and are consistent with literature reporting ketamine's antidepressant-like effect in WKY rats. (32) However, the low dose ketamine is inconsistent with the dosing strategy commonly used with healthy rat strains such as Sprague–Dawley. (10) In another divergence from the literature, we did not observe FST behavioral changes 24 h post ketamine treatment, but did 1 week and 2 weeks after, suggesting that the intrinsic behavioral differences of WKY rats are due, at least in part, to neurological structural deficiencies rather than simply reduced functionality. Although low-dose ketamine significantly reduced depressive-like behaviors, ketamine-related behavioral changes were transient (Figure 2D) compared to those observed in iPSI and LSD rats (Figure 2A,B). Immobility behaviors in the FST displayed by rats given 5.0 mg/kg ketamine increased to baseline by the third week following ketamine treatment (Figure 2D). Consistent results were observed during our final experiment, where ketamine (KET, n = 6) rats were significantly less immobile than saline (SAL, n = 6) rats 1 week following ketamine administration (p < 0.0001), due to increased swimming (p < 0.05) (Figure 2F), but 5 weeks after ketamine treatment KET and SAL rats were statistically indistinguishable from each other (Figure 2G). These results are consistent with the human demographic, (8,33) and they support further investigation of the therapeutic properties of drugs acting as 5-HT_2A receptor agonists using appropriate animal models.

Psilocybin Plus Repeated Open Field Exposure Has a Persistent Anxiolytic Effect

Clinical researchers have described the correlation between each individual's subjective experience and future outcomes as dependent upon "set and setting". (26) Set and setting contextually contribute to each individual's comfort or sense of vulnerability during their psychedelic experience and subsequent therapy sessions. Although our experimental design was unable to quantify the animals' subjective experience, animals from all groups that underwent weekly FST displayed progressively less locomotor activity immediately prior to FST testing, but animals placed in the open field arena weekly without subsequent FST evaluation did not. rPSI, but not iPSI, rats spent significantly more time in the open arms of the elevated plus maze (EPM) (p < 0.05) and significantly less time in the closed arms of the EPM (p < 0.05) than SAL rats (Figure 3A). LSD rats given a single exposure to the open field arena (during LCA analysis prior to FST) were indistinguishable from SAL rats given a single exposure (Figure 3B). It is possible that the animals that underwent weekly FST associated the open field arena with FST analysis, which they dislike, and changed their locomotor activity accordingly. Interestingly, weekly forays into the open field arena, with or without subsequent FST, resulted in psilocybin rats (rPSI and PSI) that displayed significantly less anxiety-like behavior in the EPM than control rats (Figure 3A,C), whereas drug alone (Figure 3A,B) and ketamine with weekly arena exposure did not (Figure 3C). PSI rats placed within the open field arena during weekly 5 min sessions (identical to LCA evaluation), but only those tested in the FST the first and the fifth weeks following psilocybin treatment spent significantly more time in the open arms (p < 0.05) and significantly less time in the closed arms (p < 0.05) than SAL rats. KET rats were not statistically different from SAL rats (Figure 3C).

Figure 3

Figure 3. Elevated plus maze. (A) rPSI (n = 7 due to exclusion) spent significantly more time in the open arms of the EPM (p < 0.05) and significantly less time in the closed arms of the EPM (p < 0.05) than SAL (n = 8). No differences were observed between iPSI and SAL rats. (B) No differences were observed between LSD (n = 6) and SAL (n = 6) rats. C) PSI (n = 6) rats spent significantly more time in the open arms (p < 0.05) and significantly less time in the closed arms (p < 0.05) than SAL rats. KET (n = 6) rats were not statistically different from SAL (n = 6) rats.

Antidepressant-Like Effects of Psilocybin Appear Both Biological and Context-Dependent

Despite having a rudimentary default mode network, (34) and showing interest in mirrors, video feed, and still images of other rats, (35) rats are not commonly believed to be among the menagerie of self-aware animals. Thus, as far as modern science is able to determine, rats do not have a sense of self and are incapable of having existential anxiety, pondering the meaning behind their own existence or fearing a reality in which they, as individuals, do not exist. No one knows what the subjective experience of a rat is after being given a psychedelic, but it is highly unlikely that they are able to place that within the context of their life experiences and utilize that knowledge therapeutically to improve their affective state. Therefore, because psilocybin has robust effects similar to those of other antidepressants in rats that is very long lasting, which is similar to the long lasting antidepressant effects of psilocybin to alleviate the symptoms of depression in humans, we posit that the basis for the antidepressant effects in humans is at its core biological in nature, and that while correlated to antidepressant effect (27) peak ego dissolution subjective experiences following psilocybin administration is not causational to antidepressant effect. These biological processes could include cellular proliferation, increased synaptic connectivity, and anti-inflammatory effects. Drugs like LSD and psilocybin have been demonstrated to elicit these types of changes in preclinical models, and these types of physiological effects have each been associated with antidepressant-like behavioral outcomes. (32,36)

Although we propose that the antidepressant-like effects are primarily rooted in biological processes, our data suggest that post drug administration environmental factors also play a critical role in overall drug effects. Our results suggest that psilocybin facilitates a period of behavioral flexibility in which exploration of a non-home-cage environment reduces their anxiety during future exploration of a novel environment (the EPM, Figure 3A), but FST evaluation 1 week after psilocybin blunts the antidepressant-like effect in the FST (Figure 2A,F,G). In this context, psilocybin may open a window during which time certain experiences are salient to the development of new coping strategies, similar to MDMA-facilitated social learning reported in mice. (37) As the FST measures the coping strategies of rodents challenged with the threat of drowning, successfully surviving the first trial by floating may make rats given psilocybin more likely to use this coping strategy in the future, whereas rats given psilocybin and not subjected to FST for 5 weeks choose active coping strategies. Interestingly, that is not true of ketamine, as ketamine's antidepressant-like effect was independent of repeated FST, but transient (Figure 2D,G) and no anxiolytic effect was observed (Figure 3C). Therefore, overall efficacy in humans is likely a combination of both the acute neurological effects of the drug and subjective, contextual experiences during and/or immediately following the drug administration session.

Conclusions

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The antidepressant-like and anxiolytic effects of psychedelics are measurable and significant in males of a rat experimental system that has been used by several other groups over many decades for the study of mood disorders in humans. These effects are evident many weeks after administration, are more persistent than those of ketamine, and are modulated by the rats' experiences in the first week following administration. The more persistent therapeutic effects of a single administration of psilocybin compared to ketamine in our experimental system support the notion that serotonin 5-HT_2A receptor directed therapeutic strategies may be superior to ketamine-based treatments in the clinic for depression. Finally, our experimental rodent system, which recapitulates the major features of psilocybin to treat depression in human patients, may represent a valuable system to utilize for the elucidation of molecular, cellular, and genetic mechanisms underlying the ability of psilocybin to produce the robust and long lasting antidepressant effects found in human clinical trials toward developing new and effective therapeutic strategies for treating depression.

Methods

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Animals

Results of a small pilot study we performed in healthy Sprague–Dawley rats indicated that although psilocybin's antidepressant-like effects persist for at least a month or longer after drug administration, they may not appear for a week or more after drug administration. This potential delayed efficacy excluded the use of chronic stress models of depression for evaluation in a model of depression because these models require testing immediately after 21 consecutive days of stress. (38,39) We chose to use a selectively bred rat strain, but we excluded the more commonly used Flinders Sensitive Line (FSL) rats, as FSL rats have abnormally low central 5HT_2A mRNA expression (40,41) and esketamine-related changes in the depressive-like behavior of that strain has been shown to be independent of the 5HT_2A receptor and instead be 5HT_1B-dependent. (36) Given that the antidepressant effects of psychedelics are believed to be directly related to 5HT_2A agonism, (20) it is unsurprising that a recent study found no antidepressant-like effects of psilocybin in FSL rats. (42) Therefore, we chose to use the Wistar–Kyoto (WKY) rat, a less frequently used but well established and validated intrinsic model for the study of depression and anxiety vulnerability. (32,43−52) WKY rats display high immobility in the FST, (32,43,45−47,51,53) increased anxiety-like behaviors, (44,54) and an elevated stress response compared to control rats. (48,51,52) As very few publications have reported measures of baseline behaviors in female WKY rats, or their response to antidepressants, females were excluded from this study, but will be examined in future studies.

Male WKY rats aged 50–56 days were obtained from Charles River and allowed to habituate to the colony room for at least 7 days prior to drug administration. Rats were pair-housed with a standard 12:12 light–dark cycle, handled daily, and given ad libitum access to water and food. All protocols were approved by the Institutional Animal Care and Use Committee and were consistent with the Guide, eighth edition.

Drugs

Psilocybin (PSI) and lysergic acid diethylamide tartrate (2:1) (LSD) were provided by the National Institute on Drug Abuse (Bethesda, MD), and ketamine (KET) was obtained from the LSUHSC Division of Animal Care and supplied by Henry Schein Animal Health (Dublin, OH). A single bolus injection of sterile saline or drug in saline vehicle was administered in a volume of 1 mL/kg intraperitoneally (IP) to each rat corresponding to their assigned treatment groups (day 0) (PSI = 1.0 mg/kg; LSD = 0.15 mg/kg; KET = 5.0, 20, or 100 mg/kg). Route of administration and dosing regimen were chosen using guidance from the literature, (10,29,32,55) a small pilot study, and in consultation with Dr. David E. Nichols (Purdue Univeristy).

Experimental Design

Persistent Antidepressant-like and Anxiolytic Effects of Psilocybin

To evaluate the antidepressant-like effects of a single injection of psilocybin in male WKY rats, three treatment groups were defined as saline (SAL, n = 8), repeat measures psilocybin (rPSI, n = 8), and interval psilocybin (iPSI, n = 8). Rats were treated on day 0. SAL and rPSI groups underwent a single FST pre-exposure on day 6 post-treatment and were tested in the FST on days 7, 14, 21, 28, and 35. The iPSI group was pre-exposed to the FST on day 34 post-treatment and was tested in the FST on day 35. All rats were tested for anxiety-like behaviors in the EPM on day 41. iPSI FST scores were compared with SAL FST scores from day 7 to avoid potential confounding by repeat measures. An interval-saline group was determined to be redundant, as there is no evidence that the slight age difference in these rats affects FST behavior, and previously published literature has established that FST behaviors throughout this age range is consistent. (56,57) Thus, we excluded the redundant control group for ethical animal resource use. (58) Further, our design allowed for within-subject comparison. LCA was assessed in the open field immediately prior to each FST (Figure 1A,B).

Persistent Antidepressant-like Effects of LSD

To evaluate the long-term antidepressant-like effects of a single injection of LSD in male WKY rats, two treatment groups were defined as saline (SAL, n = 6) and LSD (LSD, n = 6). Rats were treated on day 0, pre-exposed to the FST on day 34 post-treatment, and then tested for depressive-like behaviors in the FST on day 35. LCA was assessed in the open field immediately prior to the FST. Rats were tested for anxiety-like behaviors in the EPM on day 40 (Figure 1C).

Ketamine Dose–Response

To determine an antidepressant-like dose of ketamine in male WKY rats and to determine the persistence of ketamine's antidepressant-like effect, rats were given saline or ketamine (5, 20, or 100 mg/kg) IP and tested weekly in the FST. Group 1 rats (n = 6) were given saline 2 days prior to the first FST and 5 mg/kg a day prior to the second FST. Group 2 rats (n = 6) were given 20 mg/kg ketamine 2 days prior to the first FST and 100 mg/kg a day prior to the fifth FST (Figure 2D-E).

Salience of Experience to Behavioral End points of Psilocybin and Ketamine

To evaluate the contribution of experience to anxiolytic effect and apparent reduction in antidepressant-like effect of psilocybin observed in rPSI rats, three treatment groups of male WKY rats were defined as saline (SAL, n = 6), ketamine (KET, 5.0 mg/kg, n = 6), and psilocybin (PSI, n = 6). Rats were treated on day 0, pre-exposed to the FST on day 6, and tested for depressive-like behaviors in the FST on day 7. All rats were placed individually in the open field arena for 5 min sessions once per week for the next 3 weeks, pre-exposed to the FST for a second time on day 34, and tested for depressive-like behaviors at day 35. LCA was assessed in the open field arena immediately prior to each FST. Rats were tested for anxiety-like behaviors in the EPM on day 41 (Figure 1D).

Forced Swim Test

To test for the effects of psilocybin on depressive-like behavior, we used the FST as our primary outcome measure. The FST is a behavioral despair paradigm often used to measure depressive-like behavior and to screen for antidepressant-like effects in rats. (59) The FST interprets immobility, a passive coping strategy, as a depressive-like behavior, and reductions in immobility as evidence of antidepressant-like effect. (57,59) The FST measures coping strategies that are not solely mediated by neurocircuits known to be dysfunctional in the human demographic and thus lacks construct validity. However, it remains the most reliable measure of passive coping strategy, a depressive-like behavior, in both male and female rats, (60,61) as measures of anhedonia like the sucrose preference test have been shown to be inconsistent in females (60,61) and negatively correlated to behavioral despair independent of chronic stress paradigms. (62) The FST can be used to screen for antidepressant-like action of drugs given to otherwise healthy rats, (57,60) for depressive-like behaviors in animal models of depression, (63,64) or for antidepressant-like action of drugs given to animals modeling depression. (63−65) Our use of the term "antidepressant-like" when referring to the effects of psilocybin here are in reference to the published effects of antidepressants typically used to treat humans on rat behaviors, and not to the effects of antidepressants on human behaviors. As the FST measures active behaviors, overall locomotor activity also must be assessed immediately prior to the FST to control for nonspecific sedative or stimulant effects that might otherwise lead to false positive or negative results. (57) Increased immobility or activity in the FST is only meaningful if overall locomotor activity is unchanged, which we found to be the case in each of our experiments. A 15 min pre-exposure to the paradigm is required to elicit measurable depressive-like behavior in otherwise healthy rats. It had been widely assumed that each subsequent/additional exposure to an FST would increase immobility. (66) This assumption was shown to be false in a 2011 study that used a single 15 min pre-exposure and weekly FST. (66) Multiple experiments were performed during our study, using both repeat measures and interval testing. While there is evidence of differences in FST behavior between distinct phases of a rat's life, prepubertal (<4 weeks), adult (2–18 months), and aged rats (18 months), (56) all tests in this study occurred during the same phase, young adulthood (9–15 weeks), (67) during which time FST behaviors are known to be consistent. Thus, we chose to reduce animal resources in studies with repeat measures by comparing our interval-tested treatment groups with the first FST of the repeatedly tested saline groups. Although our intent was not to confirm the validity of repeat measures FST, our results are consistent with those of Mezadri et al., (66) in that we found repeated exposure to the FST did not increase or decrease immobility in control rats. However, antidepressant-like effects in animals given psilocybin and repeatedly exposed to the FST were not as robust as in those given the same drug, but only exposed to a single FST. We address this finding in the Results and Discussion section.

FST was conducted as previously described with some modifications. (57) During the pre-exposure, rats were placed into a plastic cylindrical tank (114 cm × 30.5 cm) that contained 30 cm of water at 28–30 °C. The water depth was such that the rats could not support themselves by touching the bottom of the tank with their hind paws, and their tails could not touch the bottom of the tank while keeping their noses above water. After a 15 min swim, the rats were removed, dried with paper towels, and replaced in their home cages. Fresh water was used for each animal. At the time of testing, a video camera was mounted to the side of the tank, and the rats were exposed to a 5 min swim under the conditions described above and then removed, dried with paper towels, and returned to their home cages. The 5 min swim was recorded for later scoring for immobility, swimming, climbing, or diving. FST scoring was performed by trained scorers blind to the treatment options and employed the modified sampling technique. (57) Immobility was defined as no active attempts to escape while maintaining a floating posture in which the rats make only the movements necessary to keep their heads above water. Swimming was defined as actively attempting escape with motions directed outward against the wall of the cylinder. Climbing was defined as actively attempting escape with motions directed upward against the wall of the cylinder. Diving was defined as actively attempting escape with motions directed downward below the water and the head of the rat submerged. Significantly greater immobility than control (SAL) rats indicates depressive-like behavior, and significantly less immobility indicates an antidepressant-like effect. Significantly increased swimming may suggest increased serotonergic signaling, and significantly increased climbing may suggest increased noradrenergic signaling. Diving is rarely observed and not correlated with specific neurotransmitter activity or drugs known to influence specific neurotransmitter activity. (57) No diving was observed during this study; thus, the behavior was not included in our results or analyses. Behaviors were manually scored by two independent observers blind to the treatments.

Locomotor Activity

Locomotor activity was assessed immediately prior to each FST in order to prevent confounding by nonspecific sedative or stimulant effects. LCA assessment was performed by placing each rat into a square open field arena (61 × 61 cm²) with opaque walls 45 cm high and allowing the rats to explore freely for 5 min. The rats' movements within the arena were recorded and later scored for distance traveled (cm) using EthoVision XT 8.5 tracking software (Noldus Information Technology).

Elevated Plus Maze

To test for anxiety-like behavior we used the EPM, a widely used approach-avoidance assay that exploits the conflict between exploration behaviors and defensive thigmotaxis in a novel environment. (68) The EPM was conducted as previously described. (68) The maze apparatus consists of four equally sized arms, two of which are open runways and two of which are enclosed by walls. Each rat was allowed to habituate to the testing room for at least 15 min prior to exposure to the maze. After habituation, rats were placed at the junction (10 × 10 cm²) of the four arms of the maze (114 × 114 × 114 cm³ externally, runways 50 × 10 cm²) facing an open arm and allowed to explore freely for 5 min during which time an overhead camera recorded their movements. Video recordings of the sessions were scored for time spent in the open arms, the closed arms, and the junction of the open and closed arms using EthoVision 8.5 (Noldus Information Technology). Although EPM data are traditionally presented as a ratio of open/closed arms, two rPSI rats never entered the closed arms. Thus, we chose to present EPM data as time spent in the open and closed arms during the 5 min (300 s) assay and to not report time spent in the hub/center of the EPM.

Statistical Analyses

Group sizes were determined using power analysis for a two-tailed t test, and conservative estimates based upon previously published literature (53) (μ0 = 45, μ1 = 35, σ = 7, α = 0.05, power = 0.80). Data were compared by t test or two-way ANOVA with repeated measures and Holm–Sidak posthoc using Prism software (Graphpad, La Jolla, CA), and significant results from relevant comparisons are summarized in Supplementary Table 1. Data are expressed in figures as mean ± standard error of the mean.

Exclusions

During our first experiment, one rPSI rat was excluded from the EPM analysis due to confounding environmental disruptions during his trial. Thus, rPSI n = 7 for EPM behavior for that experiment. However, because FST and EPM behaviors are independent of each other, the rat excluded from EPM analysis was not excluded from the FST analysis, so that for FST n = 8 for all groups in that experiment. During the ketamine dose–response study, the first two LCA sessions suffered from equipment failure that resulted in exclusion of LCA data for those sessions. However, as no differences were observed in FST behavior corresponding to the excluded LCA sessions, the excluded LCA data were not needed for accurate FST analysis.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acschemneuro.9b00493.

• Open field locomotor activity (PDF)

• Summary of significant results from relevant comparisons made during the four experiments presented (PDF)

• cn9b00493_liveslides.mp4 (7.15 MB)
• cn9b00493_si_001.pdf (937.27 kb)
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Author Information

---

• • Charles D. Nichols - Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, United States; http://orcid.org/0000-0002-0615-0646; Email: [email protected]

• • Meghan Hibicke - Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, United States

  • Alexus N. Landry - Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, United States

  • Hannah M. Kramer - Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, United States

  • Zoe K. Talman - Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, United States

• This work was supported by Eleusis, PBC.

• The authors declare the following competing financial interest(s): C.D.N. has a sponsored research contract with Eleusis PBC. and is a member of its Scientific Advisory Board.
  

Acknowledgments

---

The authors wish to thank Adam Levin and Alejandro Jose Molina for their time and effort scoring videos of rats in the FST, and Dr. D.E. Nichols for his assistance determining LSD dosing concentration.

This article references 68 other publications.

1. 1

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   The sequenced treatment alternatives to relieve depression (STAR*D) trial: a review

   Sinyor Mark; Schaffer Ayal; Levitt Anthony

   Canadian journal of psychiatry. Revue canadienne de psychiatrie (2010), 55 (3), 126-35 ISSN:.

   OBJECTIVE: The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial is the largest open-label, pragmatic trial that has been undertaken to examine the treatment of major depressive disorder. At a cost of US$35 million over 6 years, STAR*D sought to test the effectiveness both of pharmacotherapy and of cognitive therapy, and to ascertain whether certain treatments are more optimal after one or more failed trials. METHOD: Patients (n = 2876) who presented to either a psychiatry or family practice setting seeking treatment for depression were included in the STAR*D analysis. In the 4 levels of STAR*D, patients were randomized to various treatment monotherapies, combinations, or augmentation strategies. The primary outcome was remission, based on the Hamilton Depression Rating Scale. Secondary outcomes were response, as measured by clinician and patient self-report as well as various measures of patients' level of function and (or) quality of life. RESULTS: Remission rates for treatment levels 1 to 2 and 3 to 4 were 18% to 30% and 7% to 25%, respectively. There was no difference in effectiveness between any treatments at any treatment level. Patients with longer index episodes, more concurrent psychiatric or general medical disorders, and (or) lower measures of baseline function were less likely to achieve remission. There were no major differences between outcomes in patients treated in primary, compared with specialist care, nor were there significant differences between depression rating scores obtained through clinician ratings, compared with self-report. CONCLUSION: Results of the STAR*D trial have shed important light on the effectiveness of current treatment strategies for patients with depression.

   https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3c3kt1CqtQ%253D%253D&md5=3346e3fc76a367c02c8fc43d8c19a918

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   Current psychiatry reports (2007), 9 (6), 449-59 ISSN:1523-3812.

   The Sequenced Treatment Alternatives to Relieve Depression trial enrolled outpatients with nonpsychotic major depressive disorder treated prospectively in a series of randomized controlled trials. These were conducted in representative primary and psychiatric practices. Remission rates for treatment steps 1 to 4 based on the 16-item Quick Inventory of Depressive Symptomatology-Self-report were 37%, 31%, 14%, and 13%, respectively. There were no differences in remission rates or times to remission among medication switch or among medication augmentation strategies at any treatment level. Participants who required increasing numbers of treatment steps showed greater depressive illness burden and increasingly greater relapse rates in the naturalistic follow-up period (40%-71%). Prognosis was better at all levels for participants who entered follow-up in remission as opposed to those who entered with response without remission. These results highlight the prevalence of treatment-resistant depression and suggest potential benefit for using more vigorous treatments in the earlier steps.

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   Lam, R. W. (2016) Efficacy of Bright Light Treatment, Fluoxetine, and the Combination in Patients With Nonseasonal Major Depressive Disorder: A Randomized Clinical Trial. JAMA Psychiatry 73 , 56– 63,  DOI: 10.1001/jamapsychiatry.2015.2235

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   Efficacy of Bright Light Treatment, Fluoxetine, and the Combination in Patients With Nonseasonal Major Depressive Disorder: A Randomized Clinical Trial

   Lam Raymond W; Michalak Erin E; Yatham Lakshmi N; Tam Edwin M; Levitt Anthony J; Cheung Amy H; Levitan Robert D; Morehouse Rachel; Ramasubbu Rajamannar

   JAMA psychiatry (2016), 73 (1), 56-63 ISSN:.

   IMPORTANCE: Bright light therapy is an evidence-based treatment for seasonal depression, but there is limited evidence for its efficacy in nonseasonal major depressive disorder (MDD). OBJECTIVE: To determine the efficacy of light treatment, in monotherapy and in combination with fluoxetine hydrochloride, compared with a sham-placebo condition in adults with nonseasonal MDD. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo- and sham-controlled, 8-week trial in adults (aged 19-60 years) with MDD of at least moderate severity in outpatient psychiatry clinics in academic medical centers. Data were collected from October 7, 2009, to March 11, 2014. Analysis was based on modified intent to treat (randomized patients with ≥1 follow-up rating). INTERVENTIONS: Patients were randomly assigned to (1) light monotherapy (active 10,000-lux fluorescent white light box for 30 min/d in the early morning plus placebo pill); (2) antidepressant monotherapy (inactive negative ion generator for 30 min/d plus fluoxetine hydrochloride, 20 mg/d); (3) combination light and antidepressant; or (4) placebo (inactive negative ion generator plus placebo pill). MAIN OUTCOMES AND MEASURES: Change score on the Montgomery-ÅAsberg Depression Rating Scale (MADRS) from baseline to the 8-week end point. Secondary outcomes included response (≥50% reduction in MADRS score) and remission (MADRS score ≤10 at end point). RESULTS: A total of 122 patients were randomized (light monotherapy, 32; fluoxetine monotherapy, 31; combination therapy, 29; placebo, 30). The mean (SD) changes in MADRS score for the light, fluoxetine, combination, and placebo groups were 13.4 (7.5), 8.8 (9.9), 16.9 (9.2), and 6.5 (9.6), respectively. The combination (effect size [d] = 1.11; 95% CI, 0.54 to 1.64) and light monotherapy (d = 0.80; 95% CI, 0.28 to 1.31) were significantly superior to placebo in the MADRS change score, but fluoxetine monotherapy (d = 0.24; 95% CI, -0.27 to 0.74) was not superior to placebo. For the respective placebo, fluoxetine, light, and combination groups at the end point, response was achieved by 10 (33.3%), 9 (29.0%), 16 (50.0%), and 22 (75.9%) and remission was achieved by 9 (30.0%), 6 (19.4%), 14 (43.8%), and 17 (58.6%). Combination therapy was superior to placebo in MADRS response (β = 1.70; df = 1; P = .005) and remission (β = 1.33; df = 1; P = .02), with numbers needed to treat of 2.4 (95% CI, 1.6 to 5.8) and 3.5 (95% CI, 2.0 to 29.9), respectively. All treatments were generally well tolerated, with few significant differences in treatment-emergent adverse events. CONCLUSIONS AND RELEVANCE: Bright light treatment, both as monotherapy and in combination with fluoxetine, was efficacious and well tolerated in the treatment of adults with nonseasonal MDD. The combination treatment had the most consistent effects. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00958204.

   https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28visl2jtg%253D%253D&md5=56022771bb376ab122c9f48669960ce7

4. 4

   Maeng, S. and Zarate, C. A. (2007) The role of glutamate in mood disorders: Results from the ketamine in major depression study and the presumed cellular mechanism underlying its antidepressant effects. Curr. Psychiatry Rep. 9 , 467– 474,  DOI: 10.1007/s11920-007-0063-1

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   The role of glutamate in mood disorders: results from the ketamine in major depression study and the presumed cellular mechanism underlying its antidepressant effects

   Maeng Sungho; Zarate Carlos A Jr

   Current psychiatry reports (2007), 9 (6), 467-74 ISSN:1523-3812.

   In this article, we first review a study showing that the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine leads to rapid, robust, and relatively sustained antidepressant effects in patients with treatment-resistant major depression. We then discuss our hypothesis that the therapeutic effects of monoaminergic antidepressants and ketamine may be mediated by increased AMPA-to-NMDA glutamate receptor throughput in critical neuronal circuits. We hypothesize that ketamine directly mediates this throughput, whereas monoaminergic antidepressants work indirectly and gradually; this may explain, in part, the lag of onset of several weeks to months that is observed with traditional antidepressants.

   https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1c%252Fmslektw%253D%253D&md5=bb110ec8a8830efd5f40e46684d25be8

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   Mathews, D. C. , Henter, I. D. , and Zarate, C. A. (2012) Targeting the Glutamatergic System to Treat Major Depressive Disorder. Drugs 72 , 1313– 1333,  DOI: 10.2165/11633130-000000000-00000

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   Targeting the glutamatergic system to treat major depressive disorder: rationale and progress to date

   Mathews, Daniel C.; Henter, Ioline D.; Zarate, Carlos A., Jr.

   Drugs (2012), 72 (10), 1313-1333CODEN: DRUGAY; ISSN:0012-6667. (Adis Data Information BV)

   A review. Major depressive disorder (MDD) is a severe, debilitating medical illness that affects millions of individuals worldwide. The young age of onset and chronicity of the disorder has a significant impact on the long-term disability that affected individuals face. Most existing treatments have focused on the 'monoamine hypothesis' for rational design of compds. However, patients continue to experience low remission rates, residual subsyndromal symptoms, relapses and overall functional impairment. In this context, growing evidence suggests that the glutamatergic system is uniquely central to the neurobiol. and treatment of MDD. Here, we review data supporting the involvement of the glutamatergic system in the pathophysiol. of MDD, and discuss the efficacy of glutamatergic agents as novel therapeutics. Preliminary clin. evidence has been promising, particularly with regard to the N-methyl-D-aspartate (NMDA) antagonist ketamine as a 'proof-of-concept' agent. The review also highlights potential mol. and inflammatory mechanisms that may contribute to the rapid antidepressant response seen with ketamine. Because existing pharmacol. treatments for MDD are often insufficient for many patients, the next generation of treatments needs to be more effective, rapid acting and better tolerated than currently available medications. There is extant evidence that the glutamatergic system holds considerable promise for developing the next generation of novel and mechanistically distinct agents for the treatment of MDD.

   https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xht1GmurfP&md5=01f65a28be0ad13b41951964f96b1acb

6. 6

   Murrough, J. W. (2013) Rapid and Longer-Term Antidepressant Effects of Repeated Ketamine Infusions in Treatment-Resistant Major Depression. Biol. Psychiatry 74 , 250– 256,  DOI: 10.1016/j.biopsych.2012.06.022

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   Rapid and Longer-Term Antidepressant Effects of Repeated Ketamine Infusions in Treatment-Resistant Major Depression

   Murrough, James W.; Perez, Andrew M.; Pillemer, Sarah; Stern, Jessica; Parides, Michael K.; aan het Rot, Marije; Collins, Katherine A.; Mathew, Sanjay J.; Charney, Dennis S.; Iosifescu, Dan V.

   Biological Psychiatry (2013), 74 (4), 250-256CODEN: BIPCBF; ISSN:0006-3223. (Elsevier)

   Ketamine is reported to have rapid antidepressant effects; however, there is limited understanding of the time-course of ketamine effects beyond a single infusion. A previous report including 10 participants with treatment-resistant major depression (TRD) found that six ketamine infusions resulted in a sustained antidepressant effect. In the current report, we examd. the pattern and durability of antidepressant effects of repeated ketamine infusions in a larger sample, inclusive of the original.Participants with TRD (n = 24) underwent a washout of antidepressant medication followed by a series of up to six IV infusions of ketamine (.5 mg/kg) administered open-label three times weekly over a 12-day period. Participants meeting response criteria were monitored for relapse for up to 83 days from the last infusion.The overall response rate at study end was 70.8%. There was a large mean decrease in Montgomery-Åsberg Depression Rating Scale score at 2 h after the first ketamine infusion (18.9 ± 6.6, p < .001), and this decrease was largely sustained for the duration of the infusion period. Response at study end was strongly predicted by response at 4 h (94% sensitive, 71% specific). Among responders, median time to relapse after the last ketamine infusion was 18 days.Ketamine was assocd. with a rapid antidepressant effect in TRD that was predictive of a sustained effect. Future controlled studies will be required to identify strategies to maintain an antidepressant response among patients who benefit from a course of ketamine.

   https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtFahsbnJ&md5=073e82993c3014743e84c7abe982f14e

7. 7

   Dong, C. (2016) Rapid and Sustained Antidepressant Action of the mGlu2/3 Receptor Antagonist MGS0039 in the Social Defeat Stress Model: Comparison with Ketamine. Int. J. Neuropsychopharmacol. pyw089,  DOI: 10.1093/ijnp/pyw089

8. 8

   Rong, C. (2018) Predictors of Response to Ketamine in Treatment Resistant Major Depressive Disorder and Bipolar Disorder. Int. J. Environ. Res. Public Health 15 , 771,  DOI: 10.3390/ijerph15040771

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   Predictors of response to ketamine in treatment resistant major depressive disorder and bipolar disorder

   Rong, Carola; Park, Caroline; Rosenblat, Joshua D.; Subramaniapillai, Mehala; Zuckerman, Hannah; Fus, Dominika; Lee, Yena L.; Pan, Zihang; Brietzke, Elisa; Mansur, Rodrigo B.; Cha, Danielle S.; Lui, Leanna M. W.; McIntyre, Roger S.

   International Journal of Environmental Research and Public Health (2018), 15 (4), 771/1-771/10CODEN: IJERGQ; ISSN:1660-4601. (MDPI AG)

   Objectives: Extant evidence indicates that ketamine exerts rapid antidepressant effects in treatment-resistant depressive (TRD) symptoms as a part of major depressive disorder (MDD) and bipolar disorder (BD). The identification of depressed sub-populations that are more likely to benefit from ketamine treatment remains a priority. In keeping with this view, the present narrative review aims to identify the pretreatment predictors of response to ketamine in TRD as part of MDD and BD. Method: Electronic search engines PubMed/MEDLINE, ClinicalTrials.gov, and Scopus were searched for relevant articles from inception to Jan. 2018. The search term ketamine was cross-referenced with the terms depression, major depressive disorder, bipolar disorder, predictors, and response and/or remission. Results: Multiple baseline pretreatment predictors of response were identified, including clin. (i.e., Body Mass Index (BMI), history of suicide, family history of alc. use disorder), peripheral biochem. (i.e., adiponectin levels, vitamin B12 levels), polysomnog. (abnormalities in delta sleep ratio), neurochem. (i.e., glutamine/glutamate ratio), neuroimaging (i.e., anterior cingulate cortex activity), genetic variation (i.e., Val66Met BDNF allele), and cognitive functioning (i.e., processing speed). High BMI and a pos. family history of alc. use disorder were the most replicated predictors. Conclusions: A pheno-biotype of depression more, or less likely, to benefit with ketamine treatment is far from complete. Notwithstanding, metabolic-inflammatory alterations are emerging as possible pretreatment response predictors of depressive symptom improvement, most notably being cognitive impairment. Sophisticated data-driven computational methods that are iterative and agnostic are more likely to provide actionable baseline pretreatment predictive information.

   https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitlGls7rM&md5=9fa060fe7f13ba61e49fe0b931eba04f

10. 10

    Sarkar, A. and Kabbaj, M. (2016) Sex Differences in Effects of Ketamine on Behavior, Spine Density, and Synaptic Proteins in Socially Isolated Rats. Biol. Psychiatry 80 , 448– 456,  DOI: 10.1016/j.biopsych.2015.12.025

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    Sex Differences in Effects of Ketamine on Behavior, Spine Density, and Synaptic Proteins in Socially Isolated Rats

    Sarkar, Ambalika; Kabbaj, Mohamed

    Biological Psychiatry (2016), 80 (6), 448-456CODEN: BIPCBF; ISSN:0006-3223. (Elsevier)

    The mechanistic underpinnings of sex differences in occurrence of depression and efficacy of antidepressant treatments are poorly understood. We examd. the effects of isolation stress (IS) and the fast-acting antidepressant ketamine on anhedonia and depression-like behavior, spine d., and synaptic proteins in male and female rats. We used a chronic social IS paradigm to test the effects of ketamine (0, 2.5 mg/kg, and 5 mg/kg) on behavior and levels of synaptic proteins synapsin-1, postsynaptic d. protein 95, and glutamate receptor 1 in male rats and female rats in diestrus. Medial prefrontal cortex spine d. was also examd. in male rats and female rats that received ketamine during either the diestrus or the proestrus phase of their estrous cycle. Male rats showed anhedonia and depression-like behavior after 8 wk of IS, concomitant with decreases in spine d. and levels of synapsin-1, postsynaptic d. protein 95, and glutamate receptor 1 in the medial prefrontal cortex; these changes were reversed by a single injection of ketamine (5 mg/kg). After 11 wk of IS, female rats showed depression-like behavior but no signs of anhedonia. Although both doses of ketamine rescued depression-like behavior in female rats, the decline obsd. in synaptic proteins and spine d. in IS and in diestrus female rats could not be reversed by ketamine. Spine d. was higher in female rats during proestrus than in diestrus. Our findings implicate a role for synaptic proteins synapsin-1, postsynaptic d. protein 95, and glutamate receptor 1 and medial prefrontal cortex spine d. in the antidepressant effects of ketamine in male rats subjected to IS but not in female rats subjected to IS, suggesting dissimilar underlying mechanisms for efficacy of ketamine in the two sexes.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XjvVGhtLc%253D&md5=378f1aa4ba6ebd10da9510e456ea06ce

11. 11

    Ly, C. (2018) Psychedelics Promote Structural and Functional Neural Plasticity. Cell Rep. 23 , 3170– 3182,  DOI: 10.1016/j.celrep.2018.05.022

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    11

    Psychedelics Promote Structural and Functional Neural Plasticity

    Ly, Calvin; Greb, Alexandra C.; Cameron, Lindsay P.; Wong, Jonathan M.; Barragan, Eden V.; Wilson, Paige C.; Burbach, Kyle F.; Soltanzadeh Zarandi, Sina; Sood, Alexander; Paddy, Michael R.; Duim, Whitney C.; Dennis, Megan Y.; McAllister, A. Kimberley; Ori-McKenney, Kassandra M.; Gray, John A.; Olson, David E.

    Cell Reports (2018), 23 (11), 3170-3182CODEN: CREED8; ISSN:2211-1247. (Cell Press)

    Atrophy of neurons in the prefrontal cortex (PFC) plays a key role in the pathophysiol. of depression and related disorders. The ability to promote both structural and functional plasticity in the PFC has been hypothesized to underlie the fast-acting antidepressant properties of the dissociative anesthetic ketamine. Here, we report that, like ketamine, serotonergic psychedelics are capable of robustly increasing neuritogenesis and/or spinogenesis both in vitro and in vivo. These changes in neuronal structure are accompanied by increased synapse no. and function, as measured by fluorescence microscopy and electrophysiol. The structural changes induced by psychedelics appear to result from stimulation of the TrkB, mTOR, and 5-HT2A signaling pathways and could possibly explain the clin. effectiveness of these compds. Our results underscore the therapeutic potential of psychedelics and, importantly, identify several lead scaffolds for medicinal chem. efforts focused on developing plasticity-promoting compds. as safe, effective, and fast-acting treatments for depression and related disorders.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtFCmsLnL&md5=30676eee898172471110241296057df6

12. 12

    Ampuero, E. (2010) Chronic fluoxetine treatment induces structural plasticity and selective changes in glutamate receptor subunits in the rat cerebral cortex. Neuroscience 169 , 98– 108,  DOI: 10.1016/j.neuroscience.2010.04.035

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    12

    Chronic fluoxetine treatment induces structural plasticity and selective changes in glutamate receptor subunits in the rat cerebral cortex

    Ampuero, E.; Rubio, F. J.; Falcon, R.; Sandoval, M.; Diaz-Veliz, G.; Gonzalez, R. E.; Earle, N.; Dagnino-Subiabre, A.; Aboitiz, F.; Orrego, F.; Wyneken, U.

    Neuroscience (Amsterdam, Netherlands) (2010), 169 (1), 98-108CODEN: NRSCDN; ISSN:0306-4522. (Elsevier B.V.)

    It has been postulated that chronic administration of antidepressant drugs induces delayed structural and mol. adaptations at glutamatergic forebrain synapses that might underlie mood improvement. To gain further insight into these changes in the cerebral cortex, rats were treated with fluoxetine (flx) for 4 wk. These animals showed decreased anxiety and learned helplessness. N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor subunit levels (NR1, NR2A, NR2B, GluR1 and GluR2) were analyzed in the forebrain by both western blot of homogenates and immunohistochem. Both methods demonstrated an upregulation of NR2A, GluR1 and GluR2 that was esp. significant in the retrosplenial granular b cortex (RSGb). However, when analyzing subunit content in postsynaptic densities and synaptic membranes, we found increases of NR2A and GluR2 but not GluR1. Instead, GluR1 was augmented in a microsomal fraction contg. intracellular membranes. NR1 and GluR2 were co-immunopptd. from postsynaptic densities and synaptic membranes. In the immunoppts., NR2A was increased while GluR1 was decreased supporting a change in receptor stoichiometry. The changes of subunit levels were assocd. with an upregulation of dendritic spine d. and of large, mushroom-type spines. These mol. and structural adaptations might be involved in neuronal network stabilization following long-term flx treatment.

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13. 13

    Andrade, C. (2014) Antidepressant augmentation with anti-inflammatory agents. J. Clin. Psychiatry 75 , 975– 977,  DOI: 10.4088/JCP.14f09432

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    Antidepressant augmentation with anti-inflammatory agents

    Andrade Chittaranjan

    The Journal of clinical psychiatry (2014), 75 (9), 975-7 ISSN:.

    Antidepressant augmentation strategies are commonly employed to treat depressed patients who do not respond to antidepressant monotherapy. Neuroinflammatory mechanisms have been implicated in depression, and nonsteroidal anti-inflammatory drugs (NSAIDs) have been found effective in animal models of depression both in monotherapy and when used to augment antidepressant drugs. However, results with NSAIDs have been mixed in human observational studies, with both better and worse depression outcomes reported. Four small (pooled N = 160) randomized controlled trials suggest that celecoxib (200-400 mg/d) augmentation of antidepressant medication improves 4-6 week outcomes in major depressive disorder. There are no data, however, to support the use of celecoxib or other NSAIDs in antidepressant-resistant depression. There are also concerns about adverse events associated with NSAID treatment, and about pharmacodynamic drug interactions between these drugs and serotonin reuptake inhibitors. A reasonable conclusion for the present is that NSAID augmentation of antidepressants is, at best, a tentative approach in nonrefractory major depression.

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14. 14

    Gałecki, P. , Mossakowska-Wójcik, J. , and Talarowska, M. (2018) The anti-inflammatory mechanism of antidepressants - SSRIs, SNRIs. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 80 , 291– 294,  DOI: 10.1016/j.pnpbp.2017.03.016

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    14

    The anti-inflammatory mechanism of antidepressants - SSRIs, SNRIs

    Galecki, Piotr; Mossakowska-Wojcik, Joanna; Talarowska, Monika

    Progress in Neuro-Psychopharmacology & Biological Psychiatry (2018), 80 (Part_C), 291-294CODEN: PNPPD7; ISSN:0278-5846. (Elsevier Inc.)

    A review. The cytokine theory of depression no longer brings about any doubts. Expts. and research studies conducted in the last ten years have confirmed that both phys. and psychol. (emotional) stress increases the likelihood of occurrence of mental disorders (including depressive disorders) owing to the action of a series of hormonal and biochem. mechanisms. Selective serotonin reuptake inhibitors (SSRI) as well as serotonin and norepinephrine reuptake inhibitors (SNRIs) are some of the most commonly applied drugs in the world during pharmacotherapy of recurrent depressive disorder. The underestimated anti-inflammatory and anti-oxidative effect may be one of the potential mechanisms of action of the prepns. mentioned above. The detailed specificity of action of this mechanism still remains unknown. The aim of our work will be to perform a review of contemporary literature in order to present the latest scientific reports regarding the anti-inflammatory effects of SSRIs and SNRIs. The mechanism of anti-inflammatory action may serve as a possible explanation for the efficacy of antidepressants from the groups of SSRIs and SNRIs.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXltlWmtLg%253D&md5=c63b2959decd36c661a215e166e6926e

15. 15

    Abelaira, J. M. , Reus, G. Z. , Neotti, M. V. , and Quevedo, J. (2014) The role of mTOR in depression and antidepressant responses. Life Sci. 101 , 10– 14,  DOI: 10.1016/j.lfs.2014.02.014

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    15

    The role of mTOR in depression and antidepressant responses

    Abelaira, Helena M.; Reus, Gislaine Z.; Neotti, Morgana V.; Quevedo, Joao

    Life Sciences (2014), 101 (1-2), 10-14CODEN: LIFSAK; ISSN:0024-3205. (Elsevier B.V.)

    A review. The aim of this study was to characterize the mTOR signaling cascade in depression and the actions that antidepressant drugs have on this pathway. Herein, a literature review was performed by verification and comparison of textbooks and journal articles that describe the characterization of the mTOR signaling cascade and its relationship to depression and antidepressant drugs, esp. ketamine. Postmortem studies have shown robust deficits in the mammalian target of rapamycin (mTOR) signaling in the prefrontal cortex of subjects diagnosed with major depressive disorder. However, besides the mTOR signaling pathway having an antidepressant response to various drugs, this seems to be more assocd. with antidepressant N-methyl-d-aspartate (NMDA) receptor antagonists, such as ketamine. The characterization of the mTOR signaling pathway in depression and its action in response to antidepressants show great potential for the identification of new therapeutic targets for the development of antidepressant drugs.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXkt1Wiuro%253D&md5=f2d3f07b925c285e85a5a848949078b5

16. 16

    Li, N. (2010) mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists. Science 329 , 959– 964,  DOI: 10.1126/science.1190287

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    mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists

    Li, Nanxin; Lee, Boyoung; Liu, Rong-Jian; Banasr, Mounira; Dwyer, Jason M.; Iwata, Masaaki; Li, Xiao-Yuan; Aghajanian, George; Duman, Ronald S.

    Science (Washington, DC, United States) (2010), 329 (5994), 959-964CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)

    The rapid antidepressant response after ketamine administration in treatment-resistant depressed patients suggests a possible new approach for treating mood disorders compared to the weeks or months required for std. medications. However, the mechanisms underlying this action of ketamine [a glutamate N-methyl-D-aspartic acid (NMDA) receptor antagonist] have not been identified. We obsd. that ketamine rapidly activated the mammalian target of rapamycin (mTOR) pathway, leading to increased synaptic signaling proteins and increased no. and function of new spine synapses in the prefrontal cortex of rats. Moreover, blockade of mTOR signaling completely blocked ketamine induction of synaptogenesis and behavioral responses in models of depression. Our results demonstrate that these effects of ketamine are opposite to the synaptic deficits that result from exposure to stress and could contribute to the fast antidepressant actions of ketamine.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtVaqurzI&md5=10e346a65ae3aa8eb30f16fccbda28b3

17. 17

    Jernigan, C. S. (2011) The mTOR signaling pathway in the prefrontal cortex is compromised in major depressive disorder. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 35 , 1774– 1779,  DOI: 10.1016/j.pnpbp.2011.05.010

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    17

    The mTOR signaling pathway in the prefrontal cortex is compromised in major depressive disorder

    Jernigan, Courtney S.; Goswami, Dharmendra B.; Austin, Mark C.; Iyo, Abiye H.; Chandran, Agata; Stockmeier, Craig A.; Karolewicz, Beata

    Progress in Neuro-Psychopharmacology & Biological Psychiatry (2011), 35 (7), 1774-1779CODEN: PNPPD7; ISSN:0278-5846. (Elsevier B.V.)

    Recent studies demonstrate that rapid antidepressant response to ketamine is mediated by activation of the mammalian target of rapamycin (mTOR) signaling pathway, leading to increased synaptic proteins in the prefrontal cortex (PFC) of rats. Our postmortem studies indicate robust deficits in prominent postsynaptic proteins including N-methyl-D-aspartate (NMDA) receptor subunits (NR2A, NR2B), metabotropic glutamate receptor subtype 5 (mGluR5) and postsynaptic d. protein 95 kDa (PSD-95) in the PFC in major depressive disorder (MDD). We hypothesize that deficits in the mTOR-dependent translation initiation pathway contribute to the mol. pathol. seen in the PFC of MDD subjects, and that a rapid reversal of these abnormalities may underlie antidepressant activity. The majority of known translational regulation occurs at the level of initiation. MTOR regulates translation initiation via its downstream components: p70-kDa ribosomal protein S6 kinase (p70S6K), and eukaryotic initiation factors 4E and 4B (eIF4E and eIF4B). In this study, we examd. the expression of mTOR and its core downstream signaling targets: p70S6K, eIF4E, and eIF4B in the PFC of 12 depressed subjects and 12 psychiatrically healthy controls using Western blot. Levels of eIF4E phosphorylated at serine 209 (p-eIF4E-Ser209) and eIF4B phosphorylated at serine 504 (p-eIF4B-Ser504) were also examd. Adjacent cortical tissue samples from both cohorts of subjects were used in our previous postmortem analyses. There was a significant redn. in mTOR, p70S6K, eIF4B and p-eIF4B protein expression in MDD subjects relative to controls. No group differences were obsd. in eIF4E, p-eIF4E or actin levels. Our findings show deficits in mTOR-dependent translation initiation in MDD particularly via the p70S6K/eIF4B pathway, and indicate a potential assocn. between marked deficits in synaptic proteins and dysregulation of mTOR signaling in MDD.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtVels7nO&md5=02e9ee94c02b77d4225d528c2435ffb3

18. 18

    Buchborn, T. , Schröder, H. , Höllt, V. , and Grecksch, G. (2014) Repeated lysergic acid diethylamide in an animal model of depression: Normalisation of learning behaviour and hippocampal serotonin 5-HT2 signalling. J. Psychopharmacol. (London, U. K.) 28 , 545– 552,  DOI: 10.1177/0269881114531666

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    18

    Repeated lysergic acid diethylamide in an animal model of depression: normalisation of learning behaviour and hippocampal serotonin 5-HT2 signalling

    Buchborn, Tobias; Schroeder, Helmut; Hoellt, Volker; Grecksch, Gisela

    Journal of Psychopharmacology (London, United Kingdom) (2014), 28 (6), 545-552, 8 pp.CODEN: JOPSEQ; ISSN:0269-8811. (Sage Publications Ltd.)

    A re-balance of postsynaptic serotonin (5-HT) receptor signalling, with an increase in 5-HT1A and a decrease in 5-HT2A signalling, is a final common pathway multiple antidepressants share. Given that the 5-HT1A/2A agonist lysergic acid diethylamide (LSD), when repeatedly applied, selectively downregulates 5-HT2A, but not 5-HT1A receptors, one might expect LSD to similarly re-balance the postsynaptic 5-HT signalling. Challenging this idea, we use an animal model of depression specifically responding to repeated antidepressant treatment (olfactory bulbectomy), and test the antidepressant-like properties of repeated LSD treatment (0.13 mg/kg/d, 11 d). In line with former findings, we observe that bulbectomized rats show marked deficits in active avoidance learning. These deficits, similarly as we earlier noted with imipramine, are largely reversed by repeated LSD administration. Addnl., bulbectomized rats exhibit distinct anomalies of monoamine receptor signalling in hippocampus and/or frontal cortex; from these, only the hippocampal decrease in 5-HT2 related [35S]-GTP-gamma-S binding is normalized by LSD. Importantly, the sham-operated rats do not profit from LSD, and exhibit reduced hippocampal 5-HT2 signalling. As behavioral deficits after bulbectomy respond to agents classified as antidepressants only, we conclude that the effect of LSD in this model can be considered antidepressant-like, and discuss it in terms of a re-balance of hippocampal 5-HT2/5-HT1A signalling.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhslWgur3E&md5=d039a1ae9269e438cefaef2b79e82da4

19. 19

    Cameron, L. P. , Benson, C. J. , Dunlap, L. E. , and Olson, D. E. (2018) Effects of N,N-Dimethyltryptamine on Rat Behaviors Relevant to Anxiety and Depression. ACS Chem. Neurosci. 9 , 1582,  DOI: 10.1021/acschemneuro.8b00134

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    19

    Effects of N,N-Dimethyltryptamine on Rat Behaviors Relevant to Anxiety and Depression

    Cameron, Lindsay P.; Benson, Charlie J.; Dunlap, Lee E.; Olson, David E.

    ACS Chemical Neuroscience (2018), 9 (7), 1582-1590CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)

    Depression and anxiety disorders are debilitating diseases resulting in substantial economic costs to society. Traditional antidepressants often take weeks to months to pos. affect mood and are ineffective for about 30% of the population. Alternatives, such as ketamine, a dissociative anesthetic capable of producing hallucinations, and the psychoactive tisane ayahuasca, have shown great promise due to their fast-acting nature and effectiveness in treatment-resistant populations. Here, we investigate the effects of N,N-dimethyltryptamine (DMT), the principle hallucinogenic component of ayahuasca, in rodent behavioral assays relevant to anxiety and depression using adult, male, Sprague-Dawley rats. We find that while DMT elicits initial anxiogenic responses in several of these paradigms, its long-lasting effects tend to reduce anxiety by facilitating the extinction of cued fear memory. Furthermore, DMT reduces immobility in the forced swim test, which is a characteristic behavioral response induced by many antidepressants. Our results demonstrate that DMT produces antidepressant and anxiolytic behavioral effects in rodents, warranting further investigation of ayahuasca and classical psychedelics as treatments for depression and post-traumatic stress disorder.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXns12gt74%253D&md5=078d22f8b2efb03fef5071a960fe5305

20. 20

    Nichols, D. E. (2012) Structure–activity relationships of serotonin 5-HT2A agonists. Wiley Interdiscip. Rev. Membr. Transp. Signal. 1 , 559– 579,  DOI: 10.1002/wmts.42

21. 21

    Li, Q. , Hosaka, T. , Harada, N. , Nakaya, Y. , and Funaki, M. (2013) Activation of Akt through 5-HT2A receptor ameliorates serotonin-induced degradation of insulin receptor substrate-1 in adipocytes. Mol. Cell. Endocrinol. 365 , 25– 35,  DOI: 10.1016/j.mce.2012.08.022

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    21

    Activation of Akt through 5-HT2A receptor ameliorates serotonin-induced degradation of insulin receptor substrate-1 in adipocytes

    Li, Qinkai; Hosaka, Toshio; Harada, Nagakatsu; Nakaya, Yutaka; Funaki, Makoto

    Molecular and Cellular Endocrinology (2013), 365 (1), 25-35CODEN: MCEND6; ISSN:0303-7207. (Elsevier Ireland Ltd.)

    Serotonin (5-hydroxytryptamine, 5-HT) was found to be elevated in the serum of diabetic patients. In this study, we investigate the mechanism of insulin desensitization caused by 5-HT. In 3T3-L1 adipocytes, 5-HT treatment induced the translocation of insulin receptor substrate-1 (IRS-1) from low d. microsome (LDM), the important intracellular compartment for its functions, to cytosol, inducing IRS-1 ubiquitination and degrdn. Moreover, inhibition of 5-HT-stimulated Akt activation by either ketanserin (a specific 5-HT2A receptor antagonist) or knocking-down the expression of 5-HT2A receptor promoted 5-HT-stimulated IRS-1 dissocn. from 14-3-3β in LDM, leading to drastic ubiquitination. Interestingly, sarpogrelate, another antagonist of 5-HT2A receptor, protected IRS-1 from degrdn. through activation of Akt. This implicates the importance of Akt activation in extending IRS-1 life span through maintaining their optimal sub-location into adipocytes. Taken together, this study suggest that activation of Akt may be able to compensate the adverse effects of 5-HT by stabilizing IRS-1 in LDM.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsVemtbrI&md5=56fea2af7066bc828cac01ee9089d1e3

22. 22

    Grob, C. S. (2011) Pilot Study of Psilocybin Treatment for Anxiety in Patients With Advanced-Stage Cancer. Arch. Gen. Psychiatry 68 , 71– 78,  DOI: 10.1001/archgenpsychiatry.2010.116

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    22

    Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer

    Grob, Charles S.; Danforth, Alicia L.; Chopra, Gurpreet S.; Hagerty, Marycie; McKay, Charles R.; Halberstadt, Adam L.; Greer, George R.

    Archives of General Psychiatry (2011), 68 (1), 71-78CODEN: ARGPAQ; ISSN:0003-990X. (American Medical Association)

    Context: Researchers conducted extensive investigations of hallucinogens in the 1950s and 1960s. By the early 1970s, however, political and cultural pressures forced the cessation of all projects. This investigation reexamines a potentially promising clin. application of hallucinogens in the treatment of anxiety reactive to advanced-stage cancer. Objective: To explore the safety and efficacy of psilocybin in patients with advanced-stage cancer and reactive anxiety. Design: A double-blind, placebo-controlled study of patients with advanced-stage cancer and anxiety, with subjects acting as their own control, using a moderate dose (0.2 mg/kg) of psilocybin. Setting: A clin. research unit within a large public sector academic medical center. Participants: Twelve adults with advanced-stage cancer and anxiety. Main Outcome Measures: In addn. to monitoring safety and subjective experience before and during exptl. treatment sessions, follow-up data including results from the Beck Depression Inventory, Profile of Mood States, and State-Trait Anxiety Inventory were collected unblinded for 6 mo after treatment. Results: Safe physiol. and psychol. responses were documented during treatment sessions. There were no clin. significant adverse events with psilocybin. The State-Trait Anxiety Inventory trait anxiety subscale demonstrated a significant redn. in anxiety at 1 and 3 mo after treatment. The Beck Depression Inventory revealed an improvement of mood that reached significance at 6 mo; the Profile of Mood States identified mood improvement after treatment with psilocybin that approached but did not reach significance. Conclusions: This study established the feasibility and safety of administering moderate doses of psilocybin to patients with advanced-stage cancer and anxiety. Some of the data revealed a pos. trend toward improved mood and anxiety. These results support the need for more research in this long-neglected field. Trial Registration: clinicaltrials.gov Identifier: NCT00302744.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtVKrtr8%253D&md5=5b4a2ef5e1631c95c9a39c5ca175fca7

23. 23

    Carhart-Harris, R. L. (2016) Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. Lancet Psychiatry 3 , 619– 627,  DOI: 10.1016/S2215-0366(16)30065-7

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    23

    Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study

    Carhart-Harris Robin L; Bolstridge Mark; Day Camilla M J; Erritzoe David; Kaelen Mendel; Nutt David J; Rucker James; Bloomfield Michael; Rickard James A; Forbes Ben; Feilding Amanda; Taylor David; Pilling Steve; Curran Valerie H

    The lancet. Psychiatry (2016), 3 (7), 619-27 ISSN:.

    BACKGROUND: Psilocybin is a serotonin receptor agonist that occurs naturally in some mushroom species. Recent studies have assessed the therapeutic potential of psilocybin for various conditions, including end-of-life anxiety, obsessive-compulsive disorder, and smoking and alcohol dependence, with promising preliminary results. Here, we aimed to investigate the feasibility, safety, and efficacy of psilocybin in patients with unipolar treatment-resistant depression. METHODS: In this open-label feasibility trial, 12 patients (six men, six women) with moderate-to-severe, unipolar, treatment-resistant major depression received two oral doses of psilocybin (10 mg and 25 mg, 7 days apart) in a supportive setting. There was no control group. Psychological support was provided before, during, and after each session. The primary outcome measure for feasibility was patient-reported intensity of psilocybin's effects. Patients were monitored for adverse reactions during the dosing sessions and subsequent clinic and remote follow-up. Depressive symptoms were assessed with standard assessments from 1 week to 3 months after treatment, with the 16-item Quick Inventory of Depressive Symptoms (QIDS) serving as the primary efficacy outcome. This trial is registered with ISRCTN, number ISRCTN14426797. FINDINGS: Psilocybin's acute psychedelic effects typically became detectable 30-60 min after dosing, peaked 2-3 h after dosing, and subsided to negligible levels at least 6 h after dosing. Mean self-rated intensity (on a 0-1 scale) was 0·51 (SD 0·36) for the low-dose session and 0·75 (SD 0·27) for the high-dose session. Psilocybin was well tolerated by all of the patients, and no serious or unexpected adverse events occurred. The adverse reactions we noted were transient anxiety during drug onset (all patients), transient confusion or thought disorder (nine patients), mild and transient nausea (four patients), and transient headache (four patients). Relative to baseline, depressive symptoms were markedly reduced 1 week (mean QIDS difference -11·8, 95% CI -9·15 to -14·35, p=0·002, Hedges' g=3·1) and 3 months (-9·2, 95% CI -5·69 to -12·71, p=0·003, Hedges' g=2) after high-dose treatment. Marked and sustained improvements in anxiety and anhedonia were also noted. INTERPRETATION: This study provides preliminary support for the safety and efficacy of psilocybin for treatment-resistant depression and motivates further trials, with more rigorous designs, to better examine the therapeutic potential of this approach. FUNDING: Medical Research Council.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2s%252FitFGmsg%253D%253D&md5=81f97f567242b7763113e3930123fcf2

24. 24

    Ross, S. (2016) Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. J. Psychopharmacol. 30 , 1165– 1180,  DOI: 10.1177/0269881116675512

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    24

    Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial

    Ross, Stephen; Bossis, Anthony; Guss, Jeffrey; Agin-Liebes, Gabrielle; Malone, Tara; Cohen, Barry; Mennenga, Sarah E.; Belser, Alexander; Kalliontzi, Krystallia; Babb, James; Su, Zhe; Corby, Patricia; Schmidt, Brian L.

    Journal of Psychopharmacology (London, United Kingdom) (2016), 30 (12), 1165-1180CODEN: JOPSEQ; ISSN:0269-8811. (Sage Publications Ltd.)

    Background: Clin. significant anxiety and depression are common in patients with cancer, and are assocd. with poor psychiatric and medical outcomes. Historical and recent research suggests a role for psilocybin to treat cancer-related anxiety and depression. Methods: In this double-blind, placebo-controlled, crossover trial, 29 patients with cancer-related anxiety and depression were randomly assigned and received treatment with single-dose psilocybin (0.3 mg/kg) or niacin, both in conjunction with psychotherapy. The primary outcomes were anxiety and depression assessed between groups prior to the crossover at 7 wk. Results: Prior to the crossover, psilocybin produced immediate, substantial, and sustained improvements in anxiety and depression and led to decreases in cancer-related demoralization and hopelessness, improved spiritual wellbeing, and increased quality of life. At the 6.5-mo follow-up, psilocybin was assocd. with enduring anxiolytic and anti-depressant effects (approx. 60-80% of participants continued with clin. significant redns. in depression or anxiety), sustained benefits in existential distress and quality of life, as well as improved attitudes towards death. The psilocybin-induced mystical experience mediated the therapeutic effect of psilocybin on anxiety and depression. Conclusions: In conjunction with psychotherapy, single moderate-dose psilocybin produced rapid, robust and enduring anxiolytic and anti-depressant effects in patients with cancer-related psychol. distress.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsVGrur7M&md5=e0c6afc0eaa5ced7da47f7d417efec82

25. 25

    Reiche, S. (2018) Serotonergic hallucinogens in the treatment of anxiety and depression in patients suffering from a life-threatening disease: A systematic review. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 81 , 1– 10,  DOI: 10.1016/j.pnpbp.2017.09.012

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    25

    Serotonergic hallucinogens in the treatment of anxiety and depression in patients suffering from a life-threatening disease: A systematic review

    Reiche, Simon; Hermle, Leo; Gutwinski, Stefan; Jungaberle, Henrik; Gasser, Peter; Majic, Tomislav

    Progress in Neuro-Psychopharmacology & Biological Psychiatry (2018), 81 (), 1-10CODEN: PNPPD7; ISSN:0278-5846. (Elsevier Inc.)

    Anxiety and depression are some of the most common psychiatric symptoms of patients suffering with life-threatening diseases, often assocd. with a low quality of life and a poor overall prognosis. 5-HT2A-receptor agonists (serotonergic hallucinogens, 'psychedelics') like lysergic acid diethylamide (LSD) and psilocybin were first investigated as therapeutic agents in the 1960s. Recently, after a long hiatus period of regulatory obstacles, interest in the clin. use of these substances has resumed. The current article provides a systematic review of studies investigating psychedelics in the treatment of symptoms of existential distress in life-threatening diseases across different periods of research, highlighting how underlying concepts have developed over time. A systematic search for clin. trials from 1960 to 2017 revealed 11 eligible clin. trials involving a total no. of N = 445 participants, of which 7 trials investigated the use of lysergic acid diethylamide (LSD) (N = 323), 3 trials investigated the use of psilocybin (N = 92), and one trial investigated the use of dipropyltryptamine (DPT) (N = 30). The 4 more recent randomized controlled trials (RCTs) (N = 104) showed a significantly higher methodol. quality than studies carried out in the 1960s and 1970s. Evidence supports that patients with life threatening diseases assocd. with symptoms of depression and anxiety benefit from the anxiolytic and antidepressant properties of serotonergic hallucinogens. Some studies anecdotally reported improvements in patients' quality of life and reduced fear of death. Moreover, low rates of side effects were reported in studies that adhered to safety guidelines. Further studies are needed to det. how these results can be transferred into clin. practice.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsFyqtrjK&md5=94a9bbba17854afcb0b38474dcee9cc9

26. 26

    Hendricks, P. S. (2018) Awe: a putative mechanism underlying the effects of classic psychedelic-assisted psychotherapy. Int. Rev. Psychiatry Abingdon Engl. 30 , 331– 342,  DOI: 10.1080/09540261.2018.1474185

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    26

    Awe: a putative mechanism underlying the effects of classic psychedelic-assisted psychotherapy

    Hendricks Peter S

    International review of psychiatry (Abingdon, England) (2018), 30 (4), 331-342 ISSN:.

    A psychological model of classic psychedelic-assisted psychotherapy informed by contemporary scientific data is presented in this paper. It is suggested that classic psychedelic-occasioned mystical experience is characterized by profound awe, a discrete emotion experienced in the presence of a vast stimulus requiring accommodation of mental structures. Awe, in turn, promotes the small self, a construct that, in the extreme, is analogous to those of unitive experience and ego dissolution. The small self is conceptualized as key to understanding the downstream effects of mystical experience occasioned in the context of classic psychedelic-assisted psychotherapy. With this novel theoretical framework in mind, a number of clinical implications and recommendations are provided so as to advance this incipient field of study.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3czjt1OktQ%253D%253D&md5=ccf3713913d7e5a1cea7c4b570ec279d

27. 27

    Roseman, L. , Nutt, D. J. , and Carhart-Harris, R. L. (2018) Quality of Acute Psychedelic Experience Predicts Therapeutic Efficacy of Psilocybin for Treatment-Resistant Depression. Front. Pharmacol. 8 , 974,  DOI: 10.3389/fphar.2017.00974

28. 28

    Nichols, D. E. , Johnson, M. W. , and Nichols, C. D. (2017) Psychedelics as Medicines: An Emerging New Paradigm. Clin. Pharmacol. Ther. 101 , 209– 219,  DOI: 10.1002/cpt.557

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    28

    Psychedelics as Medicines: An Emerging New Paradigm

    Nichols D E; Johnson M W; Nichols C D

    Clinical pharmacology and therapeutics (2017), 101 (2), 209-219 ISSN:.

    Scientific interest in serotonergic psychedelics (e.g., psilocybin and LSD; 5-HT2A receptor agonists) has dramatically increased within the last decade. Clinical studies administering psychedelics with psychotherapy have shown preliminary evidence of robust efficacy in treating anxiety and depression, as well as addiction to tobacco and alcohol. Moreover, recent research has suggested that these compounds have potential efficacy against inflammatory diseases through novel mechanisms, with potential advantages over existing antiinflammatory agents. We propose that psychedelics exert therapeutic effects for psychiatric disorders by acutely destabilizing local brain network hubs and global network connectivity via amplification of neuronal avalanches, providing the occasion for brain network "resetting" after the acute effects have resolved. Antiinflammatory effects may hold promise for efficacy in treatment of inflammation-related nonpsychiatric as well as potentially for psychiatric disorders. Serotonergic psychedelics operate through unique mechanisms that show promising effects for a variety of intractable, debilitating, and lethal disorders, and should be rigorously researched.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1c%252FovFSksw%253D%253D&md5=f9dbaa48fd257802568e22ac2e3c5b88

29. 29

    Davis, M. and Walters, J. K. (1977) Psilocybin: Biphasic dose-response effects on the acoustic startle reflex in the rat. Pharmacol., Biochem. Behav. 6 , 427– 431,  DOI: 10.1016/0091-3057(77)90180-0

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    29

    Psilocybin: biphasic dose-response effects on the acoustic startle reflex in the rat

    Davis, Michael; Walters, James K.

    Pharmacology, Biochemistry and Behavior (1977), 6 (4), 427-31CODEN: PBBHAU; ISSN:0091-3057.

    The startle reflex was measured in rats after intraperitoneal injection of saline or 0.25, 0.50, 0.75, 1.0, 2.0, 4.0, or 8.0 mg psilocybin (I) [520-52-5]/kg. Low doses (0.75-2.0 mg/kg) increased startle amplitude, whereas high doses (4.0-8.0 mg/kg) depressed startle. Selected low (0.71 mg/kg) or high (5.70 mg/kg) doses of psilocin [520-53-6] also had a biphasic dose-response effect on startle comparable in magnitude to equimolar doses of I. This biphasic dose-response relationship of the indole hallucinogen, I, on startle is consistent with the hypothesis that startle is increased when the firing rates of midbrain raphe neurons are selectively inhibited but is depressed when neurons postsynaptic to raphe cells are also inhibited.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE2sXkvFKjsr8%253D&md5=8f4b09a4612597a3be318673787106e0

30. 30

    Archer, S. , Chrenek, C. , and Swainson, J. (2018) Maintenance Ketamine Therapy for Treatment-Resistant Depression. J. Clin. Psychopharmacol. 1 , 380,  DOI: 10.1097/JCP.0000000000000894

31. 31

    Nair, A. B. and Jacob, S. (2016) A simple practice guide for dose conversion between animals and human. J. Basic Clin. Pharm. 7 , 27– 31,  DOI: 10.4103/0976-0105.177703

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    A simple practice guide for dose conversion between animals and human

    Nair Anroop B; Jacob Shery

    Journal of basic and clinical pharmacy (2016), 7 (2), 27-31 ISSN:0976-0105.

    Understanding the concept of extrapolation of dose between species is important for pharmaceutical researchers when initiating new animal or human experiments. Interspecies allometric scaling for dose conversion from animal to human studies is one of the most controversial areas in clinical pharmacology. Allometric approach considers the differences in body surface area, which is associated with animal weight while extrapolating the doses of therapeutic agents among the species. This review provides basic information about translation of doses between species and estimation of starting dose for clinical trials using allometric scaling. The method of calculation of injection volume for parenteral formulation based on human equivalent dose is also briefed.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28fotV2hsQ%253D%253D&md5=527e4c74daabcb030b1e475cc22d8404

32. 32

    Tizabi, Y. , Bhatti, B. H. , Manaye, K. F. , Das, J. R. , and Akinfiresoye, L. (2012) Antidepressant-like effects of low ketamine dose is associated with increased hippocampal AMPA/NMDA receptor density ratio in female Wistar-Kyoto rats. Neuroscience 213 , 72– 80,  DOI: 10.1016/j.neuroscience.2012.03.052

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    Antidepressant-like effects of low ketamine dose is associated with increased hippocampal AMPA/NMDA receptor density ratio in female Wistar-Kyoto rats

    Tizabi, Y.; Bhatti, B. H.; Manaye, K. F.; Das, J. R.; Akinfiresoye, L.

    Neuroscience (Amsterdam, Netherlands) (2012), 213 (), 72-80CODEN: NRSCDN; ISSN:0306-4522. (Elsevier B.V.)

    Preclin. as well as limited clin. studies indicate that ketamine, a non-competitive glutamate N-methyl-D-aspartate (NMDA) receptor antagonist, may exert a quick and prolonged antidepressant effect. It has been postulated that ketamine action is due to inhibition of NMDA and stimulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors. Here, we sought to det. whether ketamine would exert antidepressant effects in Wistar-Kyoto (WKY) rats, a putative animal model of depression and whether this effect would be assocd. with changes in AMPA/NMDA receptor densities in the hippocampus. Adult female WKY rats and their control Wistar rats were subjected to acute and chronic ketamine doses and their locomotor activity (LMA) and immobility in the forced swim test (FST) were evaluated. Hippocampal AMPA and NMDA receptor densities were also measured following a chronic ketamine dose. Ketamine, both acutely (0.5-5.0 mg/kg i.p.) and chronically (0.5-2.5 mg/kg daily for 10 days) resulted in a dose-dependent and prolonged decrease in immobility in FST in WKY rats only, suggesting an antidepressant-like effect in this model. Chronic treatment with an ED of ketamine also resulted in an increase in AMPA/NMDA receptor d. ratio in the hippocampus of WKY rats. LMA was not affected by any ketamine treatment in either strain. These results indicate a rapid and lasting antidepressant-like effect of a low ketamine dose in WKY rat model of depression. Moreover, the increase in AMPA/NMDA receptor d. in the hippocampus could be a contributory factor to behavioral effects of ketamine. These findings suggest potential therapeutic benefit in simultaneous redn. of central NMDA and elevation of AMPA receptor function in treatment of depression.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XotValsbc%253D&md5=05b668993ff089ddfba7a7e54a01ab1d

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    Carhart-Harris, R. L. (2018) Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Psychopharmacology (Berl.) 235 , 399– 408,  DOI: 10.1007/s00213-017-4771-x

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    33

    Psilocybin with psychological support for treatment-resistant depression: six-month follow-up

    Carhart-Harris R L; Bolstridge M; Day C M J; Rucker J; Watts R; Erritzoe D E; Kaelen M; Giribaldi B; Nutt D J; Bolstridge M; Day C M J; Rucker J; Rucker J; Bloomfield M; Pilling S; Curran H V; Rickard J A; Forbes B; Feilding A; Taylor D; Curran H V

    Psychopharmacology (2018), 235 (2), 399-408 ISSN:.

    RATIONALE: Recent clinical trials are reporting marked improvements in mental health outcomes with psychedelic drug-assisted psychotherapy. OBJECTIVES: Here, we report on safety and efficacy outcomes for up to 6 months in an open-label trial of psilocybin for treatment-resistant depression. METHODS: Twenty patients (six females) with (mostly) severe, unipolar, treatment-resistant major depression received two oral doses of psilocybin (10 and 25 mg, 7 days apart) in a supportive setting. Depressive symptoms were assessed from 1 week to 6 months post-treatment, with the self-rated QIDS-SR16 as the primary outcome measure. RESULTS: Treatment was generally well tolerated. Relative to baseline, marked reductions in depressive symptoms were observed for the first 5 weeks post-treatment (Cohen's d = 2.2 at week 1 and 2.3 at week 5, both p < 0.001); nine and four patients met the criteria for response and remission at week 5. Results remained positive at 3 and 6 months (Cohen's d = 1.5 and 1.4, respectively, both p < 0.001). No patients sought conventional antidepressant treatment within 5 weeks of psilocybin. Reductions in depressive symptoms at 5 weeks were predicted by the quality of the acute psychedelic experience. CONCLUSIONS: Although limited conclusions can be drawn about treatment efficacy from open-label trials, tolerability was good, effect sizes large and symptom improvements appeared rapidly after just two psilocybin treatment sessions and remained significant 6 months post-treatment in a treatment-resistant cohort. Psilocybin represents a promising paradigm for unresponsive depression that warrants further research in double-blind randomised control trials.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1M7ptlKkug%253D%253D&md5=0d464e6b3f97242e325b0945f204bb00

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    Lu, H. (2012) Rat brains also have a default mode network. Proc. Natl. Acad. Sci. U. S. A. 109 , 3979– 3984,  DOI: 10.1073/pnas.1200506109

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    34

    Rat brains also have a default mode network

    Lu, Hanbing; Zou, Qihong; Gu, Hong; Raichle, Marcus E.; Stein, Elliot A.; Yang, Yihong

    Proceedings of the National Academy of Sciences of the United States of America (2012), 109 (10), 3979-3984CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)

    The default mode network (DMN) in humans has been suggested to support a variety of cognitive functions and has been implicated in an array of neuropsychol. disorders. However, its function(s) remains poorly understood. We show that rats possess a DMN that is broadly similar to the DMNs of nonhuman primates and humans. Our data suggest that, despite the distinct evolutionary paths between rodent and primate brain, a well-organized, intrinsically coherent DMN appears to be a fundamental feature in the mammalian brain whose primary functions might be to integrate multimodal sensory and affective information to guide behavior in anticipation of changing environmental contingencies.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XjvFymtbw%253D&md5=5b38b45e77b2e4088d1f54f650c0dc17

35. 35

    Yakura, T. (2018) Visual recognition of mirror, video-recorded, and still images in rats. PLoS One 13 , e0194215,  DOI: 10.1371/journal.pone.0194215

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    Visual recognition of mirror, video-recorded, and still images in rats

    Yakura, Tomiko; Yokota, Hiroki; Ohmichi, Yusuke; Ohmichi, Mika; Nakano, Takashi; Naito, Munekazu

    PLoS One (2018), 13 (3), e0194215/1-e0194215/11CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)

    Several recent studies have claimed that rodents have good visual recognition abilities. However, the extent to which rats can recognize other rats and distinguish between males and females using visual information alone remains unclear. In the present study, we investigated the ability of rats to visually recognize mirror, video-recorded, and still images and to discriminate between images of males and females. Rats were tested in a place preference app. with a mirror, a video-recorded image of a rat, or a still image of a rat at one end. The data were assessed using t-test with Bonferroni correction. Male and female rats spent significantly more time in the mirror chamber and the video-recorded image chamber than in their resp. blank chambers (P < 0.05), and male rats also spent more time in the chamber contg. a still image. Furthermore, it was found that male rats exhibited significantly more sniffing behavior around the mirror than in the blank chamber (P < 0.05), whereas female rats were no significant differences in the sniffing behaviors in the mirror, moving or still image expts. Identical results were obtained regardless of whether the rat in the image was the same or opposite sex. These results indicate that rats can process the differences in mirror, video-recorded, and still images as visual information, but are unable to use this information to distinguish between the sexes.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXit1elsrfN&md5=bcb9eabe109f2c19e8a4407fc6ca0e83

36. 36

    du Jardin, K. G. (2018) S-Ketamine Mediates Its Acute and Sustained Antidepressant-Like Activity through a 5-HT1B Receptor Dependent Mechanism in a Genetic Rat Model of Depression. Front. Pharmacol. 8 , 978,  DOI: 10.3389/fphar.2017.00978

37. 37

    Nardou, R. (2019) Oxytocin-dependent reopening of a social reward learning critical period with MDMA. Nature 569 , 116,  DOI: 10.1038/s41586-019-1075-9

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    Oxytocin-dependent reopening of a social reward learning critical period with MDMA

    Nardou, Romain; Lewis, Eastman M.; Rothhaas, Rebecca; Xu, Ran; Yang, Aimei; Boyden, Edward; Dolen, Gul

    Nature (London, United Kingdom) (2019), 569 (7754), 116-120CODEN: NATUAS; ISSN:0028-0836. (Nature Research)

    A crit. period is a developmental epoch during which the nervous system is expressly sensitive to specific environmental stimuli that are required for proper circuit organization and learning. Mechanistic characterization of crit. periods has revealed an important role for exuberant brain plasticity during early development, and for constraints that are imposed on these mechanisms as the brain matures1. In disease states, closure of crit. periods limits the ability of the brain to adapt even when optimal conditions are restored. Thus, identification of manipulations that reopen crit. periods has been a priority for translational neuroscience2. Here we provide evidence that developmental regulation of oxytocin-mediated synaptic plasticity (long-term depression) in the nucleus accumbens establishes a crit. period for social reward learning. Furthermore, we show that a single dose of (+/-)-3,4-methylendioxymethamphetamine (MDMA) reopens the crit. period for social reward learning and leads to a metaplastic upregulation of oxytocin-dependent long-term depression. MDMA-induced reopening of this crit. period requires activation of oxytocin receptors in the nucleus accumbens, and is recapitulated by stimulation of oxytocin terminals in the nucleus accumbens. These findings have important implications for understanding the pathogenesis of neuro-developmental diseases that are characterized by social impairments and of disorders that respond to social influence or are the result of social injury3.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXosVSiur8%253D&md5=2cbb7c060ca08076ff43270aae95a37e

38. 38

    Chiba, S. (2012) Chronic restraint stress causes anxiety- and depression-like behaviors, downregulates glucocorticoid receptor expression, and attenuates glutamate release induced by brain-derived neurotrophic factor in the prefrontal cortex. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 39 , 112– 119,  DOI: 10.1016/j.pnpbp.2012.05.018

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    Chronic restraint stress causes anxiety- and depression-like behaviors, downregulates glucocorticoid receptor expression, and attenuates glutamate release induced by brain-derived neurotrophic factor in the prefrontal cortex

    Chiba, Shuichi; Numakawa, Tadahiro; Ninomiya, Midori; Richards, Misty C.; Wakabayashi, Chisato; Kunugi, Hiroshi

    Progress in Neuro-Psychopharmacology & Biological Psychiatry (2012), 39 (1), 112-119CODEN: PNPPD7; ISSN:0278-5846. (Elsevier Inc.)

    Stress and the resulting increase in glucocorticoid levels have been implicated in the pathophysiol. of depressive disorders. We investigated the effects of chronic restraint stress (CRS: 6 h × 28 days) on anxiety- and depression-like behaviors in rats and on the possible changes in glucocorticoid receptor (GR) expression as well as brain-derived neurotrophic factor (BDNF)-dependent neural function in the prefrontal cortex (PFC). We obsd. significant redns. in body wt. gain, food intake and sucrose preference from 1 wk after the onset of CRS. In the 5th week of CRS, we conducted open-field (OFT), elevated plus-maze (EPM) and forced swim tests (FST). We obsd. a decrease in the no. of entries into open arms during the EPM (anxiety-like behavior) and increased immobility during the FST (depression-like behavior). When the PFC was removed after CRS and subject to western blot anal., the GR expression reduced compared with control, while the levels of BDNF and its receptors remained unchanged. Basal glutamate concns. in PFC acute slice which were measured by high performance liq. chromatog. were not influenced by CRS. However, BDNF-induced glutamate release was attenuated after CRS. These results suggest that reduced GR expression and altered BDNF function may be involved in chronic stress-induced anxiety- and depression-like behaviors.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtFKntL7I&md5=ed33ed1f1ff04c1f09dff2e262fe69a8

39. 39

    McLaughlin, K. J. , Gomez, J. L. , Baran, S. E. , and Conrad, C. D. (2007) The effects of chronic stress on hippocampal morphology and function: An evaluation of chronic restraint paradigms. Brain Res. 1161 , 56– 64,  DOI: 10.1016/j.brainres.2007.05.042

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    The effects of chronic stress on hippocampal morphology and function: An evaluation of chronic restraint paradigms

    McLaughlin, Katie J.; Gomez, Juan L.; Baran, Sarah E.; Conrad, Cheryl D.

    Brain Research (2007), 1161 (), 56-64CODEN: BRREAP; ISSN:0006-8993. (Elsevier Ltd.)

    Chronic restraint stress for 6 h/21 days causes hippocampal CA3 apical dendritic retraction, which parallels spatial memory impairments in male rats. Recent research suggests that chronic immobilization stress for 2 h/10 days induces CA3 dendritic retraction and questions whether CA3 dendritic retraction and spatial memory deficits can be produced sooner than found following 6 h/21 days of restraint stress. Therefore, this study investigated the effects of four different durations of chronic restraint stress (varied by hours/day and total no. of days) and the subsequent effects on hippocampal CA3 morphol. and spatial memory in the same male Sprague-Dawley rats. The results showed that only rats exposed to the 6 h/21 days restraint paradigm exhibited CA3 apical dendritic retraction, consistent spatial memory deficits, and decreased body wt. gain compared to exptl. counterparts and controls. While chronically stressing a rat with wire mesh restraint has a phys. component, it acts primarily as a psychol. stressor, and these findings support the interpretation that chronic psychol. stress produces hippocampal-dependent cognitive deficits that are consistent with hippocampal structural changes. Differences in stress effects obsd. across different studies may be due to rat strain, type of stressor, and housing conditions; however, the current findings support the use of chronic restraint stress, with wire mesh, for 6 h/21 days as a reliable and efficient method to produce psychol. stress and to cause CA3 dendritic retraction and spatial memory deficits in male Sprague-Dawley rats.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXotVantrw%253D&md5=86c61bd4c6a32bf88acdeeff032db1b5

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    Österlund, M. K. , Overstreet, D. H. , and Hurd, Y. L. (1999) The Flinders Sensitive Line rats, a genetic model of depression, show abnormal serotonin receptor mRNA expression in the brain that is reversed by 17β-estradiol. Mol. Brain Res. 74 , 158– 166,  DOI: 10.1016/S0169-328X(99)00274-0

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    40

    The Flinders Sensitive Line rats, a genetic model of depression, show abnormal serotonin receptor mRNA expression in the brain that is reversed by 17β-estradiol

    Osterlund, M. K.; Overstreet, D. H.; Hurd, Y. L.

    Molecular Brain Research (1999), 74 (1,2), 158-166CODEN: MBREE4; ISSN:0169-328X. (Elsevier Science B.V.)

    The possible link between estrogen and serotonin (5-HT) in depression was investigated using a genetic animal model of depression, the Flinders Sensitive Line (FSL) rats, in comparison to control Flinders Resistant Line rats. The mRNA levels of the estrogen receptor (ER) α and β subtypes and the 5-HT1A and 5-HT2A receptors were analyzed in several limbic-related areas of ovariectomized FSL and FRL rats treated with 17β-estradiol (0.15 μg/g) or vehicle. The FSL animals were shown to express significantly lower levels of the 5-HT2A receptor transcripts in the perirhinal cortex, piriform cortex, and medial anterodorsal amygdala and higher levels in the CA 2-3 region of the hippocampus. The only significant difference between the rat lines in ER mRNA expression was found in the medial posterodorsal amygdala, where the FSL rats showed lower ERα expression levels. Overall, estradiol treatment increased 5-HT2A and decreased 5-HT1A receptor mRNA levels in several of the examd. regions of both lines. Thus, in many areas, estradiol was found to regulate the 5-HT receptor mRNA expression in the opposite direction to the alterations found in the FSL rats. These findings further support the implication of 5-HT receptors, in particular the 5-HT2A subtype, in the etiol. of affective disorders. Moreover, the ability of estradiol to regulate the expression of the 5-HT1A and 5-HT2A receptor genes might account for the reported influence of gonadal hormones in mood and depression.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXltVeluw%253D%253D&md5=cd89fb4a7f2e28bdf6026cfdf153f207

41. 41

    Du Jardin, K. G. , Müller, H. K. , Sanchez, C. , Wegener, G. , and Elfving, B. (2017) Gene expression related to serotonergic and glutamatergic neurotransmission is altered in the flinders sensitive line rat model of depression: Effect of ketamine. Synapse 71 , 37– 45,  DOI: 10.1002/syn.21940

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    Gene expression related to serotonergic and glutamatergic neurotransmission is altered in the Flinders Sensitive Line rat model of depression: Effect of ketamine

    du Jardin, Kristian Gaarn; Mueller, Heidi Kaastrup; Sanchez, Connie; Wegener, Gregers; Elfving, Betina

    Synapse (Hoboken, NJ, United States) (2017), 71 (1), 37-45CODEN: SYNAET; ISSN:0887-4476. (Wiley-Blackwell)

    Major depressive disorder (MDD) is assocd. with dysfunctional serotonergic and glutamatergic neurotransmission, and the genetic animal model of depression Flinders Sensitive Line (FSL) rats display alterations in these systems relatively to their control strain Flinders Resistant Line (FRL). However, changes on transcript level related to serotonergic and glutamatergic signaling have only been sparsely studied in this model. The non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has fast-onset antidepressant properties, and recent data implicate serotonergic neurotransmission in ketamine's antidepressant-like activities in rodents. Here, we investigated the transcript levels of 40 genes involved in serotonergic and glutamatergic neurotransmission in FSL and FRL rats in response to a single dose of ketamine (15 mg/kg; 90 min prior to euthanization). Using real-time quant. polymerase chain reaction, we studied the effect of ketamine in the hippocampus, whereas strain differences were investigated in both hippocampus and frontal cortex. The expression of genes involved in serotonergic and glutamatergic neurotransmission were unaffected by a single dose of ketamine in the hippocampus. Relative to FRL rats, FSL rats displayed enhanced hippocampal transcript levels of 5-ht2c, and P11, whereas the expression was reduced for 5-ht2a, Nr2a, and Mglur2. In the frontal cortex, we found higher transcript levels of 5-ht2c and Mglur2, whereas the expression of 5-ht2a was reduced in FSL rats. Thus, ketamine is not assocd. with hippocampal alterations in serotonergic or glutamatergic genes at 90 min after an antidepressant dose. Furthermore, FSL rats display serotonergic and glutamatergic abnormalities on gene expression level that partly may resemble findings in MDD patients. This article is protected by copyright. All rights reserved.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsVGgt7nJ&md5=26cb9718f251912c1aa64b57bc4e28a3

42. 42

    Jefsen, O. (2019) Psilocybin lacks antidepressant-like effect in the Flinders Sensitive Line rat. Acta Neuropsychiatr. 31 , 213,  DOI: 10.1017/neu.2019.15

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    42

    Psilocybin lacks antidepressant-like effect in the Flinders Sensitive Line rat

    Jefsen Oskar; Hojgaard Kristoffer; Christiansen Sofie Laage; Elfving Betina; Wegener Gregers; Muller Heidi Kaastrup; Nutt David John

    Acta neuropsychiatrica (2019), 31 (4), 213-219 ISSN:.

    OBJECTIVE: Psilocybin is a serotonin receptor agonist with a therapeutic potential for treatment-resistant depression and other psychiatric illnesses. We investigated whether the administration of psilocybin had an antidepressant-like effect in a rat model of depression. METHODS: Using the Flinders Sensitive Line (FSL) rat model of depression, we assessed the antidepressant-like effect of psilocin and psilocybin, measured as a reduction in immobility time in the forced swim test (FST). We measured locomotor activity in an open field test (OFT) to control for stimulant properties of the drugs. We performed a set of experiments to test different doses, treatment paradigms, and timing of the tests in relation to the drug administration. RESULTS: Psilocin and psilocybin showed no effect on immobility, struggling, or swimming behaviour in the FST and no effect on locomotor activity in the OFT. FSL rats did show significantly more immobility than their control strain, the Flinders Resistant Line, as expected. CONCLUSION: Psilocin and psilocybin showed no antidepressant-like effect in the FSL rats, despite a positive effect in humans. This suggests that other animal models of depression and other behavioural tests may be more appropriate for translational studies in the effects of psilocybin.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3M7nsFGgtw%253D%253D&md5=e687384dd04667cc17288b43646a1e21

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    Lahmame, A. , del Arco, C. , Pazos, A. , Yritia, M. , and Armario, A. (1997) Are Wistar-Kyoto rats a genetic animal model of depression resistant to antidepressants?. Eur. J. Pharmacol. 337 , 115– 123,  DOI: 10.1016/S0014-2999(97)01276-4

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    43

    Are Wistar-Kyoto rats a genetic animal model of depression resistant to antidepressants?

    Lahmame, Abdeljalil; del Arco, Carmen; Pazos, Angel; Yritia, Mercedes; Armario, Antonio

    European Journal of Pharmacology (1997), 337 (2/3), 115-123CODEN: EJPHAZ; ISSN:0014-2999. (Elsevier)

    Wistar-Kyoto rats are reported to be very passive in the forced swimming test. In addn., they did not respond to acute administration of either desipramine or 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). In the present expt., it was studied whether or not they respond to acute and chronic administration of imipramine and the possible relation to down-regulation of β-adrenoceptors and 5-HT1 and 5-HT2 receptors. Sprague-Dawley and Brown-Norway rats were included in the study as it has been previously demonstrated that the two strains respond to acute desipramine and 8-OH-DPAT administration. Whereas acute administration of imipramine (15 mg/kg, three times in a 24 h period) significantly increased struggling and reduced immobility in Sprague-Dawley and Brown Norway rats, Wistar-Kyoto rats failed to respond to the drug. After chronic treatment with imipramine (13 days plus the acute imipramine treatment at the end of the treatment period), the three strains showed a pos. response that was always significantly greater than the response to acute administration, but which was much lower in Wistar-Kyoto than in the other two strains. Down-regulation of both β-adrenoceptors and 5-HT2 receptors was obsd. 24 h after the forced swimming test in acutely and chronically imipramine-treated rats of the three strains, except that in Sprague-Dawley rats β-adrenoceptors did not change after acute imipramine. No significant decrease in 5-HT1 binding sites was obsd. in any strain. Acute imipramine administration caused a similar anorexia in Wistar-Kyoto as in the other strains and at least the same level of down-regulation of β-adrenoceptors and 5-HT2 receptors. In addn., serum imipramine levels on the day after the last drug administration were higher in Wistar-Kyoto than in the other two strains. All these data suggest that the subsensitivity to imipramine obsd. in Wistar-Kyoto rats: (i) can not be primarily explained by pharmacokinetic differences, and (ii) does not appear to be related to the monoaminergic systems. Wistar-Kyoto rats might be therefore not only a good animal model of depressive-like (passive) behavior, but also a model of resistance to antidepressants which could be used to investigate the neurobiol. basis of such resistance, which is also obsd. in some depressed patients.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXmsVKlsr0%253D&md5=1ae73e21d902d9ea8e9cb8dfaf9ac9dc

44. 44

    Paré, W. P. and Redei, E. (1993) Sex differences and stress response of WKY rats. Physiol. Behav. 54 , 1179– 1185,  DOI: 10.1016/0031-9384(93)90345-G

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    Sex differences and stress response of WKY rats

    Pare W P; Redei E

    Physiology & behavior (1993), 54 (6), 1179-85 ISSN:0031-9384.

    Wistar Kyoto (WKY), Fischer-344 (F-344), and Wistar male and female rats during either proestrus-estrus or diestrus phases of the estrus cycle were exposed to the ulcerogenic procedure of water restraint. Both male and female WKY rats revealed significantly more stomach ulcers as compared to Wistar and F-344 rats of the same sex. No persistent sex difference was observed, but ulcer severity was more pronounced during the proestrus-estrus phase as compared to the diestrus phase of the estrus cycle particularly in WKY female rats. In the second study, WKY females were observed as more active in the open-field test (OFT), but more immobile in the forced swim test (FST), as compared to WKY male rats. In addition, proestrus-estrus WKY females were less active in the OFT and significantly more immobile in the FST as compared to diestrus females. Thus, proestrus-estrus WKY females were judged as more emotional in the OFT and as exhibiting more signs of behavioral depression according to the FST. These studies suggest that the steroid hormone milieu in WKY rats may be responsible for these behavioral changes as well as the stress responsiveness in this stress-susceptible rat strain.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK2c7is1Cmug%253D%253D&md5=79b58062942721e5d7211c0dfa2d956c

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    Yamada, M. (2013) Upregulation of the dorsal raphe nucleus-prefrontal cortex serotonin system by chronic treatment with escitalopram in hyposerotonergic Wistar-Kyoto rats. Neuropharmacology 72 , 169– 178,  DOI: 10.1016/j.neuropharm.2013.04.044

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    Upregulation of the dorsal raphe nucleus-prefrontal cortex serotonin system by chronic treatment with escitalopram in hyposerotonergic Wistar-Kyoto rats

    Yamada, Makiko; Kawahara, Yukie; Kaneko, Fumi; Kishikawa, Yuki; Sotogaku, Naoki; Poppinga, Wilfred J.; Folgering, Joost H. A.; Dremencov, Eliyahu; Kawahara, Hiroshi; Nishi, Akinori

    Neuropharmacology (2013), 72 (), 169-178CODEN: NEPHBW; ISSN:0028-3908. (Elsevier B.V.)

    Wistar-Kyoto (WKY) rats are sensitive to chronic stressors and exhibit depression-like behavior. Dorsal raphe nucleus (DRN) serotonin (5-HT) neurons projecting to the prefrontal cortex (PFC) comprise the important neurocircuitry underlying the pathophysiol. of depression. To evaluate the DRN-PFC 5-HT system in WKY rats, we examd. the effects of escitalopram (ESCIT) on the extracellular 5-HT level in comparison with Wistar rats using dual-probe microdialysis. The basal levels of 5-HT in the DRN, but not in the PFC, in WKY rats was reduced as low as 30% of Wistar rats. Responses of 5-HT in the DRN and PFC to ESCIT administered systemically and locally were attenuated in WKY rats. Feedback inhibition of DRN 5-HT release induced by ESCIT into the PFC was also attenuated in WKY rats. Chronic ESCIT induced upregulation of the DRN-PFC 5-HT system in WKY rats, with increases in basal 5-HT in the DRN, responsiveness to ESCIT in the DRN and PFC, and feedback inhibition, whereas downregulation of these effects was induced in Wistar rats. Thus, the WKY rat is an animal model of depression with low activity of the DRN-PFC 5HT system. The finding that chronic ESCIT upregulates the 5-HT system in hyposerotonergic WKY rats may contribute to improved understanding of mechanisms of action of antidepressants, esp. in depression with 5-HT deficiency.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtVWgu7fE&md5=8c5e0530ee8fae3a327b2eb5aaf63a33

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    Overstreet, D. H. (2012) Modeling Depression in Animal Models. In Psychiatric Disorders ( Kobeissy, F. H. , Ed. ), Vol. 829, pp 125– 144, Humana Press.

47. 47

    López-Rubalcava, C. and Lucki, I. (2000) Strain differences in the behavioral effects of antidepressant drugs in the rat forced swimming test. Neuropsychopharmacology 22 , 191,  DOI: 10.1016/S0893-133X(99)00100-1

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    Strain differences in the behavioral effects of antidepressant drugs in the rat forced swimming test

    Lopez-Rubalcava C; Lucki I

    Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology (2000), 22 (2), 191-9 ISSN:0893-133X.

    Wistar-Kyoto (WKY) rats provide a model of stress-induced depressive behavior, because they show enhanced vulnerability to the effects of stressors. The present study examined differences in the behavioral response to different types of antidepressant drugs between WKY and Sprague-Dawley (SD) rats in the forced swimming test (FST). WKY rats displayed significantly greater immobility than SD rats during their exposure to the FST. The noradrenergic antidepressant, desipramine, produced a dose-dependent reduction of immobility and increase of climbing behavior in the SD rats. In WKY rats, desipramine reduced immobility at a lower dose and produced increases of both swimming and climbing behavior. The serotonergic compounds, fluoxetine and 8-OH-DPAT, produced dose-dependent reductions of immobility and increases of swimming behavior in the FST in SD rats, but the response to the serotonergic drugs were blunted in WKY rats. These results indicate that genetic or constitutive differences may determine the distinct behavioral profiles for antidepressant compounds with selective pharmacological effects in different rat strains, and these effects may be related to genetic heterogeneity of antidepressant responses in depressed patients.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3c7hsVSqsw%253D%253D&md5=9db4767a4ec32bb38535de33c1b4399f

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    De La Garza, R. and Mahoney, J. J. (2004) A distinct neurochemical profile in WKY rats at baseline and in response to acute stress: implications for animal models of anxiety and depression. Brain Res. 1021 , 209– 218,  DOI: 10.1016/j.brainres.2004.06.052

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    48

    A distinct neurochemical profile in WKY rats at baseline and in response to acute stress: implications for animal models of anxiety and depression

    De La Garza, Richard; Mahoney, James J.

    Brain Research (2004), 1021 (2), 209-218CODEN: BRREAP; ISSN:0006-8993. (Elsevier B.V.)

    Wistar-Kyoto (WKY) rats exhibit hyper-responsive neuroendocrine and behavioral responses to stress that exceed normal controls and are esp. prone to develop stress-induced depressive disorder. Pharmacol. studies indicate altered serotonin (5-HT), norepinephrine (NE) and dopamine (DA) systems functioning in WKY rats, yet no attempt has been made to provide a comprehensive assessment of the neurochem. profile for WKY rats as compared to the outbred progenitor controls, Wistar rats. To this end, male, WKY and Wistar rats (N=6/group) were exposed to an acute forced-swim stress or were left untreated as controls. The prefrontal cortex (PFCtx), striatum, nucleus accumbens (NAS), and amygdala were assayed for levels of NE, DA and 5-HT, as well as major metabolites, by HPLC with electrochem. detection. In a sep. expt., designed to assess baseline and stress-induced neuroendocrine activation, male, Wistar and WKY rats (N=6/group) were exposed to an acute forced-swim stress of 15 min or were left untreated as controls. Animals were killed immediately after the test (T=0), 30 min after the test (T=30) or 60 min after the test (T=60), and control animals were killed immediately after weighing. After decapitation, trunk blood was collected and plasma was isolated by centrifugation and analyzed for corticosterone by immunoassay. The neurochem. results demonstrate distinct patterns of baseline and stress-induced monoamine turnover in WKY rats, including alterations to DA and 5-HT turnovers in prefrontal cortex and nucleus accumbens, two crit. brain areas implicated in anxiety, depression and drug reward. The neuroendocrine results indicate that WKY rats exhibited a sustained corticosterone response to acute stress, as compared to Wistar controls. Overall, these data are predicted to be useful for understanding the anxiety- and depressive-like behavioral phenotype exhibited by these animals and for increased understanding of the role genetic background in altering neurochem. function.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXntlSntbg%253D&md5=5262a1aa9e61abcdf430768227af3ffc

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    Hurley, L. L. (2013) Antidepressant-like effects of curcumin in WKY rat model of depression is associated with an increase in hippocampal BDNF. Behav. Brain Res. 239 , 27– 30,  DOI: 10.1016/j.bbr.2012.10.049

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    Antidepressant-like effects of curcumin in WKY rat model of depression is associated with an increase in hippocampal BDNF

    Hurley, Laura L.; Akinfiresoye, Luli; Nwulia, Evaristus; Kamiya, Atsushi; Kulkarni, Amol A.; Tizabi, Yousef

    Behavioural Brain Research (2013), 239 (), 27-30CODEN: BBREDI; ISSN:0166-4328. (Elsevier B.V.)

    Curcumin is the principal active ingredient found in turmeric (Curcuma longa), a plant used in traditional Asian diets and herbal medicines. It is known to have a wide range of biol. actions including antidepressant-like effects which have been obsd. in stress-induced depression models. This study was designed to investigate the antidepressant potential of curcumin in a non-induced model of depression. Moreover, since brain derived neurotrophic factor (BDNF) has been implicated in antidepressant effects of many drugs, we also evaluated the effects of curcumin on BDNF in the hippocampus. Adult male Wistar Kyoto (WKY) rats, a putative model of depression, were injected acutely or chronically (10 d) with 50, 100, and 200 mg/kg curcumin. Open field locomotor activity (OFLA) and forced swim test (FST), a measure of helplessness, were measured 1 h after acute and 18-20 h after last chronic injection. Results showed a dose-dependent redn. of immobility in the FST by curcumin in both acute and chronic studies, without any significant effect on OFLA. The effect of higher chronic curcumin dose in FST was still evident a week later. Chronic curcumin also resulted in a dose-dependent increase in hippocampal BDNF. This data provides evidence for an antidepressant-like effect of curcumin, possibly through increased neurotrophic activity, in the WKY model of depression, and support the notion that curcumin may prove an effective and lasting natural antidepressant.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvVektbvL&md5=13459e486637b34768f731564056f4e8

50. 50

    Paré, W. P. and Tejani-Butt, S. M. (1996) Effect of stress on the behavior and 5-HT system in Sprague-Dawley and Wistar Kyoto rat strains. Integr. Physiol. Behav. Sci. 31 , 112– 121,  DOI: 10.1007/BF02699783

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    Effect of stress on the behavior and 5-HT system in Sprague-Dawley and Wistar Kyoto rat strains

    Pare W P; Tejani-Butt S M

    Integrative physiological and behavioral science : the official journal of the Pavlovian Society (1996), 31 (2), 112-21 ISSN:1053-881X.

    The effects of chronic novel stressors, for 21 days, on the behavior and the serotoninergic (5-HT) system in Sprague-Dawley (SD) and Wistar Kyoto (WKY) rats were studied. Open-field and forced-swim tests revealed a significantly greater behavioral depression in the WKY strain. SD rats showed a decrease in 3H-DPAT binding to 5-HT1A receptors in the hippocampus, whereas WKY rats revealed an increase in 3H-DPAT binding in the hippocampus and hypothalamus. Stress did not appear to alter the binding of 3H-DPAT to 5-HT1A sites in the dorsal raphe or median raphe in either strains. SD rats revealed a modest increase in 5-HT transporter (5-HTT) sites in the cortex; WKY rats revealed a decrease in 5-HTT sites in the cortex and the hippocampus. Stress caused an increase in 3H-CNIMI binding to 5-HTT sites in the dorsal and median raphe nuclei in both strains. The results suggest that the greater susceptibility to behavioral depression in WKY rats may account for the differential effects on 5HT1A sites as well as 5-HTT sites in limbic regions and cell body area as compared to SD rats.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK28vgsFCmtw%253D%253D&md5=ea649b7c0158ea698b540e901125f8b7

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    Rittenhouse, P. A. , López-Rubalcava, C. , Stanwood, G. D. , and Lucki, I. (2002) Amplified behavioral and endocrine responses to forced swim stress in the Wistar–Kyoto rat. Psychoneuroendocrinology 27 , 303– 318,  DOI: 10.1016/S0306-4530(01)00052-X

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    Amplified behavioral and endocrine responses to forced swim stress in the Wistar-Kyoto rat

    Rittenhouse Peter A; Lopez-Rubalcava Carolina; Stanwood Gregg D; Lucki Irwin

    Psychoneuroendocrinology (2002), 27 (3), 303-18 ISSN:0306-4530.

    The Wistar Kyoto (WKY) rat may be a useful model for the study of depressive behavior because they exhibit exaggerated responses to a number of stressors. These studies compared the behavioral and endocrine responses to swimming stress in WKY rats with Sprague-Dawley (SD) rats. In the first experiment, the onset of behavioral immobility and the endocrine stress responses (adrenocorticotropin hormone (ACTH) and corticosterone (CORT)) were examined as the duration of a swimming session was increased. In the second experiment, WKY and SD rats were swum for 15 min, then sacrificed at different intervals after completion of the swim, to examine the time course of endocrine stress responses. The final experiment compared the suppression of ACTH and CORT secretion by dexamethasone of peak diurnal ACTH and CORT levels in WKY and SD rats. Behaviorally, the WKY rats displayed early and prolonged immobility compared to SD rats regardless of the length of the swim stress. Plasma CORT and ACTH increased in WKY and SD rats as the duration of the stressor lengthened. The swim stress (15 min) produced higher levels of ACTH and CORT secretion at the end of the stress interval that persisted after termination of the stressor in WKY compared to SD rats. Peak diurnal CORT levels, but not ACTH levels, were higher in WKY than in SD rats. Dexamethasone suppressed ACTH levels less in WKY than in SD rats. These results indicate that the WKY rat that displays increased behavioral immobility also demonstrates exaggerated secretion of stress hormones during swimming stress, and the results may be due, in part, to reduced sensitivity of glucocorticoid receptors that supply negative feedback to the hypothalamic-pituitary-adrenal axis. The exaggerated behavioral and endocrine stress responses in the WKY rat support its potential usefulness as a model for studying stress-evoked depressive behavior.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD387pslCltg%253D%253D&md5=a17fc5de4065c63e249a1b6b929ece57

52. 52

    Solberg, L. C. , Olson, S. L. , Turek, F. W. , and Redei, E. (2001) Altered hormone levels and circadian rhythm of activity in the WKY rat, a putative animal model of depression. Am. J. Physiol. - Regul. Integr. Comp. Physiol. 281 , R786– R794,  DOI: 10.1152/ajpregu.2001.281.3.R786

53. 53

    Carr, G. V. (2010) Antidepressant-Like Effects of κ-Opioid Receptor Antagonists in Wistar Kyoto Rats. Neuropsychopharmacology 35 , 752– 763,  DOI: 10.1038/npp.2009.183

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    Antidepressant-Like Effects of κ-Opioid Receptor Antagonists in Wistar Kyoto Rats

    Carr, Gregory V.; Bangasser, Debra A.; Bethea, Thelma; Young, Matthew; Valentino, Rita J.; Lucki, Irwin

    Neuropsychopharmacology (2010), 35 (3), 752-763CODEN: NEROEW; ISSN:0893-133X. (Nature Publishing Group)

    The Wistar Kyoto (WKY) rat strain is a putative genetic model of comorbid depression and anxiety. Previous research showing increased κ-opioid receptor (KOR) gene expression in the brains of WKY rats, combined with studies implicating the KOR in animal models of depression and anxiety, suggests that alterations in the KOR system could have a role in the WKY behavioral phenotype. Here, the effects of KOR antagonists in the forced swim test (FST) were compared with the WKY and the Sprague-Dawley (SD) rat strains. As previously reported, WKY rats showed more immobility behavior than SD rats. The KOR antagonists selectively produced antidepressant-like effects in the WKY rats. By contrast, the antidepressant desipramine reduced immobility in both strains. Brain regions potentially underlying the strain-specific effects of KOR antagonists in the FST were identified using c-fos expression as a marker of neuronal activity. The KOR antagonist nor-binaltorphimine produced differential effects on the no. of c-fos-pos. profiles in the piriform cortex and nucleus accumbens shell between SD and WKY rats. The piriform cortex and nucleus accumbens also contained higher levels of KOR protein and dynorphin A peptide, resp., in the WKY strain. In addn., local administration of nor-binaltorphimine directly into the piriform cortex produced antidepressant-like effects in WKY rats further implicating this region in the antidepressant-like response to KOR antagonists. These results support the use of the WKY rat as a model of affective disorders potentially involving KOR overactivity and provide more evidence that KOR antagonists could potentially be used as novel antidepressants. Neuropsychopharmacol. (2010) 35, 752-763; doi:10.1038/npp.2009.183; published online 18 Nov. 2009.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtlCrurw%253D&md5=fc79000faa07963bcfee949cde4ebd0d

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    McAuley, J. D. (2009) Wistar-Kyoto rats as an animal model of anxiety vulnerability: support for a hypervigilance hypothesis. Behav. Brain Res. 204 , 162– 168,  DOI: 10.1016/j.bbr.2009.05.036

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    Wistar-Kyoto rats as an animal model of anxiety vulnerability: support for a hypervigilance hypothesis

    McAuley J D; Stewart A L; Webber E S; Cromwell H C; Servatius R J; Pang K C H

    Behavioural brain research (2009), 204 (1), 162-8 ISSN:.

    Inbred Wistar-Kyoto (WKY) rats have been proposed as a model of anxiety vulnerability as they display behavioral inhibition and a constellation of learning and reactivity abnormalities relative to outbred Sprague-Dawley (SD) rats. Together, the behaviors of the WKY rat suggest a hypervigilant state that may contribute to its anxiety vulnerability. To test this hypothesis, open-field behavior, acoustic startle, pre-pulse inhibition and timing behavior were assessed in WKY and Sprague-Dawley (SD) rats. Timing behavior was evaluated using a modified version of the peak-interval timing procedure. Training and testing of timing first occurred without audio-visual (AV) interference. Following this initial test, AV interference was included on some trials. Overall, WKY rats took much longer to leave the center of the arena, made fewer line crossings, and reared less, than did SD rats. WKY rats showed much greater startle responses to acoustic stimuli and significantly greater pre-pulse inhibition than did the SD rats. During timing conditions without AV interference, timing accuracy for both strains was similar; peak times for WKY and SD rats were not different. During interference conditions, however, the timing behavior of the two strains was very different. Whereas peak times for SD rats were similar between non-interference and interference conditions, peak times for WKY rats were shorter and response rates higher in interference conditions than in non-interference conditions. The enhanced acoustic startle response, greater prepulse inhibition and altered timing behavior with audio-visual interference supports a characterization of WKY strain as hypervigilant and provides further evidence for the use of the WKY strain as a model of anxiety vulnerability.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1MrjvVahtA%253D%253D&md5=9b303ca7058678f601e8a8aecf16b849

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    Pálenícek, T. , Hlinák, Z. , Bubeníková-Valesová, V. , Novák, T. , and Horácek, J. (2010) Sex differences in the effects of N,N-diethyllysergamide (LSD) on behavioural activity and prepulse inhibition. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 34 , 588– 596,  DOI: 10.1016/j.pnpbp.2010.02.008

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    Sex differences in the effects of N,N-diethyllysergamide (LSD) on behavioral activity and prepulse inhibition

    Palenicek, Tomas; Hlinak, Zdenek; Bubenikova-Valesova, Vera; Novak, Tomas; Horacek, Jiri

    Progress in Neuro-Psychopharmacology & Biological Psychiatry (2010), 34 (4), 588-596CODEN: PNPPD7; ISSN:0278-5846. (Elsevier B.V.)

    The aim of this study was to describe sex differences in the behavioral effects of N,N-diethyllysergamide (LSD) (locomotor activity and other behavioral repertoire in the open field) and its effects on sensorimotor gating in rats (prepulse inhibition (PPI) of the acoustic startle reaction). Three groups of animals were analyzed: males, oestral and pro-oestral phase females (EP females), and metoestral and dioestral phase females (MD females). LSD (5, 50 and 200 μg/kg s.c.) attenuated locomotor activity and normal behavioral repertoire, and induced flat body posture, wet dog shakes and disrupted PPI. The most prominent behavioral findings of LSD were for LSD 200 μg/kg which suppressed almost all behavioral activity. LSD had mainly inhibitory locomotor effects in males and MD females, yet in EP female rats LSD increased locomotion during the second half of testing period. The main sex differences were obsd. in locomotor and exploratory behavior. Both EP and MD females were less sensitive to hypolocomotor effects of LSD and had less pronounced thigmotaxis than males. Further EP females had increased rearing after LSD 5 μg/kg. On the contrary although LSD disrupted PPI in males and MD female rats, EP females were protected from this disruptive effect. Thus, EP females seem to have a lower sensitivity to LSD behavioral actions.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXlvVSlt7c%253D&md5=ce3b2ef4f09283bb3caf2f8d5acddce2

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    Turner, R. C. (2012) Effects of aging on behavioral assessment performance: implications for clinically relevant models of neurological disease: Laboratory investigation. J. Neurosurg. 117 , 629– 637,  DOI: 10.3171/2012.5.JNS112224

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    Effects of aging on behavioral assessment performance: implications for clinically relevant models of neurological disease

    Turner Ryan C; Seminerio Michael J; Naser Zachary J; Ford J Neal; Martin Samantha J; Matsumoto Rae R; Rosen Charles L; Huber Jason D

    Journal of neurosurgery (2012), 117 (3), 629-37 ISSN:.

    OBJECT: Despite the role of aging in development of neurological and neurodegenerative diseases, the effects of age are often disregarded in experimental design of preclinical studies. Functional assessment increases the clinical relevance of animal models of neurological disease and adds value beyond traditional histological measures. However, the relationship between age and functional impairment has not been systematically assessed through a battery of functional tests. METHODS: In this study, various sensorimotor and behavioral tests were used to evaluate effects of aging on functional performance in naive animals. Sensorimotor measures included locomotor activity; Rotarod, inclined plane, and grip-strength testing; and modified Neurological Severity Score. The Morris water maze was used to examine differences in learning and memory, and the elevated plus maze and forced swim test were used to assess anxiety-like and depressive-like behaviors, respectively. RESULTS: Older Sprague-Dawley rats (18-20 months) were found to perform significantly worse on the inclined plane tests, and they exhibited alterations in elevated-plus maze and forced swim test compared with young adult rats (3-4 months). Specifically, older rats exhibited reduced exploration of open arms in elevated plus maze and higher immobility time in forced swim test. Spatial acquisition and reference memory were diminished in older rats compared with those in young adult rats. CONCLUSIONS: This study demonstrates clear differences between naive young adult and older animals, which may have implications in functional assessment for preclinical models of neurological disease.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC38jmtVOntQ%253D%253D&md5=7b153d56a47b74cdc6b8870bf48d6d31

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    Slattery, D. A. and Cryan, J. F. (2012) Using the rat forced swim test to assess antidepressant-like activity in rodents. Nat. Protoc. 7 , 1009– 14,  DOI: 10.1038/nprot.2012.044

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    Using the rat forced swim test to assess antidepressant-like activity in rodents

    Slattery, David A.; Cryan, John F.

    Nature Protocols (2012), 7 (6), 1009-1014CODEN: NPARDW; ISSN:1750-2799. (Nature Publishing Group)

    The forced swim test (FST) is one of the most commonly used animal models for assessing antidepressant-like behavior. This protocol details using the FST in rats, which takes place over 48 h and is followed by the video anal. of the behavior. The swim test involves the scoring of active (swimming and climbing) or passive (immobility) behavior when rodents are forced to swim in a cylinder from which there is no escape. There are two versions that are used, namely the traditional and modified FSTs, which differ in their exptl. setup. For both versions, a pretest of 15 min (although a no. of labs. have used a 10-min pretest with success) is included, as this accentuates the different behaviors in the 5-min swim test following drug treatment. Redn. in passive behavior is interpreted as an antidepressant-like effect of the manipulation, provided it does not increase general locomotor activity, which could provide a false pos. result in the FST.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XmsFClsLg%253D&md5=233fde8d745f3edacb78d2a38b6249f9

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    Russell, W. M. S., Burch, R. L., and Balls, M. (2009) The three Rs and the humanity criterion, FRAME.

59. 59

    Porsolt, R. D. , Le Pichon, M. , and Jalfre, M. (1977) Depression: a new animal model sensitive to antidepressant treatments. Nature 266 , 730– 732,  DOI: 10.1038/266730a0

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    Depression: a new animal model sensitive to antidepressant treatments

    Porsolt, R. D.; Le Pichon, M.; Jalfre, M.

    Nature (London, United Kingdom) (1977), 266 (5604), 730-2CODEN: NATUAS; ISSN:0028-0836.

    When forced to swim for 5 min in a vertical cylinder contg. water, rats developed a state of immobile resignation to their watery fate; redn. of this state of immobility by iprindole-HCl (40 mg/kg), mianserin-HCl (15 or 30 mg/kg), or viloxazine-HCl (50 mg/kg) showed that the rats were indeed feeling rather depressed. When rats were again placed into the water 24 h later they remained immobile for 75% of the 5-min period; drugs were injected i.p. 24, 5 and 1 h before this second aq. experience. All antidepressants, as well as electroconvulsive shock, reduced immobility, though tricyclic compds. produced sedative effects outside the test situation and mianserin and iprindole at 60 mg/kg did not effect immobility and markedly reduced muscle tonus. (+)-Amphetamine sulfate (0.75-3.0 mg/kg) and caffeine (3.75-15 mg/kg) also reduced immobility.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE2sXkvFGhur4%253D&md5=9bbf15ae1f0ddfad654c253a9517a9f6

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    Kokras, N. and Dalla, C. (2014) Sex differences in animal models of psychiatric disorders. Br. J. Pharmacol. 171 , 4595– 4619,  DOI: 10.1111/bph.12710

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    Sex differences in animal models of psychiatric disorders

    Kokras, N.; Dalla, C.

    British Journal of Pharmacology (2014), 171 (20), 4595-4619CODEN: BJPCBM; ISSN:1476-5381. (Wiley-Blackwell)

    Psychiatric disorders are characterized by sex differences in their prevalence, symptomatol. and treatment response. Animal models have been widely employed for the investigation of the neurobiol. of such disorders and the discovery of new treatments. However, mostly male animals have been used in preclin. pharmacol. studies. In this review, we highlight the need for the inclusion of both male and female animals in exptl. studies aiming at gender-oriented prevention, diagnosis and treatment of psychiatric disorders. We present behavioral findings on sex differences from animal models of depression, anxiety, post-traumatic stress disorder, substance-related disorders, obsessive-compulsive disorder, schizophrenia, bipolar disorder and autism. Moreover, when available, we include studies conducted across different stages of the oestrous cycle. By inspection of the relevant literature, it is obvious that robust sex differences exist in models of all psychiatric disorders. However, many times results are conflicting, and no clear conclusion regarding the direction of sex differences and the effect of the oestrous cycle is drawn. Moreover, there is a lack of considerable amt. of studies using psychiatric drugs in both male and female animals, in order to evaluate the differential response between the two sexes. Notably, while in most cases animal models successfully mimic drug response in both sexes, test parameters and treatment-sensitive behavioral indexes are not always the same for male and female rodents. Thus, there is an increasing need to validate animal models for both sexes and use std. procedures across different labs. Linked Articles : This article is part of a themed section on Animal Models in Psychiatry Research. To view the other articles in this section visit.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1Sqtr3K&md5=3c51690f5b89e3b7f93f2d973d86a405

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    Dalla, C. , Pitychoutis, P. M. , Kokras, N. , and Papadopoulou-Daifoti, Z. (2010) Sex Differences in Animal Models of Depression and Antidepressant Response. Basic Clin. Pharmacol. Toxicol. 106 , 226– 233,  DOI: 10.1111/j.1742-7843.2009.00516.x

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    Sex differences in animal models of depression and antidepressant response

    Dalla, Christina; Pitychoutis, Pothitos M.; Kokras, Nikolaos; Papadopoulou-Daifoti, Zeta

    Basic & Clinical Pharmacology & Toxicology (2010), 106 (3), 226-233CODEN: BCPTBO; ISSN:1742-7835. (Wiley-Blackwell)

    A review. Many stress-related mental disorders, including depression and post-traumatic stress disorder occur more often in women than in men. While social and cultural factors certainly contribute to these differences, neurobiol. sex differences seem to also play an important role. A rapidly burgeoning literature from basic and clin. research documents sex differences in brain anatomy, chem. and function, as well as in stress and drug responses. For example, some clin. studies have reported that women may have a better outcome when treated with selective serotonin re-uptake inhibitors, in comparison to tricyclic antidepressants. Furthermore, relatively limited basic research has been devoted to developing animal models and consequently describing drug treatments which are sensitive to sex differences. In this MiniReview, we discuss sex differences in behavioral aspects, as well as neurochem., neurobiol. and pharmacol. findings that we have collected from several different animal models and tests of depression. These are the forced swim test, the chronic mild stress and the learned helplessness models, the Flinders sensitive line rats, which is a genetic model of depression and the lipopolysaccharide-induced sickness behavior, a putative inflammatory model of depression. Collectively, our data have shown that in all animal models assayed, serotonergic neurochem. responses were differently affected in males and females, ultimately producing sex-dependent behavioral effects. In addn., Flinders sensitive line rats exhibited a sexually dimorphic response to chronic antidepressant treatment. These sex-differentiated neurochem. and behavioral alterations lend support to a major role of serotonin in the mediation of sexually dimorphic responses.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXivVShtbk%253D&md5=530cad79456109d2ba080f73fd37cf4c

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    Brenes Sáenz, J. C. , Villagra, O. R. , and Fornaguera Trías, J. (2006) Factor analysis of Forced Swimming test, Sucrose Preference test and Open Field test on enriched, social and isolated reared rats. Behav. Brain Res. 169 , 57– 65,  DOI: 10.1016/j.bbr.2005.12.001

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    Factor analysis of Forced Swimming test, Sucrose Preference test and Open Field test on enriched, social and isolated reared rats

    Brenes Saenz Juan Carlos; Villagra Odir Rodriguez; Fornaguera Trias Jaime

    Behavioural brain research (2006), 169 (1), 57-65 ISSN:0166-4328.

    Developmental and social factors are known to play a crucial role in the pathogenesis of affective disorders. Although it has been demonstrated that early life aversive experiences can be a risk factor in the development of human depression, most of the investigation in animals that try to model depression do not include postnatal manipulations. Since housing represents a fundamental ethological factor which modifies behavior and brain development, this study aimed to investigate the impact of different social and structural housing conditions on the development of a depressive-like syndrome in the behavioral despair paradigm and an anxiety-like syndrome in the unconditioned anxiety paradigm. The present study uses several multivariate analyses to study the impact of housing conditions in animal models of depression and anxiety. In this study, social isolation was able to reproduce the effects found in other animals models based on stress, suggesting that only 2 months of social isolation are enough to produce effects that can be useful as behavioral model of depression. Moreover, environmental enrichment showed an antidepressive and anxiolytic like effect in animal models of depression and anxiety. This effect, which has not been reported in earlier studies, suggests that stimulation during the first stages of growth might play a "protective" role on behavior and brain development.

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    Adolescent chronic restraint stress (aCRS) elicits robust depressive-like behavior in freely cycling, adult female rats without increasing anxiety-like behaviors

    Hibicke, Meghan; Graham, Martha A.; Hayslett, Renee L.

    Experimental and Clinical Psychopharmacology (2017), 25 (2), 74-83CODEN: ECLPES; ISSN:1936-2293. (American Psychological Association)

    Stress during times of rapid development is a risk factor for Major Depressive Disorder, a mood disorder that disproportionately affects women. We developed an adolescent chronic restraint stress (aCRS) protocol using female rats to address the impact of adolescent stress on female adult depressive-like behavior. Animals were divided into 4 treatment groups: not restrained:saline (NRSAL), not restrained: desipramine (NRDES), restrained:saline (RSAL), and restrained:desipramine (RDES). NRSAL and NRDES rats were housed in a sep. colony room from RSAL and RDES rats. All animals were weighed and handled daily. Beginning postnatal day (PND) 34(±1), RSAL and RDES rats were restrained for 1 h daily for 14 consecutive days. Beginning PND 55(±1), NRDES and RDES rats were given s.c. desipramine (5 mg/kg), which served as a pos. control, daily for 14 consecutive days. During that same time period, NRSAL and RSAL rats were given s.c. saline daily. aCRS (RSAL and RDES) rats showed significantly attenuated wt. gain compared with nonrestrained (NRSAL and NRDES) rats during the restraint period. Wt. gain normalized after the final restraint session. Behavioral testing took place PND 68-69(±1), and included open field testing, the elevated plus maze, locomotor activity, and the forced swim test (FST). RSAL rats showed significantly more immobility in the FST vs. all other groups, indicating depressive-like behavior. No differences between groups were obsd. in the other behavioral measures. These results indicate that aCRS elicits depressive-like behavioral characteristics in adult female rats without increasing anxiety-like behaviors.

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    Journal of Neuroscience Methods (2011), 195 (2), 200-205CODEN: JNMEDT; ISSN:0165-0270. (Elsevier B.V.)

    The forced swim test (FST) is a pre-clin. test to short and long term treatment with antidepressant drugs (ADT), which requires between-subject designs. Herein a modified protocol of the FST using within-subject design (repeated rat-FST) was evaluated. Male Wistar rats were submitted to 15 min of swimming (Day 1: pretest) followed by three subsequent 5 min-swimming tests one week apart (Day 2: test, Day 7: retest 1, Day 14: retest 2). To det. the temporal and factorial characteristics of the variables scored in the repeated rat-FST, the protocol was carried out in untreated animals (E1). To validate the method, daily injections of Fluoxetine (FLX, 2.5 mg/kg, i.p.) or saline were given over a 2-wk period (E2). Tests and retests have been videotaped for further register of the latency, frequency and duration of behaviors. Over retesting the latency to immobility decreased whereas duration of immobility tended to increase. Factorial anal. revealed that the test, the retest 1 as well as the retest 2 have variables suitable to detection of antidepressant-like effects of ADT. Compared to saline, FLX chronically administrated reduced duration of immobility whereas increased duration of swimming in retest 2. The data suggest that repeated rat-FST detected the gradual increase in the efficacy of low doses of FLX over time. Therefore, repeated rat-FST seemed suitable to detect short and long term effects of selective serotonin reuptake inhibitors, or other ADT, thus reducing the no. of animals used in the screenings of this type of compds.

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    The elevated plus maze is a widely used behavioral assay for rodents and it has been validated to assess the anti-anxiety effects of pharmacol. agents and steroid hormones, and to define brain regions and mechanisms underlying anxiety-related behavior. Briefly, rats or mice are placed at the junction of the four arms of the maze, facing an open arm, and entries/duration in each arm are recorded by a video-tracking system and observer simultaneously for 5 min. Other ethol. parameters (i.e., rears, head dips and stretched-attend postures) can also be obsd. An increase in open arm activity (duration and/or entries) reflects anti-anxiety behavior. In our lab., rats or mice are exposed to the plus maze on one occasion; thus, results can be obtained in 5 min per rodent.

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• Figures
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• Abstract

  

  Figure 1

  

  Figure 1. Experimental design. (A) Rats were injected with IP saline or 1.0 mg/kg psilocybin (PSI) on day 0. Locomotor activity (LCA) and forced swim test (FST) behaviors were assessed in SAL (n = 8) and rPSI (n = 8) rats on days 7, 14, 21, 28, and 35, and elevated plus maze (EPM) behaviors were assessed on day 41. (B) iPSI (n = 8) rats were injected with 1.0 mg/kg PSI on day 0. LCA and FST behaviors were assessed on day 35, and EPM behaviors were assessed on Day 41. The iPSI group was concurrent with SAL and rPSI shown above. (C) Rats were injected with IP saline (n = 6) or LSD (n = 6) on day 0. LCA and FST behaviors were assessed on day 35, and EPM behaviors were assessed on day 40. (D) Rats were injected with IP saline, 5.0 mg/kg ketamine, or 1.0 mg/kg PSI on day 0. LCA and FST behaviors were assessed on days 7 and 35, and EPM behaviors were assessed on day 41.

  Figure 2

  

  Figure 2. Forced swim test. (A) Immobility in the FST by SAL (n = 8) and rPSI (n = 8) did not change significantly over time. However, t tests found rPSI rats were less immobile than SAL rats on days 28 (p < 0.05) and 35 (p < 0.05). (B) iPSI (n = 8) rats were significantly less immobile than SAL rats during their first FST session (p < 0.0001) and significantly more likely to swim (p < 0.0001) and climb (p < 0.0001) than SAL rats. (C) LSD (n = 6) rats were significantly less immobile than SAL (n = 6, p < 0.05) rats, and significantly more likely to swim (p < 0.05) and climb (p < 0.05). (D) Group 1 (n = 6) rats were given saline on day 0, and LCA and FST behaviors were assessed day 1 to establish control behaviors for groups 1 and 2 (shown in E). 5.0 mg/kg KET did not alter immobility in the FST 1 day after injection (day 7), but it significantly reduced immobility in the FST 1 week (p < 0.001) and 2 weeks (p < 0.01) after injection (days 21 and 28). No differences in immobility were observed 3, 4, or 5 weeks after injection when compared to saline (day 1). (E) Group 2 (n = 6) was studied concurrently with group 1 (shown in D) and compared with group 1 saline (day 1) as control behaviors. No significant differences were observed within group 2 at 20 or 100 mg/kg, or between group 2 and group 1 saline (day 1). (F) 5.0 mg/kg IP KET (n = 6) significantly reduced immobility (p < 0.0001), and increased swimming (p < 0.05) but not climbing in the FST 1 week after injection vs SAL (n = 6). 1.0 mg/kg IP PSI (n = 6) significantly reduced immobility (p < 0.0001), and increased swimming (p < 0.05) but not climbing in the FST 1 week after injection vs SAL. (G) PSI significantly reduced immobility (p < 0.001), and increased swimming (p < 0.05) but not climbing in the FST 5 weeks (day 35) after injection vs SAL. No significant differences were observed between PSI day 7 (shown in F) and PSI day 35. KET day 35 was not different from SAL days 7 or 35.

  Figure 3

  

  Figure 3. Elevated plus maze. (A) rPSI (n = 7 due to exclusion) spent significantly more time in the open arms of the EPM (p < 0.05) and significantly less time in the closed arms of the EPM (p < 0.05) than SAL (n = 8). No differences were observed between iPSI and SAL rats. (B) No differences were observed between LSD (n = 6) and SAL (n = 6) rats. C) PSI (n = 6) rats spent significantly more time in the open arms (p < 0.05) and significantly less time in the closed arms (p < 0.05) than SAL rats. KET (n = 6) rats were not statistically different from SAL (n = 6) rats.

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     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1c%252Fmslektw%253D%253D&md5=bb110ec8a8830efd5f40e46684d25be8

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     Mathews, D. C. , Henter, I. D. , and Zarate, C. A. (2012) Targeting the Glutamatergic System to Treat Major Depressive Disorder. Drugs 72 , 1313– 1333,  DOI: 10.2165/11633130-000000000-00000

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     5

     Targeting the glutamatergic system to treat major depressive disorder: rationale and progress to date

     Mathews, Daniel C.; Henter, Ioline D.; Zarate, Carlos A., Jr.

     Drugs (2012), 72 (10), 1313-1333CODEN: DRUGAY; ISSN:0012-6667. (Adis Data Information BV)

     A review. Major depressive disorder (MDD) is a severe, debilitating medical illness that affects millions of individuals worldwide. The young age of onset and chronicity of the disorder has a significant impact on the long-term disability that affected individuals face. Most existing treatments have focused on the 'monoamine hypothesis' for rational design of compds. However, patients continue to experience low remission rates, residual subsyndromal symptoms, relapses and overall functional impairment. In this context, growing evidence suggests that the glutamatergic system is uniquely central to the neurobiol. and treatment of MDD. Here, we review data supporting the involvement of the glutamatergic system in the pathophysiol. of MDD, and discuss the efficacy of glutamatergic agents as novel therapeutics. Preliminary clin. evidence has been promising, particularly with regard to the N-methyl-D-aspartate (NMDA) antagonist ketamine as a 'proof-of-concept' agent. The review also highlights potential mol. and inflammatory mechanisms that may contribute to the rapid antidepressant response seen with ketamine. Because existing pharmacol. treatments for MDD are often insufficient for many patients, the next generation of treatments needs to be more effective, rapid acting and better tolerated than currently available medications. There is extant evidence that the glutamatergic system holds considerable promise for developing the next generation of novel and mechanistically distinct agents for the treatment of MDD.

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xht1GmurfP&md5=01f65a28be0ad13b41951964f96b1acb

  6. 6

     Murrough, J. W. (2013) Rapid and Longer-Term Antidepressant Effects of Repeated Ketamine Infusions in Treatment-Resistant Major Depression. Biol. Psychiatry 74 , 250– 256,  DOI: 10.1016/j.biopsych.2012.06.022

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     6

     Rapid and Longer-Term Antidepressant Effects of Repeated Ketamine Infusions in Treatment-Resistant Major Depression

     Murrough, James W.; Perez, Andrew M.; Pillemer, Sarah; Stern, Jessica; Parides, Michael K.; aan het Rot, Marije; Collins, Katherine A.; Mathew, Sanjay J.; Charney, Dennis S.; Iosifescu, Dan V.

     Biological Psychiatry (2013), 74 (4), 250-256CODEN: BIPCBF; ISSN:0006-3223. (Elsevier)

     Ketamine is reported to have rapid antidepressant effects; however, there is limited understanding of the time-course of ketamine effects beyond a single infusion. A previous report including 10 participants with treatment-resistant major depression (TRD) found that six ketamine infusions resulted in a sustained antidepressant effect. In the current report, we examd. the pattern and durability of antidepressant effects of repeated ketamine infusions in a larger sample, inclusive of the original.Participants with TRD (n = 24) underwent a washout of antidepressant medication followed by a series of up to six IV infusions of ketamine (.5 mg/kg) administered open-label three times weekly over a 12-day period. Participants meeting response criteria were monitored for relapse for up to 83 days from the last infusion.The overall response rate at study end was 70.8%. There was a large mean decrease in Montgomery-Åsberg Depression Rating Scale score at 2 h after the first ketamine infusion (18.9 ± 6.6, p < .001), and this decrease was largely sustained for the duration of the infusion period. Response at study end was strongly predicted by response at 4 h (94% sensitive, 71% specific). Among responders, median time to relapse after the last ketamine infusion was 18 days.Ketamine was assocd. with a rapid antidepressant effect in TRD that was predictive of a sustained effect. Future controlled studies will be required to identify strategies to maintain an antidepressant response among patients who benefit from a course of ketamine.

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtFahsbnJ&md5=073e82993c3014743e84c7abe982f14e

  7. 7

     Dong, C. (2016) Rapid and Sustained Antidepressant Action of the mGlu2/3 Receptor Antagonist MGS0039 in the Social Defeat Stress Model: Comparison with Ketamine. Int. J. Neuropsychopharmacol. pyw089,  DOI: 10.1093/ijnp/pyw089

  8. 8

     Rong, C. (2018) Predictors of Response to Ketamine in Treatment Resistant Major Depressive Disorder and Bipolar Disorder. Int. J. Environ. Res. Public Health 15 , 771,  DOI: 10.3390/ijerph15040771

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     8

     Predictors of response to ketamine in treatment resistant major depressive disorder and bipolar disorder

     Rong, Carola; Park, Caroline; Rosenblat, Joshua D.; Subramaniapillai, Mehala; Zuckerman, Hannah; Fus, Dominika; Lee, Yena L.; Pan, Zihang; Brietzke, Elisa; Mansur, Rodrigo B.; Cha, Danielle S.; Lui, Leanna M. W.; McIntyre, Roger S.

     International Journal of Environmental Research and Public Health (2018), 15 (4), 771/1-771/10CODEN: IJERGQ; ISSN:1660-4601. (MDPI AG)

     Objectives: Extant evidence indicates that ketamine exerts rapid antidepressant effects in treatment-resistant depressive (TRD) symptoms as a part of major depressive disorder (MDD) and bipolar disorder (BD). The identification of depressed sub-populations that are more likely to benefit from ketamine treatment remains a priority. In keeping with this view, the present narrative review aims to identify the pretreatment predictors of response to ketamine in TRD as part of MDD and BD. Method: Electronic search engines PubMed/MEDLINE, ClinicalTrials.gov, and Scopus were searched for relevant articles from inception to Jan. 2018. The search term ketamine was cross-referenced with the terms depression, major depressive disorder, bipolar disorder, predictors, and response and/or remission. Results: Multiple baseline pretreatment predictors of response were identified, including clin. (i.e., Body Mass Index (BMI), history of suicide, family history of alc. use disorder), peripheral biochem. (i.e., adiponectin levels, vitamin B12 levels), polysomnog. (abnormalities in delta sleep ratio), neurochem. (i.e., glutamine/glutamate ratio), neuroimaging (i.e., anterior cingulate cortex activity), genetic variation (i.e., Val66Met BDNF allele), and cognitive functioning (i.e., processing speed). High BMI and a pos. family history of alc. use disorder were the most replicated predictors. Conclusions: A pheno-biotype of depression more, or less likely, to benefit with ketamine treatment is far from complete. Notwithstanding, metabolic-inflammatory alterations are emerging as possible pretreatment response predictors of depressive symptom improvement, most notably being cognitive impairment. Sophisticated data-driven computational methods that are iterative and agnostic are more likely to provide actionable baseline pretreatment predictive information.

     https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitlGls7rM&md5=9fa060fe7f13ba61e49fe0b931eba04f

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      Sarkar, A. and Kabbaj, M. (2016) Sex Differences in Effects of Ketamine on Behavior, Spine Density, and Synaptic Proteins in Socially Isolated Rats. Biol. Psychiatry 80 , 448– 456,  DOI: 10.1016/j.biopsych.2015.12.025

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      10

      Sex Differences in Effects of Ketamine on Behavior, Spine Density, and Synaptic Proteins in Socially Isolated Rats

      Sarkar, Ambalika; Kabbaj, Mohamed

      Biological Psychiatry (2016), 80 (6), 448-456CODEN: BIPCBF; ISSN:0006-3223. (Elsevier)

      The mechanistic underpinnings of sex differences in occurrence of depression and efficacy of antidepressant treatments are poorly understood. We examd. the effects of isolation stress (IS) and the fast-acting antidepressant ketamine on anhedonia and depression-like behavior, spine d., and synaptic proteins in male and female rats. We used a chronic social IS paradigm to test the effects of ketamine (0, 2.5 mg/kg, and 5 mg/kg) on behavior and levels of synaptic proteins synapsin-1, postsynaptic d. protein 95, and glutamate receptor 1 in male rats and female rats in diestrus. Medial prefrontal cortex spine d. was also examd. in male rats and female rats that received ketamine during either the diestrus or the proestrus phase of their estrous cycle. Male rats showed anhedonia and depression-like behavior after 8 wk of IS, concomitant with decreases in spine d. and levels of synapsin-1, postsynaptic d. protein 95, and glutamate receptor 1 in the medial prefrontal cortex; these changes were reversed by a single injection of ketamine (5 mg/kg). After 11 wk of IS, female rats showed depression-like behavior but no signs of anhedonia. Although both doses of ketamine rescued depression-like behavior in female rats, the decline obsd. in synaptic proteins and spine d. in IS and in diestrus female rats could not be reversed by ketamine. Spine d. was higher in female rats during proestrus than in diestrus. Our findings implicate a role for synaptic proteins synapsin-1, postsynaptic d. protein 95, and glutamate receptor 1 and medial prefrontal cortex spine d. in the antidepressant effects of ketamine in male rats subjected to IS but not in female rats subjected to IS, suggesting dissimilar underlying mechanisms for efficacy of ketamine in the two sexes.

      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XjvVGhtLc%253D&md5=378f1aa4ba6ebd10da9510e456ea06ce

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      Ly, C. (2018) Psychedelics Promote Structural and Functional Neural Plasticity. Cell Rep. 23 , 3170– 3182,  DOI: 10.1016/j.celrep.2018.05.022

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      11

      Psychedelics Promote Structural and Functional Neural Plasticity

      Ly, Calvin; Greb, Alexandra C.; Cameron, Lindsay P.; Wong, Jonathan M.; Barragan, Eden V.; Wilson, Paige C.; Burbach, Kyle F.; Soltanzadeh Zarandi, Sina; Sood, Alexander; Paddy, Michael R.; Duim, Whitney C.; Dennis, Megan Y.; McAllister, A. Kimberley; Ori-McKenney, Kassandra M.; Gray, John A.; Olson, David E.

      Cell Reports (2018), 23 (11), 3170-3182CODEN: CREED8; ISSN:2211-1247. (Cell Press)

      Atrophy of neurons in the prefrontal cortex (PFC) plays a key role in the pathophysiol. of depression and related disorders. The ability to promote both structural and functional plasticity in the PFC has been hypothesized to underlie the fast-acting antidepressant properties of the dissociative anesthetic ketamine. Here, we report that, like ketamine, serotonergic psychedelics are capable of robustly increasing neuritogenesis and/or spinogenesis both in vitro and in vivo. These changes in neuronal structure are accompanied by increased synapse no. and function, as measured by fluorescence microscopy and electrophysiol. The structural changes induced by psychedelics appear to result from stimulation of the TrkB, mTOR, and 5-HT2A signaling pathways and could possibly explain the clin. effectiveness of these compds. Our results underscore the therapeutic potential of psychedelics and, importantly, identify several lead scaffolds for medicinal chem. efforts focused on developing plasticity-promoting compds. as safe, effective, and fast-acting treatments for depression and related disorders.

      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtFCmsLnL&md5=30676eee898172471110241296057df6

  12. 12

      Ampuero, E. (2010) Chronic fluoxetine treatment induces structural plasticity and selective changes in glutamate receptor subunits in the rat cerebral cortex. Neuroscience 169 , 98– 108,  DOI: 10.1016/j.neuroscience.2010.04.035

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      12

      Chronic fluoxetine treatment induces structural plasticity and selective changes in glutamate receptor subunits in the rat cerebral cortex

      Ampuero, E.; Rubio, F. J.; Falcon, R.; Sandoval, M.; Diaz-Veliz, G.; Gonzalez, R. E.; Earle, N.; Dagnino-Subiabre, A.; Aboitiz, F.; Orrego, F.; Wyneken, U.

      Neuroscience (Amsterdam, Netherlands) (2010), 169 (1), 98-108CODEN: NRSCDN; ISSN:0306-4522. (Elsevier B.V.)

      It has been postulated that chronic administration of antidepressant drugs induces delayed structural and mol. adaptations at glutamatergic forebrain synapses that might underlie mood improvement. To gain further insight into these changes in the cerebral cortex, rats were treated with fluoxetine (flx) for 4 wk. These animals showed decreased anxiety and learned helplessness. N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor subunit levels (NR1, NR2A, NR2B, GluR1 and GluR2) were analyzed in the forebrain by both western blot of homogenates and immunohistochem. Both methods demonstrated an upregulation of NR2A, GluR1 and GluR2 that was esp. significant in the retrosplenial granular b cortex (RSGb). However, when analyzing subunit content in postsynaptic densities and synaptic membranes, we found increases of NR2A and GluR2 but not GluR1. Instead, GluR1 was augmented in a microsomal fraction contg. intracellular membranes. NR1 and GluR2 were co-immunopptd. from postsynaptic densities and synaptic membranes. In the immunoppts., NR2A was increased while GluR1 was decreased supporting a change in receptor stoichiometry. The changes of subunit levels were assocd. with an upregulation of dendritic spine d. and of large, mushroom-type spines. These mol. and structural adaptations might be involved in neuronal network stabilization following long-term flx treatment.

      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXnvVOmtr8%253D&md5=f6399a8b35e24a8456d7a6341dd7c33d

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      Andrade, C. (2014) Antidepressant augmentation with anti-inflammatory agents. J. Clin. Psychiatry 75 , 975– 977,  DOI: 10.4088/JCP.14f09432

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      13

      Antidepressant augmentation with anti-inflammatory agents

      Andrade Chittaranjan

      The Journal of clinical psychiatry (2014), 75 (9), 975-7 ISSN:.

      Antidepressant augmentation strategies are commonly employed to treat depressed patients who do not respond to antidepressant monotherapy. Neuroinflammatory mechanisms have been implicated in depression, and nonsteroidal anti-inflammatory drugs (NSAIDs) have been found effective in animal models of depression both in monotherapy and when used to augment antidepressant drugs. However, results with NSAIDs have been mixed in human observational studies, with both better and worse depression outcomes reported. Four small (pooled N = 160) randomized controlled trials suggest that celecoxib (200-400 mg/d) augmentation of antidepressant medication improves 4-6 week outcomes in major depressive disorder. There are no data, however, to support the use of celecoxib or other NSAIDs in antidepressant-resistant depression. There are also concerns about adverse events associated with NSAID treatment, and about pharmacodynamic drug interactions between these drugs and serotonin reuptake inhibitors. A reasonable conclusion for the present is that NSAID augmentation of antidepressants is, at best, a tentative approach in nonrefractory major depression.

      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2M7ovVWnug%253D%253D&md5=30187120c1e175c50fae814a359569ec

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      Gałecki, P. , Mossakowska-Wójcik, J. , and Talarowska, M. (2018) The anti-inflammatory mechanism of antidepressants - SSRIs, SNRIs. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 80 , 291– 294,  DOI: 10.1016/j.pnpbp.2017.03.016

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      14

      The anti-inflammatory mechanism of antidepressants - SSRIs, SNRIs

      Galecki, Piotr; Mossakowska-Wojcik, Joanna; Talarowska, Monika

      Progress in Neuro-Psychopharmacology & Biological Psychiatry (2018), 80 (Part_C), 291-294CODEN: PNPPD7; ISSN:0278-5846. (Elsevier Inc.)

      A review. The cytokine theory of depression no longer brings about any doubts. Expts. and research studies conducted in the last ten years have confirmed that both phys. and psychol. (emotional) stress increases the likelihood of occurrence of mental disorders (including depressive disorders) owing to the action of a series of hormonal and biochem. mechanisms. Selective serotonin reuptake inhibitors (SSRI) as well as serotonin and norepinephrine reuptake inhibitors (SNRIs) are some of the most commonly applied drugs in the world during pharmacotherapy of recurrent depressive disorder. The underestimated anti-inflammatory and anti-oxidative effect may be one of the potential mechanisms of action of the prepns. mentioned above. The detailed specificity of action of this mechanism still remains unknown. The aim of our work will be to perform a review of contemporary literature in order to present the latest scientific reports regarding the anti-inflammatory effects of SSRIs and SNRIs. The mechanism of anti-inflammatory action may serve as a possible explanation for the efficacy of antidepressants from the groups of SSRIs and SNRIs.

      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXltlWmtLg%253D&md5=c63b2959decd36c661a215e166e6926e

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      Abelaira, J. M. , Reus, G. Z. , Neotti, M. V. , and Quevedo, J. (2014) The role of mTOR in depression and antidepressant responses. Life Sci. 101 , 10– 14,  DOI: 10.1016/j.lfs.2014.02.014

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      15

      The role of mTOR in depression and antidepressant responses

      Abelaira, Helena M.; Reus, Gislaine Z.; Neotti, Morgana V.; Quevedo, Joao

      Life Sciences (2014), 101 (1-2), 10-14CODEN: LIFSAK; ISSN:0024-3205. (Elsevier B.V.)

      A review. The aim of this study was to characterize the mTOR signaling cascade in depression and the actions that antidepressant drugs have on this pathway. Herein, a literature review was performed by verification and comparison of textbooks and journal articles that describe the characterization of the mTOR signaling cascade and its relationship to depression and antidepressant drugs, esp. ketamine. Postmortem studies have shown robust deficits in the mammalian target of rapamycin (mTOR) signaling in the prefrontal cortex of subjects diagnosed with major depressive disorder. However, besides the mTOR signaling pathway having an antidepressant response to various drugs, this seems to be more assocd. with antidepressant N-methyl-d-aspartate (NMDA) receptor antagonists, such as ketamine. The characterization of the mTOR signaling pathway in depression and its action in response to antidepressants show great potential for the identification of new therapeutic targets for the development of antidepressant drugs.

      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXkt1Wiuro%253D&md5=f2d3f07b925c285e85a5a848949078b5

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      Li, N. (2010) mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists. Science 329 , 959– 964,  DOI: 10.1126/science.1190287

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      16

      mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists

      Li, Nanxin; Lee, Boyoung; Liu, Rong-Jian; Banasr, Mounira; Dwyer, Jason M.; Iwata, Masaaki; Li, Xiao-Yuan; Aghajanian, George; Duman, Ronald S.

      Science (Washington, DC, United States) (2010), 329 (5994), 959-964CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)

      The rapid antidepressant response after ketamine administration in treatment-resistant depressed patients suggests a possible new approach for treating mood disorders compared to the weeks or months required for std. medications. However, the mechanisms underlying this action of ketamine [a glutamate N-methyl-D-aspartic acid (NMDA) receptor antagonist] have not been identified. We obsd. that ketamine rapidly activated the mammalian target of rapamycin (mTOR) pathway, leading to increased synaptic signaling proteins and increased no. and function of new spine synapses in the prefrontal cortex of rats. Moreover, blockade of mTOR signaling completely blocked ketamine induction of synaptogenesis and behavioral responses in models of depression. Our results demonstrate that these effects of ketamine are opposite to the synaptic deficits that result from exposure to stress and could contribute to the fast antidepressant actions of ketamine.

      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtVaqurzI&md5=10e346a65ae3aa8eb30f16fccbda28b3

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      Jernigan, C. S. (2011) The mTOR signaling pathway in the prefrontal cortex is compromised in major depressive disorder. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 35 , 1774– 1779,  DOI: 10.1016/j.pnpbp.2011.05.010

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      17

      The mTOR signaling pathway in the prefrontal cortex is compromised in major depressive disorder

      Jernigan, Courtney S.; Goswami, Dharmendra B.; Austin, Mark C.; Iyo, Abiye H.; Chandran, Agata; Stockmeier, Craig A.; Karolewicz, Beata

      Progress in Neuro-Psychopharmacology & Biological Psychiatry (2011), 35 (7), 1774-1779CODEN: PNPPD7; ISSN:0278-5846. (Elsevier B.V.)

      Recent studies demonstrate that rapid antidepressant response to ketamine is mediated by activation of the mammalian target of rapamycin (mTOR) signaling pathway, leading to increased synaptic proteins in the prefrontal cortex (PFC) of rats. Our postmortem studies indicate robust deficits in prominent postsynaptic proteins including N-methyl-D-aspartate (NMDA) receptor subunits (NR2A, NR2B), metabotropic glutamate receptor subtype 5 (mGluR5) and postsynaptic d. protein 95 kDa (PSD-95) in the PFC in major depressive disorder (MDD). We hypothesize that deficits in the mTOR-dependent translation initiation pathway contribute to the mol. pathol. seen in the PFC of MDD subjects, and that a rapid reversal of these abnormalities may underlie antidepressant activity. The majority of known translational regulation occurs at the level of initiation. MTOR regulates translation initiation via its downstream components: p70-kDa ribosomal protein S6 kinase (p70S6K), and eukaryotic initiation factors 4E and 4B (eIF4E and eIF4B). In this study, we examd. the expression of mTOR and its core downstream signaling targets: p70S6K, eIF4E, and eIF4B in the PFC of 12 depressed subjects and 12 psychiatrically healthy controls using Western blot. Levels of eIF4E phosphorylated at serine 209 (p-eIF4E-Ser209) and eIF4B phosphorylated at serine 504 (p-eIF4B-Ser504) were also examd. Adjacent cortical tissue samples from both cohorts of subjects were used in our previous postmortem analyses. There was a significant redn. in mTOR, p70S6K, eIF4B and p-eIF4B protein expression in MDD subjects relative to controls. No group differences were obsd. in eIF4E, p-eIF4E or actin levels. Our findings show deficits in mTOR-dependent translation initiation in MDD particularly via the p70S6K/eIF4B pathway, and indicate a potential assocn. between marked deficits in synaptic proteins and dysregulation of mTOR signaling in MDD.

      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtVels7nO&md5=02e9ee94c02b77d4225d528c2435ffb3

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      Buchborn, T. , Schröder, H. , Höllt, V. , and Grecksch, G. (2014) Repeated lysergic acid diethylamide in an animal model of depression: Normalisation of learning behaviour and hippocampal serotonin 5-HT2 signalling. J. Psychopharmacol. (London, U. K.) 28 , 545– 552,  DOI: 10.1177/0269881114531666

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      18

      Repeated lysergic acid diethylamide in an animal model of depression: normalisation of learning behaviour and hippocampal serotonin 5-HT2 signalling

      Buchborn, Tobias; Schroeder, Helmut; Hoellt, Volker; Grecksch, Gisela

      Journal of Psychopharmacology (London, United Kingdom) (2014), 28 (6), 545-552, 8 pp.CODEN: JOPSEQ; ISSN:0269-8811. (Sage Publications Ltd.)

      A re-balance of postsynaptic serotonin (5-HT) receptor signalling, with an increase in 5-HT1A and a decrease in 5-HT2A signalling, is a final common pathway multiple antidepressants share. Given that the 5-HT1A/2A agonist lysergic acid diethylamide (LSD), when repeatedly applied, selectively downregulates 5-HT2A, but not 5-HT1A receptors, one might expect LSD to similarly re-balance the postsynaptic 5-HT signalling. Challenging this idea, we use an animal model of depression specifically responding to repeated antidepressant treatment (olfactory bulbectomy), and test the antidepressant-like properties of repeated LSD treatment (0.13 mg/kg/d, 11 d). In line with former findings, we observe that bulbectomized rats show marked deficits in active avoidance learning. These deficits, similarly as we earlier noted with imipramine, are largely reversed by repeated LSD administration. Addnl., bulbectomized rats exhibit distinct anomalies of monoamine receptor signalling in hippocampus and/or frontal cortex; from these, only the hippocampal decrease in 5-HT2 related [35S]-GTP-gamma-S binding is normalized by LSD. Importantly, the sham-operated rats do not profit from LSD, and exhibit reduced hippocampal 5-HT2 signalling. As behavioral deficits after bulbectomy respond to agents classified as antidepressants only, we conclude that the effect of LSD in this model can be considered antidepressant-like, and discuss it in terms of a re-balance of hippocampal 5-HT2/5-HT1A signalling.

      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhslWgur3E&md5=d039a1ae9269e438cefaef2b79e82da4

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      Cameron, L. P. , Benson, C. J. , Dunlap, L. E. , and Olson, D. E. (2018) Effects of N,N-Dimethyltryptamine on Rat Behaviors Relevant to Anxiety and Depression. ACS Chem. Neurosci. 9 , 1582,  DOI: 10.1021/acschemneuro.8b00134

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      19

      Effects of N,N-Dimethyltryptamine on Rat Behaviors Relevant to Anxiety and Depression

      Cameron, Lindsay P.; Benson, Charlie J.; Dunlap, Lee E.; Olson, David E.

      ACS Chemical Neuroscience (2018), 9 (7), 1582-1590CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)

      Depression and anxiety disorders are debilitating diseases resulting in substantial economic costs to society. Traditional antidepressants often take weeks to months to pos. affect mood and are ineffective for about 30% of the population. Alternatives, such as ketamine, a dissociative anesthetic capable of producing hallucinations, and the psychoactive tisane ayahuasca, have shown great promise due to their fast-acting nature and effectiveness in treatment-resistant populations. Here, we investigate the effects of N,N-dimethyltryptamine (DMT), the principle hallucinogenic component of ayahuasca, in rodent behavioral assays relevant to anxiety and depression using adult, male, Sprague-Dawley rats. We find that while DMT elicits initial anxiogenic responses in several of these paradigms, its long-lasting effects tend to reduce anxiety by facilitating the extinction of cued fear memory. Furthermore, DMT reduces immobility in the forced swim test, which is a characteristic behavioral response induced by many antidepressants. Our results demonstrate that DMT produces antidepressant and anxiolytic behavioral effects in rodents, warranting further investigation of ayahuasca and classical psychedelics as treatments for depression and post-traumatic stress disorder.

      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXns12gt74%253D&md5=078d22f8b2efb03fef5071a960fe5305

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      Nichols, D. E. (2012) Structure–activity relationships of serotonin 5-HT2A agonists. Wiley Interdiscip. Rev. Membr. Transp. Signal. 1 , 559– 579,  DOI: 10.1002/wmts.42

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      Li, Q. , Hosaka, T. , Harada, N. , Nakaya, Y. , and Funaki, M. (2013) Activation of Akt through 5-HT2A receptor ameliorates serotonin-induced degradation of insulin receptor substrate-1 in adipocytes. Mol. Cell. Endocrinol. 365 , 25– 35,  DOI: 10.1016/j.mce.2012.08.022

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      21

      Activation of Akt through 5-HT2A receptor ameliorates serotonin-induced degradation of insulin receptor substrate-1 in adipocytes

      Li, Qinkai; Hosaka, Toshio; Harada, Nagakatsu; Nakaya, Yutaka; Funaki, Makoto

      Molecular and Cellular Endocrinology (2013), 365 (1), 25-35CODEN: MCEND6; ISSN:0303-7207. (Elsevier Ireland Ltd.)

      Serotonin (5-hydroxytryptamine, 5-HT) was found to be elevated in the serum of diabetic patients. In this study, we investigate the mechanism of insulin desensitization caused by 5-HT. In 3T3-L1 adipocytes, 5-HT treatment induced the translocation of insulin receptor substrate-1 (IRS-1) from low d. microsome (LDM), the important intracellular compartment for its functions, to cytosol, inducing IRS-1 ubiquitination and degrdn. Moreover, inhibition of 5-HT-stimulated Akt activation by either ketanserin (a specific 5-HT2A receptor antagonist) or knocking-down the expression of 5-HT2A receptor promoted 5-HT-stimulated IRS-1 dissocn. from 14-3-3β in LDM, leading to drastic ubiquitination. Interestingly, sarpogrelate, another antagonist of 5-HT2A receptor, protected IRS-1 from degrdn. through activation of Akt. This implicates the importance of Akt activation in extending IRS-1 life span through maintaining their optimal sub-location into adipocytes. Taken together, this study suggest that activation of Akt may be able to compensate the adverse effects of 5-HT by stabilizing IRS-1 in LDM.

      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsVemtbrI&md5=56fea2af7066bc828cac01ee9089d1e3

  22. 22

      Grob, C. S. (2011) Pilot Study of Psilocybin Treatment for Anxiety in Patients With Advanced-Stage Cancer. Arch. Gen. Psychiatry 68 , 71– 78,  DOI: 10.1001/archgenpsychiatry.2010.116

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      22

      Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer

      Grob, Charles S.; Danforth, Alicia L.; Chopra, Gurpreet S.; Hagerty, Marycie; McKay, Charles R.; Halberstadt, Adam L.; Greer, George R.

      Archives of General Psychiatry (2011), 68 (1), 71-78CODEN: ARGPAQ; ISSN:0003-990X. (American Medical Association)

      Context: Researchers conducted extensive investigations of hallucinogens in the 1950s and 1960s. By the early 1970s, however, political and cultural pressures forced the cessation of all projects. This investigation reexamines a potentially promising clin. application of hallucinogens in the treatment of anxiety reactive to advanced-stage cancer. Objective: To explore the safety and efficacy of psilocybin in patients with advanced-stage cancer and reactive anxiety. Design: A double-blind, placebo-controlled study of patients with advanced-stage cancer and anxiety, with subjects acting as their own control, using a moderate dose (0.2 mg/kg) of psilocybin. Setting: A clin. research unit within a large public sector academic medical center. Participants: Twelve adults with advanced-stage cancer and anxiety. Main Outcome Measures: In addn. to monitoring safety and subjective experience before and during exptl. treatment sessions, follow-up data including results from the Beck Depression Inventory, Profile of Mood States, and State-Trait Anxiety Inventory were collected unblinded for 6 mo after treatment. Results: Safe physiol. and psychol. responses were documented during treatment sessions. There were no clin. significant adverse events with psilocybin. The State-Trait Anxiety Inventory trait anxiety subscale demonstrated a significant redn. in anxiety at 1 and 3 mo after treatment. The Beck Depression Inventory revealed an improvement of mood that reached significance at 6 mo; the Profile of Mood States identified mood improvement after treatment with psilocybin that approached but did not reach significance. Conclusions: This study established the feasibility and safety of administering moderate doses of psilocybin to patients with advanced-stage cancer and anxiety. Some of the data revealed a pos. trend toward improved mood and anxiety. These results support the need for more research in this long-neglected field. Trial Registration: clinicaltrials.gov Identifier: NCT00302744.

      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtVKrtr8%253D&md5=5b4a2ef5e1631c95c9a39c5ca175fca7

  23. 23

      Carhart-Harris, R. L. (2016) Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. Lancet Psychiatry 3 , 619– 627,  DOI: 10.1016/S2215-0366(16)30065-7

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      23

      Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study

      Carhart-Harris Robin L; Bolstridge Mark; Day Camilla M J; Erritzoe David; Kaelen Mendel; Nutt David J; Rucker James; Bloomfield Michael; Rickard James A; Forbes Ben; Feilding Amanda; Taylor David; Pilling Steve; Curran Valerie H

      The lancet. Psychiatry (2016), 3 (7), 619-27 ISSN:.

      BACKGROUND: Psilocybin is a serotonin receptor agonist that occurs naturally in some mushroom species. Recent studies have assessed the therapeutic potential of psilocybin for various conditions, including end-of-life anxiety, obsessive-compulsive disorder, and smoking and alcohol dependence, with promising preliminary results. Here, we aimed to investigate the feasibility, safety, and efficacy of psilocybin in patients with unipolar treatment-resistant depression. METHODS: In this open-label feasibility trial, 12 patients (six men, six women) with moderate-to-severe, unipolar, treatment-resistant major depression received two oral doses of psilocybin (10 mg and 25 mg, 7 days apart) in a supportive setting. There was no control group. Psychological support was provided before, during, and after each session. The primary outcome measure for feasibility was patient-reported intensity of psilocybin's effects. Patients were monitored for adverse reactions during the dosing sessions and subsequent clinic and remote follow-up. Depressive symptoms were assessed with standard assessments from 1 week to 3 months after treatment, with the 16-item Quick Inventory of Depressive Symptoms (QIDS) serving as the primary efficacy outcome. This trial is registered with ISRCTN, number ISRCTN14426797. FINDINGS: Psilocybin's acute psychedelic effects typically became detectable 30-60 min after dosing, peaked 2-3 h after dosing, and subsided to negligible levels at least 6 h after dosing. Mean self-rated intensity (on a 0-1 scale) was 0·51 (SD 0·36) for the low-dose session and 0·75 (SD 0·27) for the high-dose session. Psilocybin was well tolerated by all of the patients, and no serious or unexpected adverse events occurred. The adverse reactions we noted were transient anxiety during drug onset (all patients), transient confusion or thought disorder (nine patients), mild and transient nausea (four patients), and transient headache (four patients). Relative to baseline, depressive symptoms were markedly reduced 1 week (mean QIDS difference -11·8, 95% CI -9·15 to -14·35, p=0·002, Hedges' g=3·1) and 3 months (-9·2, 95% CI -5·69 to -12·71, p=0·003, Hedges' g=2) after high-dose treatment. Marked and sustained improvements in anxiety and anhedonia were also noted. INTERPRETATION: This study provides preliminary support for the safety and efficacy of psilocybin for treatment-resistant depression and motivates further trials, with more rigorous designs, to better examine the therapeutic potential of this approach. FUNDING: Medical Research Council.

      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2s%252FitFGmsg%253D%253D&md5=81f97f567242b7763113e3930123fcf2

  24. 24

      Ross, S. (2016) Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. J. Psychopharmacol. 30 , 1165– 1180,  DOI: 10.1177/0269881116675512

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      24

      Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial

      Ross, Stephen; Bossis, Anthony; Guss, Jeffrey; Agin-Liebes, Gabrielle; Malone, Tara; Cohen, Barry; Mennenga, Sarah E.; Belser, Alexander; Kalliontzi, Krystallia; Babb, James; Su, Zhe; Corby, Patricia; Schmidt, Brian L.

      Journal of Psychopharmacology (London, United Kingdom) (2016), 30 (12), 1165-1180CODEN: JOPSEQ; ISSN:0269-8811. (Sage Publications Ltd.)

      Background: Clin. significant anxiety and depression are common in patients with cancer, and are assocd. with poor psychiatric and medical outcomes. Historical and recent research suggests a role for psilocybin to treat cancer-related anxiety and depression. Methods: In this double-blind, placebo-controlled, crossover trial, 29 patients with cancer-related anxiety and depression were randomly assigned and received treatment with single-dose psilocybin (0.3 mg/kg) or niacin, both in conjunction with psychotherapy. The primary outcomes were anxiety and depression assessed between groups prior to the crossover at 7 wk. Results: Prior to the crossover, psilocybin produced immediate, substantial, and sustained improvements in anxiety and depression and led to decreases in cancer-related demoralization and hopelessness, improved spiritual wellbeing, and increased quality of life. At the 6.5-mo follow-up, psilocybin was assocd. with enduring anxiolytic and anti-depressant effects (approx. 60-80% of participants continued with clin. significant redns. in depression or anxiety), sustained benefits in existential distress and quality of life, as well as improved attitudes towards death. The psilocybin-induced mystical experience mediated the therapeutic effect of psilocybin on anxiety and depression. Conclusions: In conjunction with psychotherapy, single moderate-dose psilocybin produced rapid, robust and enduring anxiolytic and anti-depressant effects in patients with cancer-related psychol. distress.

      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsVGrur7M&md5=e0c6afc0eaa5ced7da47f7d417efec82

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      Reiche, S. (2018) Serotonergic hallucinogens in the treatment of anxiety and depression in patients suffering from a life-threatening disease: A systematic review. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 81 , 1– 10,  DOI: 10.1016/j.pnpbp.2017.09.012

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      25

      Serotonergic hallucinogens in the treatment of anxiety and depression in patients suffering from a life-threatening disease: A systematic review

      Reiche, Simon; Hermle, Leo; Gutwinski, Stefan; Jungaberle, Henrik; Gasser, Peter; Majic, Tomislav

      Progress in Neuro-Psychopharmacology & Biological Psychiatry (2018), 81 (), 1-10CODEN: PNPPD7; ISSN:0278-5846. (Elsevier Inc.)

      Anxiety and depression are some of the most common psychiatric symptoms of patients suffering with life-threatening diseases, often assocd. with a low quality of life and a poor overall prognosis. 5-HT2A-receptor agonists (serotonergic hallucinogens, 'psychedelics') like lysergic acid diethylamide (LSD) and psilocybin were first investigated as therapeutic agents in the 1960s. Recently, after a long hiatus period of regulatory obstacles, interest in the clin. use of these substances has resumed. The current article provides a systematic review of studies investigating psychedelics in the treatment of symptoms of existential distress in life-threatening diseases across different periods of research, highlighting how underlying concepts have developed over time. A systematic search for clin. trials from 1960 to 2017 revealed 11 eligible clin. trials involving a total no. of N = 445 participants, of which 7 trials investigated the use of lysergic acid diethylamide (LSD) (N = 323), 3 trials investigated the use of psilocybin (N = 92), and one trial investigated the use of dipropyltryptamine (DPT) (N = 30). The 4 more recent randomized controlled trials (RCTs) (N = 104) showed a significantly higher methodol. quality than studies carried out in the 1960s and 1970s. Evidence supports that patients with life threatening diseases assocd. with symptoms of depression and anxiety benefit from the anxiolytic and antidepressant properties of serotonergic hallucinogens. Some studies anecdotally reported improvements in patients' quality of life and reduced fear of death. Moreover, low rates of side effects were reported in studies that adhered to safety guidelines. Further studies are needed to det. how these results can be transferred into clin. practice.

      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsFyqtrjK&md5=94a9bbba17854afcb0b38474dcee9cc9

  26. 26

      Hendricks, P. S. (2018) Awe: a putative mechanism underlying the effects of classic psychedelic-assisted psychotherapy. Int. Rev. Psychiatry Abingdon Engl. 30 , 331– 342,  DOI: 10.1080/09540261.2018.1474185

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      26

      Awe: a putative mechanism underlying the effects of classic psychedelic-assisted psychotherapy

      Hendricks Peter S

      International review of psychiatry (Abingdon, England) (2018), 30 (4), 331-342 ISSN:.

      A psychological model of classic psychedelic-assisted psychotherapy informed by contemporary scientific data is presented in this paper. It is suggested that classic psychedelic-occasioned mystical experience is characterized by profound awe, a discrete emotion experienced in the presence of a vast stimulus requiring accommodation of mental structures. Awe, in turn, promotes the small self, a construct that, in the extreme, is analogous to those of unitive experience and ego dissolution. The small self is conceptualized as key to understanding the downstream effects of mystical experience occasioned in the context of classic psychedelic-assisted psychotherapy. With this novel theoretical framework in mind, a number of clinical implications and recommendations are provided so as to advance this incipient field of study.

      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3czjt1OktQ%253D%253D&md5=ccf3713913d7e5a1cea7c4b570ec279d

  27. 27

      Roseman, L. , Nutt, D. J. , and Carhart-Harris, R. L. (2018) Quality of Acute Psychedelic Experience Predicts Therapeutic Efficacy of Psilocybin for Treatment-Resistant Depression. Front. Pharmacol. 8 , 974,  DOI: 10.3389/fphar.2017.00974

  28. 28

      Nichols, D. E. , Johnson, M. W. , and Nichols, C. D. (2017) Psychedelics as Medicines: An Emerging New Paradigm. Clin. Pharmacol. Ther. 101 , 209– 219,  DOI: 10.1002/cpt.557

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      28

      Psychedelics as Medicines: An Emerging New Paradigm

      Nichols D E; Johnson M W; Nichols C D

      Clinical pharmacology and therapeutics (2017), 101 (2), 209-219 ISSN:.

      Scientific interest in serotonergic psychedelics (e.g., psilocybin and LSD; 5-HT2A receptor agonists) has dramatically increased within the last decade. Clinical studies administering psychedelics with psychotherapy have shown preliminary evidence of robust efficacy in treating anxiety and depression, as well as addiction to tobacco and alcohol. Moreover, recent research has suggested that these compounds have potential efficacy against inflammatory diseases through novel mechanisms, with potential advantages over existing antiinflammatory agents. We propose that psychedelics exert therapeutic effects for psychiatric disorders by acutely destabilizing local brain network hubs and global network connectivity via amplification of neuronal avalanches, providing the occasion for brain network "resetting" after the acute effects have resolved. Antiinflammatory effects may hold promise for efficacy in treatment of inflammation-related nonpsychiatric as well as potentially for psychiatric disorders. Serotonergic psychedelics operate through unique mechanisms that show promising effects for a variety of intractable, debilitating, and lethal disorders, and should be rigorously researched.

      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1c%252FovFSksw%253D%253D&md5=f9dbaa48fd257802568e22ac2e3c5b88

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      Davis, M. and Walters, J. K. (1977) Psilocybin: Biphasic dose-response effects on the acoustic startle reflex in the rat. Pharmacol., Biochem. Behav. 6 , 427– 431,  DOI: 10.1016/0091-3057(77)90180-0

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      29

      Psilocybin: biphasic dose-response effects on the acoustic startle reflex in the rat

      Davis, Michael; Walters, James K.

      Pharmacology, Biochemistry and Behavior (1977), 6 (4), 427-31CODEN: PBBHAU; ISSN:0091-3057.

      The startle reflex was measured in rats after intraperitoneal injection of saline or 0.25, 0.50, 0.75, 1.0, 2.0, 4.0, or 8.0 mg psilocybin (I) [520-52-5]/kg. Low doses (0.75-2.0 mg/kg) increased startle amplitude, whereas high doses (4.0-8.0 mg/kg) depressed startle. Selected low (0.71 mg/kg) or high (5.70 mg/kg) doses of psilocin [520-53-6] also had a biphasic dose-response effect on startle comparable in magnitude to equimolar doses of I. This biphasic dose-response relationship of the indole hallucinogen, I, on startle is consistent with the hypothesis that startle is increased when the firing rates of midbrain raphe neurons are selectively inhibited but is depressed when neurons postsynaptic to raphe cells are also inhibited.

      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE2sXkvFKjsr8%253D&md5=8f4b09a4612597a3be318673787106e0

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      Archer, S. , Chrenek, C. , and Swainson, J. (2018) Maintenance Ketamine Therapy for Treatment-Resistant Depression. J. Clin. Psychopharmacol. 1 , 380,  DOI: 10.1097/JCP.0000000000000894

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      Nair, A. B. and Jacob, S. (2016) A simple practice guide for dose conversion between animals and human. J. Basic Clin. Pharm. 7 , 27– 31,  DOI: 10.4103/0976-0105.177703

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      31

      A simple practice guide for dose conversion between animals and human

      Nair Anroop B; Jacob Shery

      Journal of basic and clinical pharmacy (2016), 7 (2), 27-31 ISSN:0976-0105.

      Understanding the concept of extrapolation of dose between species is important for pharmaceutical researchers when initiating new animal or human experiments. Interspecies allometric scaling for dose conversion from animal to human studies is one of the most controversial areas in clinical pharmacology. Allometric approach considers the differences in body surface area, which is associated with animal weight while extrapolating the doses of therapeutic agents among the species. This review provides basic information about translation of doses between species and estimation of starting dose for clinical trials using allometric scaling. The method of calculation of injection volume for parenteral formulation based on human equivalent dose is also briefed.

      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28fotV2hsQ%253D%253D&md5=527e4c74daabcb030b1e475cc22d8404

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      Tizabi, Y. , Bhatti, B. H. , Manaye, K. F. , Das, J. R. , and Akinfiresoye, L. (2012) Antidepressant-like effects of low ketamine dose is associated with increased hippocampal AMPA/NMDA receptor density ratio in female Wistar-Kyoto rats. Neuroscience 213 , 72– 80,  DOI: 10.1016/j.neuroscience.2012.03.052

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      32

      Antidepressant-like effects of low ketamine dose is associated with increased hippocampal AMPA/NMDA receptor density ratio in female Wistar-Kyoto rats

      Tizabi, Y.; Bhatti, B. H.; Manaye, K. F.; Das, J. R.; Akinfiresoye, L.

      Neuroscience (Amsterdam, Netherlands) (2012), 213 (), 72-80CODEN: NRSCDN; ISSN:0306-4522. (Elsevier B.V.)

      Preclin. as well as limited clin. studies indicate that ketamine, a non-competitive glutamate N-methyl-D-aspartate (NMDA) receptor antagonist, may exert a quick and prolonged antidepressant effect. It has been postulated that ketamine action is due to inhibition of NMDA and stimulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors. Here, we sought to det. whether ketamine would exert antidepressant effects in Wistar-Kyoto (WKY) rats, a putative animal model of depression and whether this effect would be assocd. with changes in AMPA/NMDA receptor densities in the hippocampus. Adult female WKY rats and their control Wistar rats were subjected to acute and chronic ketamine doses and their locomotor activity (LMA) and immobility in the forced swim test (FST) were evaluated. Hippocampal AMPA and NMDA receptor densities were also measured following a chronic ketamine dose. Ketamine, both acutely (0.5-5.0 mg/kg i.p.) and chronically (0.5-2.5 mg/kg daily for 10 days) resulted in a dose-dependent and prolonged decrease in immobility in FST in WKY rats only, suggesting an antidepressant-like effect in this model. Chronic treatment with an ED of ketamine also resulted in an increase in AMPA/NMDA receptor d. ratio in the hippocampus of WKY rats. LMA was not affected by any ketamine treatment in either strain. These results indicate a rapid and lasting antidepressant-like effect of a low ketamine dose in WKY rat model of depression. Moreover, the increase in AMPA/NMDA receptor d. in the hippocampus could be a contributory factor to behavioral effects of ketamine. These findings suggest potential therapeutic benefit in simultaneous redn. of central NMDA and elevation of AMPA receptor function in treatment of depression.

      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XotValsbc%253D&md5=05b668993ff089ddfba7a7e54a01ab1d

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      Carhart-Harris, R. L. (2018) Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Psychopharmacology (Berl.) 235 , 399– 408,  DOI: 10.1007/s00213-017-4771-x

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      33

      Psilocybin with psychological support for treatment-resistant depression: six-month follow-up

      Carhart-Harris R L; Bolstridge M; Day C M J; Rucker J; Watts R; Erritzoe D E; Kaelen M; Giribaldi B; Nutt D J; Bolstridge M; Day C M J; Rucker J; Rucker J; Bloomfield M; Pilling S; Curran H V; Rickard J A; Forbes B; Feilding A; Taylor D; Curran H V

      Psychopharmacology (2018), 235 (2), 399-408 ISSN:.

      RATIONALE: Recent clinical trials are reporting marked improvements in mental health outcomes with psychedelic drug-assisted psychotherapy. OBJECTIVES: Here, we report on safety and efficacy outcomes for up to 6 months in an open-label trial of psilocybin for treatment-resistant depression. METHODS: Twenty patients (six females) with (mostly) severe, unipolar, treatment-resistant major depression received two oral doses of psilocybin (10 and 25 mg, 7 days apart) in a supportive setting. Depressive symptoms were assessed from 1 week to 6 months post-treatment, with the self-rated QIDS-SR16 as the primary outcome measure. RESULTS: Treatment was generally well tolerated. Relative to baseline, marked reductions in depressive symptoms were observed for the first 5 weeks post-treatment (Cohen's d = 2.2 at week 1 and 2.3 at week 5, both p < 0.001); nine and four patients met the criteria for response and remission at week 5. Results remained positive at 3 and 6 months (Cohen's d = 1.5 and 1.4, respectively, both p < 0.001). No patients sought conventional antidepressant treatment within 5 weeks of psilocybin. Reductions in depressive symptoms at 5 weeks were predicted by the quality of the acute psychedelic experience. CONCLUSIONS: Although limited conclusions can be drawn about treatment efficacy from open-label trials, tolerability was good, effect sizes large and symptom improvements appeared rapidly after just two psilocybin treatment sessions and remained significant 6 months post-treatment in a treatment-resistant cohort. Psilocybin represents a promising paradigm for unresponsive depression that warrants further research in double-blind randomised control trials.

      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1M7ptlKkug%253D%253D&md5=0d464e6b3f97242e325b0945f204bb00

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      Lu, H. (2012) Rat brains also have a default mode network. Proc. Natl. Acad. Sci. U. S. A. 109 , 3979– 3984,  DOI: 10.1073/pnas.1200506109

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      34

      Rat brains also have a default mode network

      Lu, Hanbing; Zou, Qihong; Gu, Hong; Raichle, Marcus E.; Stein, Elliot A.; Yang, Yihong

      Proceedings of the National Academy of Sciences of the United States of America (2012), 109 (10), 3979-3984CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)

      The default mode network (DMN) in humans has been suggested to support a variety of cognitive functions and has been implicated in an array of neuropsychol. disorders. However, its function(s) remains poorly understood. We show that rats possess a DMN that is broadly similar to the DMNs of nonhuman primates and humans. Our data suggest that, despite the distinct evolutionary paths between rodent and primate brain, a well-organized, intrinsically coherent DMN appears to be a fundamental feature in the mammalian brain whose primary functions might be to integrate multimodal sensory and affective information to guide behavior in anticipation of changing environmental contingencies.

      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XjvFymtbw%253D&md5=5b38b45e77b2e4088d1f54f650c0dc17

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      Yakura, T. (2018) Visual recognition of mirror, video-recorded, and still images in rats. PLoS One 13 , e0194215,  DOI: 10.1371/journal.pone.0194215

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      Visual recognition of mirror, video-recorded, and still images in rats

      Yakura, Tomiko; Yokota, Hiroki; Ohmichi, Yusuke; Ohmichi, Mika; Nakano, Takashi; Naito, Munekazu

      PLoS One (2018), 13 (3), e0194215/1-e0194215/11CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)

      Several recent studies have claimed that rodents have good visual recognition abilities. However, the extent to which rats can recognize other rats and distinguish between males and females using visual information alone remains unclear. In the present study, we investigated the ability of rats to visually recognize mirror, video-recorded, and still images and to discriminate between images of males and females. Rats were tested in a place preference app. with a mirror, a video-recorded image of a rat, or a still image of a rat at one end. The data were assessed using t-test with Bonferroni correction. Male and female rats spent significantly more time in the mirror chamber and the video-recorded image chamber than in their resp. blank chambers (P < 0.05), and male rats also spent more time in the chamber contg. a still image. Furthermore, it was found that male rats exhibited significantly more sniffing behavior around the mirror than in the blank chamber (P < 0.05), whereas female rats were no significant differences in the sniffing behaviors in the mirror, moving or still image expts. Identical results were obtained regardless of whether the rat in the image was the same or opposite sex. These results indicate that rats can process the differences in mirror, video-recorded, and still images as visual information, but are unable to use this information to distinguish between the sexes.

      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXit1elsrfN&md5=bcb9eabe109f2c19e8a4407fc6ca0e83

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      du Jardin, K. G. (2018) S-Ketamine Mediates Its Acute and Sustained Antidepressant-Like Activity through a 5-HT1B Receptor Dependent Mechanism in a Genetic Rat Model of Depression. Front. Pharmacol. 8 , 978,  DOI: 10.3389/fphar.2017.00978

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      Nardou, R. (2019) Oxytocin-dependent reopening of a social reward learning critical period with MDMA. Nature 569 , 116,  DOI: 10.1038/s41586-019-1075-9

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      Oxytocin-dependent reopening of a social reward learning critical period with MDMA

      Nardou, Romain; Lewis, Eastman M.; Rothhaas, Rebecca; Xu, Ran; Yang, Aimei; Boyden, Edward; Dolen, Gul

      Nature (London, United Kingdom) (2019), 569 (7754), 116-120CODEN: NATUAS; ISSN:0028-0836. (Nature Research)

      A crit. period is a developmental epoch during which the nervous system is expressly sensitive to specific environmental stimuli that are required for proper circuit organization and learning. Mechanistic characterization of crit. periods has revealed an important role for exuberant brain plasticity during early development, and for constraints that are imposed on these mechanisms as the brain matures1. In disease states, closure of crit. periods limits the ability of the brain to adapt even when optimal conditions are restored. Thus, identification of manipulations that reopen crit. periods has been a priority for translational neuroscience2. Here we provide evidence that developmental regulation of oxytocin-mediated synaptic plasticity (long-term depression) in the nucleus accumbens establishes a crit. period for social reward learning. Furthermore, we show that a single dose of (+/-)-3,4-methylendioxymethamphetamine (MDMA) reopens the crit. period for social reward learning and leads to a metaplastic upregulation of oxytocin-dependent long-term depression. MDMA-induced reopening of this crit. period requires activation of oxytocin receptors in the nucleus accumbens, and is recapitulated by stimulation of oxytocin terminals in the nucleus accumbens. These findings have important implications for understanding the pathogenesis of neuro-developmental diseases that are characterized by social impairments and of disorders that respond to social influence or are the result of social injury3.

      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXosVSiur8%253D&md5=2cbb7c060ca08076ff43270aae95a37e

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      Chiba, S. (2012) Chronic restraint stress causes anxiety- and depression-like behaviors, downregulates glucocorticoid receptor expression, and attenuates glutamate release induced by brain-derived neurotrophic factor in the prefrontal cortex. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 39 , 112– 119,  DOI: 10.1016/j.pnpbp.2012.05.018

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      38

      Chronic restraint stress causes anxiety- and depression-like behaviors, downregulates glucocorticoid receptor expression, and attenuates glutamate release induced by brain-derived neurotrophic factor in the prefrontal cortex

      Chiba, Shuichi; Numakawa, Tadahiro; Ninomiya, Midori; Richards, Misty C.; Wakabayashi, Chisato; Kunugi, Hiroshi

      Progress in Neuro-Psychopharmacology & Biological Psychiatry (2012), 39 (1), 112-119CODEN: PNPPD7; ISSN:0278-5846. (Elsevier Inc.)

      Stress and the resulting increase in glucocorticoid levels have been implicated in the pathophysiol. of depressive disorders. We investigated the effects of chronic restraint stress (CRS: 6 h × 28 days) on anxiety- and depression-like behaviors in rats and on the possible changes in glucocorticoid receptor (GR) expression as well as brain-derived neurotrophic factor (BDNF)-dependent neural function in the prefrontal cortex (PFC). We obsd. significant redns. in body wt. gain, food intake and sucrose preference from 1 wk after the onset of CRS. In the 5th week of CRS, we conducted open-field (OFT), elevated plus-maze (EPM) and forced swim tests (FST). We obsd. a decrease in the no. of entries into open arms during the EPM (anxiety-like behavior) and increased immobility during the FST (depression-like behavior). When the PFC was removed after CRS and subject to western blot anal., the GR expression reduced compared with control, while the levels of BDNF and its receptors remained unchanged. Basal glutamate concns. in PFC acute slice which were measured by high performance liq. chromatog. were not influenced by CRS. However, BDNF-induced glutamate release was attenuated after CRS. These results suggest that reduced GR expression and altered BDNF function may be involved in chronic stress-induced anxiety- and depression-like behaviors.

      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtFKntL7I&md5=ed33ed1f1ff04c1f09dff2e262fe69a8

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      McLaughlin, K. J. , Gomez, J. L. , Baran, S. E. , and Conrad, C. D. (2007) The effects of chronic stress on hippocampal morphology and function: An evaluation of chronic restraint paradigms. Brain Res. 1161 , 56– 64,  DOI: 10.1016/j.brainres.2007.05.042

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      39

      The effects of chronic stress on hippocampal morphology and function: An evaluation of chronic restraint paradigms

      McLaughlin, Katie J.; Gomez, Juan L.; Baran, Sarah E.; Conrad, Cheryl D.

      Brain Research (2007), 1161 (), 56-64CODEN: BRREAP; ISSN:0006-8993. (Elsevier Ltd.)

      Chronic restraint stress for 6 h/21 days causes hippocampal CA3 apical dendritic retraction, which parallels spatial memory impairments in male rats. Recent research suggests that chronic immobilization stress for 2 h/10 days induces CA3 dendritic retraction and questions whether CA3 dendritic retraction and spatial memory deficits can be produced sooner than found following 6 h/21 days of restraint stress. Therefore, this study investigated the effects of four different durations of chronic restraint stress (varied by hours/day and total no. of days) and the subsequent effects on hippocampal CA3 morphol. and spatial memory in the same male Sprague-Dawley rats. The results showed that only rats exposed to the 6 h/21 days restraint paradigm exhibited CA3 apical dendritic retraction, consistent spatial memory deficits, and decreased body wt. gain compared to exptl. counterparts and controls. While chronically stressing a rat with wire mesh restraint has a phys. component, it acts primarily as a psychol. stressor, and these findings support the interpretation that chronic psychol. stress produces hippocampal-dependent cognitive deficits that are consistent with hippocampal structural changes. Differences in stress effects obsd. across different studies may be due to rat strain, type of stressor, and housing conditions; however, the current findings support the use of chronic restraint stress, with wire mesh, for 6 h/21 days as a reliable and efficient method to produce psychol. stress and to cause CA3 dendritic retraction and spatial memory deficits in male Sprague-Dawley rats.

      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXotVantrw%253D&md5=86c61bd4c6a32bf88acdeeff032db1b5

  40. 40

      Österlund, M. K. , Overstreet, D. H. , and Hurd, Y. L. (1999) The Flinders Sensitive Line rats, a genetic model of depression, show abnormal serotonin receptor mRNA expression in the brain that is reversed by 17β-estradiol. Mol. Brain Res. 74 , 158– 166,  DOI: 10.1016/S0169-328X(99)00274-0

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      40

      The Flinders Sensitive Line rats, a genetic model of depression, show abnormal serotonin receptor mRNA expression in the brain that is reversed by 17β-estradiol

      Osterlund, M. K.; Overstreet, D. H.; Hurd, Y. L.

      Molecular Brain Research (1999), 74 (1,2), 158-166CODEN: MBREE4; ISSN:0169-328X. (Elsevier Science B.V.)

      The possible link between estrogen and serotonin (5-HT) in depression was investigated using a genetic animal model of depression, the Flinders Sensitive Line (FSL) rats, in comparison to control Flinders Resistant Line rats. The mRNA levels of the estrogen receptor (ER) α and β subtypes and the 5-HT1A and 5-HT2A receptors were analyzed in several limbic-related areas of ovariectomized FSL and FRL rats treated with 17β-estradiol (0.15 μg/g) or vehicle. The FSL animals were shown to express significantly lower levels of the 5-HT2A receptor transcripts in the perirhinal cortex, piriform cortex, and medial anterodorsal amygdala and higher levels in the CA 2-3 region of the hippocampus. The only significant difference between the rat lines in ER mRNA expression was found in the medial posterodorsal amygdala, where the FSL rats showed lower ERα expression levels. Overall, estradiol treatment increased 5-HT2A and decreased 5-HT1A receptor mRNA levels in several of the examd. regions of both lines. Thus, in many areas, estradiol was found to regulate the 5-HT receptor mRNA expression in the opposite direction to the alterations found in the FSL rats. These findings further support the implication of 5-HT receptors, in particular the 5-HT2A subtype, in the etiol. of affective disorders. Moreover, the ability of estradiol to regulate the expression of the 5-HT1A and 5-HT2A receptor genes might account for the reported influence of gonadal hormones in mood and depression.

      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXltVeluw%253D%253D&md5=cd89fb4a7f2e28bdf6026cfdf153f207

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      Du Jardin, K. G. , Müller, H. K. , Sanchez, C. , Wegener, G. , and Elfving, B. (2017) Gene expression related to serotonergic and glutamatergic neurotransmission is altered in the flinders sensitive line rat model of depression: Effect of ketamine. Synapse 71 , 37– 45,  DOI: 10.1002/syn.21940

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      Gene expression related to serotonergic and glutamatergic neurotransmission is altered in the Flinders Sensitive Line rat model of depression: Effect of ketamine

      du Jardin, Kristian Gaarn; Mueller, Heidi Kaastrup; Sanchez, Connie; Wegener, Gregers; Elfving, Betina

      Synapse (Hoboken, NJ, United States) (2017), 71 (1), 37-45CODEN: SYNAET; ISSN:0887-4476. (Wiley-Blackwell)

      Major depressive disorder (MDD) is assocd. with dysfunctional serotonergic and glutamatergic neurotransmission, and the genetic animal model of depression Flinders Sensitive Line (FSL) rats display alterations in these systems relatively to their control strain Flinders Resistant Line (FRL). However, changes on transcript level related to serotonergic and glutamatergic signaling have only been sparsely studied in this model. The non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has fast-onset antidepressant properties, and recent data implicate serotonergic neurotransmission in ketamine's antidepressant-like activities in rodents. Here, we investigated the transcript levels of 40 genes involved in serotonergic and glutamatergic neurotransmission in FSL and FRL rats in response to a single dose of ketamine (15 mg/kg; 90 min prior to euthanization). Using real-time quant. polymerase chain reaction, we studied the effect of ketamine in the hippocampus, whereas strain differences were investigated in both hippocampus and frontal cortex. The expression of genes involved in serotonergic and glutamatergic neurotransmission were unaffected by a single dose of ketamine in the hippocampus. Relative to FRL rats, FSL rats displayed enhanced hippocampal transcript levels of 5-ht2c, and P11, whereas the expression was reduced for 5-ht2a, Nr2a, and Mglur2. In the frontal cortex, we found higher transcript levels of 5-ht2c and Mglur2, whereas the expression of 5-ht2a was reduced in FSL rats. Thus, ketamine is not assocd. with hippocampal alterations in serotonergic or glutamatergic genes at 90 min after an antidepressant dose. Furthermore, FSL rats display serotonergic and glutamatergic abnormalities on gene expression level that partly may resemble findings in MDD patients. This article is protected by copyright. All rights reserved.

      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsVGgt7nJ&md5=26cb9718f251912c1aa64b57bc4e28a3

  42. 42

      Jefsen, O. (2019) Psilocybin lacks antidepressant-like effect in the Flinders Sensitive Line rat. Acta Neuropsychiatr. 31 , 213,  DOI: 10.1017/neu.2019.15

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      42

      Psilocybin lacks antidepressant-like effect in the Flinders Sensitive Line rat

      Jefsen Oskar; Hojgaard Kristoffer; Christiansen Sofie Laage; Elfving Betina; Wegener Gregers; Muller Heidi Kaastrup; Nutt David John

      Acta neuropsychiatrica (2019), 31 (4), 213-219 ISSN:.

      OBJECTIVE: Psilocybin is a serotonin receptor agonist with a therapeutic potential for treatment-resistant depression and other psychiatric illnesses. We investigated whether the administration of psilocybin had an antidepressant-like effect in a rat model of depression. METHODS: Using the Flinders Sensitive Line (FSL) rat model of depression, we assessed the antidepressant-like effect of psilocin and psilocybin, measured as a reduction in immobility time in the forced swim test (FST). We measured locomotor activity in an open field test (OFT) to control for stimulant properties of the drugs. We performed a set of experiments to test different doses, treatment paradigms, and timing of the tests in relation to the drug administration. RESULTS: Psilocin and psilocybin showed no effect on immobility, struggling, or swimming behaviour in the FST and no effect on locomotor activity in the OFT. FSL rats did show significantly more immobility than their control strain, the Flinders Resistant Line, as expected. CONCLUSION: Psilocin and psilocybin showed no antidepressant-like effect in the FSL rats, despite a positive effect in humans. This suggests that other animal models of depression and other behavioural tests may be more appropriate for translational studies in the effects of psilocybin.

      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3M7nsFGgtw%253D%253D&md5=e687384dd04667cc17288b43646a1e21

  43. 43

      Lahmame, A. , del Arco, C. , Pazos, A. , Yritia, M. , and Armario, A. (1997) Are Wistar-Kyoto rats a genetic animal model of depression resistant to antidepressants?. Eur. J. Pharmacol. 337 , 115– 123,  DOI: 10.1016/S0014-2999(97)01276-4

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      43

      Are Wistar-Kyoto rats a genetic animal model of depression resistant to antidepressants?

      Lahmame, Abdeljalil; del Arco, Carmen; Pazos, Angel; Yritia, Mercedes; Armario, Antonio

      European Journal of Pharmacology (1997), 337 (2/3), 115-123CODEN: EJPHAZ; ISSN:0014-2999. (Elsevier)

      Wistar-Kyoto rats are reported to be very passive in the forced swimming test. In addn., they did not respond to acute administration of either desipramine or 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). In the present expt., it was studied whether or not they respond to acute and chronic administration of imipramine and the possible relation to down-regulation of β-adrenoceptors and 5-HT1 and 5-HT2 receptors. Sprague-Dawley and Brown-Norway rats were included in the study as it has been previously demonstrated that the two strains respond to acute desipramine and 8-OH-DPAT administration. Whereas acute administration of imipramine (15 mg/kg, three times in a 24 h period) significantly increased struggling and reduced immobility in Sprague-Dawley and Brown Norway rats, Wistar-Kyoto rats failed to respond to the drug. After chronic treatment with imipramine (13 days plus the acute imipramine treatment at the end of the treatment period), the three strains showed a pos. response that was always significantly greater than the response to acute administration, but which was much lower in Wistar-Kyoto than in the other two strains. Down-regulation of both β-adrenoceptors and 5-HT2 receptors was obsd. 24 h after the forced swimming test in acutely and chronically imipramine-treated rats of the three strains, except that in Sprague-Dawley rats β-adrenoceptors did not change after acute imipramine. No significant decrease in 5-HT1 binding sites was obsd. in any strain. Acute imipramine administration caused a similar anorexia in Wistar-Kyoto as in the other strains and at least the same level of down-regulation of β-adrenoceptors and 5-HT2 receptors. In addn., serum imipramine levels on the day after the last drug administration were higher in Wistar-Kyoto than in the other two strains. All these data suggest that the subsensitivity to imipramine obsd. in Wistar-Kyoto rats: (i) can not be primarily explained by pharmacokinetic differences, and (ii) does not appear to be related to the monoaminergic systems. Wistar-Kyoto rats might be therefore not only a good animal model of depressive-like (passive) behavior, but also a model of resistance to antidepressants which could be used to investigate the neurobiol. basis of such resistance, which is also obsd. in some depressed patients.

      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXmsVKlsr0%253D&md5=1ae73e21d902d9ea8e9cb8dfaf9ac9dc

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      Paré, W. P. and Redei, E. (1993) Sex differences and stress response of WKY rats. Physiol. Behav. 54 , 1179– 1185,  DOI: 10.1016/0031-9384(93)90345-G

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      Sex differences and stress response of WKY rats

      Pare W P; Redei E

      Physiology & behavior (1993), 54 (6), 1179-85 ISSN:0031-9384.

      Wistar Kyoto (WKY), Fischer-344 (F-344), and Wistar male and female rats during either proestrus-estrus or diestrus phases of the estrus cycle were exposed to the ulcerogenic procedure of water restraint. Both male and female WKY rats revealed significantly more stomach ulcers as compared to Wistar and F-344 rats of the same sex. No persistent sex difference was observed, but ulcer severity was more pronounced during the proestrus-estrus phase as compared to the diestrus phase of the estrus cycle particularly in WKY female rats. In the second study, WKY females were observed as more active in the open-field test (OFT), but more immobile in the forced swim test (FST), as compared to WKY male rats. In addition, proestrus-estrus WKY females were less active in the OFT and significantly more immobile in the FST as compared to diestrus females. Thus, proestrus-estrus WKY females were judged as more emotional in the OFT and as exhibiting more signs of behavioral depression according to the FST. These studies suggest that the steroid hormone milieu in WKY rats may be responsible for these behavioral changes as well as the stress responsiveness in this stress-susceptible rat strain.

      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK2c7is1Cmug%253D%253D&md5=79b58062942721e5d7211c0dfa2d956c

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      Yamada, M. (2013) Upregulation of the dorsal raphe nucleus-prefrontal cortex serotonin system by chronic treatment with escitalopram in hyposerotonergic Wistar-Kyoto rats. Neuropharmacology 72 , 169– 178,  DOI: 10.1016/j.neuropharm.2013.04.044

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      Upregulation of the dorsal raphe nucleus-prefrontal cortex serotonin system by chronic treatment with escitalopram in hyposerotonergic Wistar-Kyoto rats

      Yamada, Makiko; Kawahara, Yukie; Kaneko, Fumi; Kishikawa, Yuki; Sotogaku, Naoki; Poppinga, Wilfred J.; Folgering, Joost H. A.; Dremencov, Eliyahu; Kawahara, Hiroshi; Nishi, Akinori

      Neuropharmacology (2013), 72 (), 169-178CODEN: NEPHBW; ISSN:0028-3908. (Elsevier B.V.)

      Wistar-Kyoto (WKY) rats are sensitive to chronic stressors and exhibit depression-like behavior. Dorsal raphe nucleus (DRN) serotonin (5-HT) neurons projecting to the prefrontal cortex (PFC) comprise the important neurocircuitry underlying the pathophysiol. of depression. To evaluate the DRN-PFC 5-HT system in WKY rats, we examd. the effects of escitalopram (ESCIT) on the extracellular 5-HT level in comparison with Wistar rats using dual-probe microdialysis. The basal levels of 5-HT in the DRN, but not in the PFC, in WKY rats was reduced as low as 30% of Wistar rats. Responses of 5-HT in the DRN and PFC to ESCIT administered systemically and locally were attenuated in WKY rats. Feedback inhibition of DRN 5-HT release induced by ESCIT into the PFC was also attenuated in WKY rats. Chronic ESCIT induced upregulation of the DRN-PFC 5-HT system in WKY rats, with increases in basal 5-HT in the DRN, responsiveness to ESCIT in the DRN and PFC, and feedback inhibition, whereas downregulation of these effects was induced in Wistar rats. Thus, the WKY rat is an animal model of depression with low activity of the DRN-PFC 5HT system. The finding that chronic ESCIT upregulates the 5-HT system in hyposerotonergic WKY rats may contribute to improved understanding of mechanisms of action of antidepressants, esp. in depression with 5-HT deficiency.

      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtVWgu7fE&md5=8c5e0530ee8fae3a327b2eb5aaf63a33

  46. 46

      Overstreet, D. H. (2012) Modeling Depression in Animal Models. In Psychiatric Disorders ( Kobeissy, F. H. , Ed. ), Vol. 829, pp 125– 144, Humana Press.

  47. 47

      López-Rubalcava, C. and Lucki, I. (2000) Strain differences in the behavioral effects of antidepressant drugs in the rat forced swimming test. Neuropsychopharmacology 22 , 191,  DOI: 10.1016/S0893-133X(99)00100-1

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      Strain differences in the behavioral effects of antidepressant drugs in the rat forced swimming test

      Lopez-Rubalcava C; Lucki I

      Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology (2000), 22 (2), 191-9 ISSN:0893-133X.

      Wistar-Kyoto (WKY) rats provide a model of stress-induced depressive behavior, because they show enhanced vulnerability to the effects of stressors. The present study examined differences in the behavioral response to different types of antidepressant drugs between WKY and Sprague-Dawley (SD) rats in the forced swimming test (FST). WKY rats displayed significantly greater immobility than SD rats during their exposure to the FST. The noradrenergic antidepressant, desipramine, produced a dose-dependent reduction of immobility and increase of climbing behavior in the SD rats. In WKY rats, desipramine reduced immobility at a lower dose and produced increases of both swimming and climbing behavior. The serotonergic compounds, fluoxetine and 8-OH-DPAT, produced dose-dependent reductions of immobility and increases of swimming behavior in the FST in SD rats, but the response to the serotonergic drugs were blunted in WKY rats. These results indicate that genetic or constitutive differences may determine the distinct behavioral profiles for antidepressant compounds with selective pharmacological effects in different rat strains, and these effects may be related to genetic heterogeneity of antidepressant responses in depressed patients.

      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3c7hsVSqsw%253D%253D&md5=9db4767a4ec32bb38535de33c1b4399f

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      De La Garza, R. and Mahoney, J. J. (2004) A distinct neurochemical profile in WKY rats at baseline and in response to acute stress: implications for animal models of anxiety and depression. Brain Res. 1021 , 209– 218,  DOI: 10.1016/j.brainres.2004.06.052

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      48

      A distinct neurochemical profile in WKY rats at baseline and in response to acute stress: implications for animal models of anxiety and depression

      De La Garza, Richard; Mahoney, James J.

      Brain Research (2004), 1021 (2), 209-218CODEN: BRREAP; ISSN:0006-8993. (Elsevier B.V.)

      Wistar-Kyoto (WKY) rats exhibit hyper-responsive neuroendocrine and behavioral responses to stress that exceed normal controls and are esp. prone to develop stress-induced depressive disorder. Pharmacol. studies indicate altered serotonin (5-HT), norepinephrine (NE) and dopamine (DA) systems functioning in WKY rats, yet no attempt has been made to provide a comprehensive assessment of the neurochem. profile for WKY rats as compared to the outbred progenitor controls, Wistar rats. To this end, male, WKY and Wistar rats (N=6/group) were exposed to an acute forced-swim stress or were left untreated as controls. The prefrontal cortex (PFCtx), striatum, nucleus accumbens (NAS), and amygdala were assayed for levels of NE, DA and 5-HT, as well as major metabolites, by HPLC with electrochem. detection. In a sep. expt., designed to assess baseline and stress-induced neuroendocrine activation, male, Wistar and WKY rats (N=6/group) were exposed to an acute forced-swim stress of 15 min or were left untreated as controls. Animals were killed immediately after the test (T=0), 30 min after the test (T=30) or 60 min after the test (T=60), and control animals were killed immediately after weighing. After decapitation, trunk blood was collected and plasma was isolated by centrifugation and analyzed for corticosterone by immunoassay. The neurochem. results demonstrate distinct patterns of baseline and stress-induced monoamine turnover in WKY rats, including alterations to DA and 5-HT turnovers in prefrontal cortex and nucleus accumbens, two crit. brain areas implicated in anxiety, depression and drug reward. The neuroendocrine results indicate that WKY rats exhibited a sustained corticosterone response to acute stress, as compared to Wistar controls. Overall, these data are predicted to be useful for understanding the anxiety- and depressive-like behavioral phenotype exhibited by these animals and for increased understanding of the role genetic background in altering neurochem. function.

      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXntlSntbg%253D&md5=5262a1aa9e61abcdf430768227af3ffc

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      Hurley, L. L. (2013) Antidepressant-like effects of curcumin in WKY rat model of depression is associated with an increase in hippocampal BDNF. Behav. Brain Res. 239 , 27– 30,  DOI: 10.1016/j.bbr.2012.10.049

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      Antidepressant-like effects of curcumin in WKY rat model of depression is associated with an increase in hippocampal BDNF

      Hurley, Laura L.; Akinfiresoye, Luli; Nwulia, Evaristus; Kamiya, Atsushi; Kulkarni, Amol A.; Tizabi, Yousef

      Behavioural Brain Research (2013), 239 (), 27-30CODEN: BBREDI; ISSN:0166-4328. (Elsevier B.V.)

      Curcumin is the principal active ingredient found in turmeric (Curcuma longa), a plant used in traditional Asian diets and herbal medicines. It is known to have a wide range of biol. actions including antidepressant-like effects which have been obsd. in stress-induced depression models. This study was designed to investigate the antidepressant potential of curcumin in a non-induced model of depression. Moreover, since brain derived neurotrophic factor (BDNF) has been implicated in antidepressant effects of many drugs, we also evaluated the effects of curcumin on BDNF in the hippocampus. Adult male Wistar Kyoto (WKY) rats, a putative model of depression, were injected acutely or chronically (10 d) with 50, 100, and 200 mg/kg curcumin. Open field locomotor activity (OFLA) and forced swim test (FST), a measure of helplessness, were measured 1 h after acute and 18-20 h after last chronic injection. Results showed a dose-dependent redn. of immobility in the FST by curcumin in both acute and chronic studies, without any significant effect on OFLA. The effect of higher chronic curcumin dose in FST was still evident a week later. Chronic curcumin also resulted in a dose-dependent increase in hippocampal BDNF. This data provides evidence for an antidepressant-like effect of curcumin, possibly through increased neurotrophic activity, in the WKY model of depression, and support the notion that curcumin may prove an effective and lasting natural antidepressant.

      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvVektbvL&md5=13459e486637b34768f731564056f4e8

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      Paré, W. P. and Tejani-Butt, S. M. (1996) Effect of stress on the behavior and 5-HT system in Sprague-Dawley and Wistar Kyoto rat strains. Integr. Physiol. Behav. Sci. 31 , 112– 121,  DOI: 10.1007/BF02699783

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      Effect of stress on the behavior and 5-HT system in Sprague-Dawley and Wistar Kyoto rat strains

      Pare W P; Tejani-Butt S M

      Integrative physiological and behavioral science : the official journal of the Pavlovian Society (1996), 31 (2), 112-21 ISSN:1053-881X.

      The effects of chronic novel stressors, for 21 days, on the behavior and the serotoninergic (5-HT) system in Sprague-Dawley (SD) and Wistar Kyoto (WKY) rats were studied. Open-field and forced-swim tests revealed a significantly greater behavioral depression in the WKY strain. SD rats showed a decrease in 3H-DPAT binding to 5-HT1A receptors in the hippocampus, whereas WKY rats revealed an increase in 3H-DPAT binding in the hippocampus and hypothalamus. Stress did not appear to alter the binding of 3H-DPAT to 5-HT1A sites in the dorsal raphe or median raphe in either strains. SD rats revealed a modest increase in 5-HT transporter (5-HTT) sites in the cortex; WKY rats revealed a decrease in 5-HTT sites in the cortex and the hippocampus. Stress caused an increase in 3H-CNIMI binding to 5-HTT sites in the dorsal and median raphe nuclei in both strains. The results suggest that the greater susceptibility to behavioral depression in WKY rats may account for the differential effects on 5HT1A sites as well as 5-HTT sites in limbic regions and cell body area as compared to SD rats.

      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK28vgsFCmtw%253D%253D&md5=ea649b7c0158ea698b540e901125f8b7

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      Rittenhouse, P. A. , López-Rubalcava, C. , Stanwood, G. D. , and Lucki, I. (2002) Amplified behavioral and endocrine responses to forced swim stress in the Wistar–Kyoto rat. Psychoneuroendocrinology 27 , 303– 318,  DOI: 10.1016/S0306-4530(01)00052-X

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      Amplified behavioral and endocrine responses to forced swim stress in the Wistar-Kyoto rat

      Rittenhouse Peter A; Lopez-Rubalcava Carolina; Stanwood Gregg D; Lucki Irwin

      Psychoneuroendocrinology (2002), 27 (3), 303-18 ISSN:0306-4530.

      The Wistar Kyoto (WKY) rat may be a useful model for the study of depressive behavior because they exhibit exaggerated responses to a number of stressors. These studies compared the behavioral and endocrine responses to swimming stress in WKY rats with Sprague-Dawley (SD) rats. In the first experiment, the onset of behavioral immobility and the endocrine stress responses (adrenocorticotropin hormone (ACTH) and corticosterone (CORT)) were examined as the duration of a swimming session was increased. In the second experiment, WKY and SD rats were swum for 15 min, then sacrificed at different intervals after completion of the swim, to examine the time course of endocrine stress responses. The final experiment compared the suppression of ACTH and CORT secretion by dexamethasone of peak diurnal ACTH and CORT levels in WKY and SD rats. Behaviorally, the WKY rats displayed early and prolonged immobility compared to SD rats regardless of the length of the swim stress. Plasma CORT and ACTH increased in WKY and SD rats as the duration of the stressor lengthened. The swim stress (15 min) produced higher levels of ACTH and CORT secretion at the end of the stress interval that persisted after termination of the stressor in WKY compared to SD rats. Peak diurnal CORT levels, but not ACTH levels, were higher in WKY than in SD rats. Dexamethasone suppressed ACTH levels less in WKY than in SD rats. These results indicate that the WKY rat that displays increased behavioral immobility also demonstrates exaggerated secretion of stress hormones during swimming stress, and the results may be due, in part, to reduced sensitivity of glucocorticoid receptors that supply negative feedback to the hypothalamic-pituitary-adrenal axis. The exaggerated behavioral and endocrine stress responses in the WKY rat support its potential usefulness as a model for studying stress-evoked depressive behavior.

      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD387pslCltg%253D%253D&md5=a17fc5de4065c63e249a1b6b929ece57

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      Solberg, L. C. , Olson, S. L. , Turek, F. W. , and Redei, E. (2001) Altered hormone levels and circadian rhythm of activity in the WKY rat, a putative animal model of depression. Am. J. Physiol. - Regul. Integr. Comp. Physiol. 281 , R786– R794,  DOI: 10.1152/ajpregu.2001.281.3.R786

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      Carr, G. V. (2010) Antidepressant-Like Effects of κ-Opioid Receptor Antagonists in Wistar Kyoto Rats. Neuropsychopharmacology 35 , 752– 763,  DOI: 10.1038/npp.2009.183

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      Antidepressant-Like Effects of κ-Opioid Receptor Antagonists in Wistar Kyoto Rats

      Carr, Gregory V.; Bangasser, Debra A.; Bethea, Thelma; Young, Matthew; Valentino, Rita J.; Lucki, Irwin

      Neuropsychopharmacology (2010), 35 (3), 752-763CODEN: NEROEW; ISSN:0893-133X. (Nature Publishing Group)

      The Wistar Kyoto (WKY) rat strain is a putative genetic model of comorbid depression and anxiety. Previous research showing increased κ-opioid receptor (KOR) gene expression in the brains of WKY rats, combined with studies implicating the KOR in animal models of depression and anxiety, suggests that alterations in the KOR system could have a role in the WKY behavioral phenotype. Here, the effects of KOR antagonists in the forced swim test (FST) were compared with the WKY and the Sprague-Dawley (SD) rat strains. As previously reported, WKY rats showed more immobility behavior than SD rats. The KOR antagonists selectively produced antidepressant-like effects in the WKY rats. By contrast, the antidepressant desipramine reduced immobility in both strains. Brain regions potentially underlying the strain-specific effects of KOR antagonists in the FST were identified using c-fos expression as a marker of neuronal activity. The KOR antagonist nor-binaltorphimine produced differential effects on the no. of c-fos-pos. profiles in the piriform cortex and nucleus accumbens shell between SD and WKY rats. The piriform cortex and nucleus accumbens also contained higher levels of KOR protein and dynorphin A peptide, resp., in the WKY strain. In addn., local administration of nor-binaltorphimine directly into the piriform cortex produced antidepressant-like effects in WKY rats further implicating this region in the antidepressant-like response to KOR antagonists. These results support the use of the WKY rat as a model of affective disorders potentially involving KOR overactivity and provide more evidence that KOR antagonists could potentially be used as novel antidepressants. Neuropsychopharmacol. (2010) 35, 752-763; doi:10.1038/npp.2009.183; published online 18 Nov. 2009.

      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtlCrurw%253D&md5=fc79000faa07963bcfee949cde4ebd0d

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      McAuley, J. D. (2009) Wistar-Kyoto rats as an animal model of anxiety vulnerability: support for a hypervigilance hypothesis. Behav. Brain Res. 204 , 162– 168,  DOI: 10.1016/j.bbr.2009.05.036

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      Wistar-Kyoto rats as an animal model of anxiety vulnerability: support for a hypervigilance hypothesis

      McAuley J D; Stewart A L; Webber E S; Cromwell H C; Servatius R J; Pang K C H

      Behavioural brain research (2009), 204 (1), 162-8 ISSN:.

      Inbred Wistar-Kyoto (WKY) rats have been proposed as a model of anxiety vulnerability as they display behavioral inhibition and a constellation of learning and reactivity abnormalities relative to outbred Sprague-Dawley (SD) rats. Together, the behaviors of the WKY rat suggest a hypervigilant state that may contribute to its anxiety vulnerability. To test this hypothesis, open-field behavior, acoustic startle, pre-pulse inhibition and timing behavior were assessed in WKY and Sprague-Dawley (SD) rats. Timing behavior was evaluated using a modified version of the peak-interval timing procedure. Training and testing of timing first occurred without audio-visual (AV) interference. Following this initial test, AV interference was included on some trials. Overall, WKY rats took much longer to leave the center of the arena, made fewer line crossings, and reared less, than did SD rats. WKY rats showed much greater startle responses to acoustic stimuli and significantly greater pre-pulse inhibition than did the SD rats. During timing conditions without AV interference, timing accuracy for both strains was similar; peak times for WKY and SD rats were not different. During interference conditions, however, the timing behavior of the two strains was very different. Whereas peak times for SD rats were similar between non-interference and interference conditions, peak times for WKY rats were shorter and response rates higher in interference conditions than in non-interference conditions. The enhanced acoustic startle response, greater prepulse inhibition and altered timing behavior with audio-visual interference supports a characterization of WKY strain as hypervigilant and provides further evidence for the use of the WKY strain as a model of anxiety vulnerability.

      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1MrjvVahtA%253D%253D&md5=9b303ca7058678f601e8a8aecf16b849

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      Pálenícek, T. , Hlinák, Z. , Bubeníková-Valesová, V. , Novák, T. , and Horácek, J. (2010) Sex differences in the effects of N,N-diethyllysergamide (LSD) on behavioural activity and prepulse inhibition. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 34 , 588– 596,  DOI: 10.1016/j.pnpbp.2010.02.008

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      Sex differences in the effects of N,N-diethyllysergamide (LSD) on behavioral activity and prepulse inhibition

      Palenicek, Tomas; Hlinak, Zdenek; Bubenikova-Valesova, Vera; Novak, Tomas; Horacek, Jiri

      Progress in Neuro-Psychopharmacology & Biological Psychiatry (2010), 34 (4), 588-596CODEN: PNPPD7; ISSN:0278-5846. (Elsevier B.V.)

      The aim of this study was to describe sex differences in the behavioral effects of N,N-diethyllysergamide (LSD) (locomotor activity and other behavioral repertoire in the open field) and its effects on sensorimotor gating in rats (prepulse inhibition (PPI) of the acoustic startle reaction). Three groups of animals were analyzed: males, oestral and pro-oestral phase females (EP females), and metoestral and dioestral phase females (MD females). LSD (5, 50 and 200 μg/kg s.c.) attenuated locomotor activity and normal behavioral repertoire, and induced flat body posture, wet dog shakes and disrupted PPI. The most prominent behavioral findings of LSD were for LSD 200 μg/kg which suppressed almost all behavioral activity. LSD had mainly inhibitory locomotor effects in males and MD females, yet in EP female rats LSD increased locomotion during the second half of testing period. The main sex differences were obsd. in locomotor and exploratory behavior. Both EP and MD females were less sensitive to hypolocomotor effects of LSD and had less pronounced thigmotaxis than males. Further EP females had increased rearing after LSD 5 μg/kg. On the contrary although LSD disrupted PPI in males and MD female rats, EP females were protected from this disruptive effect. Thus, EP females seem to have a lower sensitivity to LSD behavioral actions.

      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXlvVSlt7c%253D&md5=ce3b2ef4f09283bb3caf2f8d5acddce2

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      Turner, R. C. (2012) Effects of aging on behavioral assessment performance: implications for clinically relevant models of neurological disease: Laboratory investigation. J. Neurosurg. 117 , 629– 637,  DOI: 10.3171/2012.5.JNS112224

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      Effects of aging on behavioral assessment performance: implications for clinically relevant models of neurological disease

      Turner Ryan C; Seminerio Michael J; Naser Zachary J; Ford J Neal; Martin Samantha J; Matsumoto Rae R; Rosen Charles L; Huber Jason D

      Journal of neurosurgery (2012), 117 (3), 629-37 ISSN:.

      OBJECT: Despite the role of aging in development of neurological and neurodegenerative diseases, the effects of age are often disregarded in experimental design of preclinical studies. Functional assessment increases the clinical relevance of animal models of neurological disease and adds value beyond traditional histological measures. However, the relationship between age and functional impairment has not been systematically assessed through a battery of functional tests. METHODS: In this study, various sensorimotor and behavioral tests were used to evaluate effects of aging on functional performance in naive animals. Sensorimotor measures included locomotor activity; Rotarod, inclined plane, and grip-strength testing; and modified Neurological Severity Score. The Morris water maze was used to examine differences in learning and memory, and the elevated plus maze and forced swim test were used to assess anxiety-like and depressive-like behaviors, respectively. RESULTS: Older Sprague-Dawley rats (18-20 months) were found to perform significantly worse on the inclined plane tests, and they exhibited alterations in elevated-plus maze and forced swim test compared with young adult rats (3-4 months). Specifically, older rats exhibited reduced exploration of open arms in elevated plus maze and higher immobility time in forced swim test. Spatial acquisition and reference memory were diminished in older rats compared with those in young adult rats. CONCLUSIONS: This study demonstrates clear differences between naive young adult and older animals, which may have implications in functional assessment for preclinical models of neurological disease.

      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC38jmtVOntQ%253D%253D&md5=7b153d56a47b74cdc6b8870bf48d6d31

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      Slattery, D. A. and Cryan, J. F. (2012) Using the rat forced swim test to assess antidepressant-like activity in rodents. Nat. Protoc. 7 , 1009– 14,  DOI: 10.1038/nprot.2012.044

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      Using the rat forced swim test to assess antidepressant-like activity in rodents

      Slattery, David A.; Cryan, John F.

      Nature Protocols (2012), 7 (6), 1009-1014CODEN: NPARDW; ISSN:1750-2799. (Nature Publishing Group)

      The forced swim test (FST) is one of the most commonly used animal models for assessing antidepressant-like behavior. This protocol details using the FST in rats, which takes place over 48 h and is followed by the video anal. of the behavior. The swim test involves the scoring of active (swimming and climbing) or passive (immobility) behavior when rodents are forced to swim in a cylinder from which there is no escape. There are two versions that are used, namely the traditional and modified FSTs, which differ in their exptl. setup. For both versions, a pretest of 15 min (although a no. of labs. have used a 10-min pretest with success) is included, as this accentuates the different behaviors in the 5-min swim test following drug treatment. Redn. in passive behavior is interpreted as an antidepressant-like effect of the manipulation, provided it does not increase general locomotor activity, which could provide a false pos. result in the FST.

      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XmsFClsLg%253D&md5=233fde8d745f3edacb78d2a38b6249f9

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      Porsolt, R. D. , Le Pichon, M. , and Jalfre, M. (1977) Depression: a new animal model sensitive to antidepressant treatments. Nature 266 , 730– 732,  DOI: 10.1038/266730a0

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      Depression: a new animal model sensitive to antidepressant treatments

      Porsolt, R. D.; Le Pichon, M.; Jalfre, M.

      Nature (London, United Kingdom) (1977), 266 (5604), 730-2CODEN: NATUAS; ISSN:0028-0836.

      When forced to swim for 5 min in a vertical cylinder contg. water, rats developed a state of immobile resignation to their watery fate; redn. of this state of immobility by iprindole-HCl (40 mg/kg), mianserin-HCl (15 or 30 mg/kg), or viloxazine-HCl (50 mg/kg) showed that the rats were indeed feeling rather depressed. When rats were again placed into the water 24 h later they remained immobile for 75% of the 5-min period; drugs were injected i.p. 24, 5 and 1 h before this second aq. experience. All antidepressants, as well as electroconvulsive shock, reduced immobility, though tricyclic compds. produced sedative effects outside the test situation and mianserin and iprindole at 60 mg/kg did not effect immobility and markedly reduced muscle tonus. (+)-Amphetamine sulfate (0.75-3.0 mg/kg) and caffeine (3.75-15 mg/kg) also reduced immobility.

      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE2sXkvFGhur4%253D&md5=9bbf15ae1f0ddfad654c253a9517a9f6

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      Kokras, N. and Dalla, C. (2014) Sex differences in animal models of psychiatric disorders. Br. J. Pharmacol. 171 , 4595– 4619,  DOI: 10.1111/bph.12710

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      Sex differences in animal models of psychiatric disorders

      Kokras, N.; Dalla, C.

      British Journal of Pharmacology (2014), 171 (20), 4595-4619CODEN: BJPCBM; ISSN:1476-5381. (Wiley-Blackwell)

      Psychiatric disorders are characterized by sex differences in their prevalence, symptomatol. and treatment response. Animal models have been widely employed for the investigation of the neurobiol. of such disorders and the discovery of new treatments. However, mostly male animals have been used in preclin. pharmacol. studies. In this review, we highlight the need for the inclusion of both male and female animals in exptl. studies aiming at gender-oriented prevention, diagnosis and treatment of psychiatric disorders. We present behavioral findings on sex differences from animal models of depression, anxiety, post-traumatic stress disorder, substance-related disorders, obsessive-compulsive disorder, schizophrenia, bipolar disorder and autism. Moreover, when available, we include studies conducted across different stages of the oestrous cycle. By inspection of the relevant literature, it is obvious that robust sex differences exist in models of all psychiatric disorders. However, many times results are conflicting, and no clear conclusion regarding the direction of sex differences and the effect of the oestrous cycle is drawn. Moreover, there is a lack of considerable amt. of studies using psychiatric drugs in both male and female animals, in order to evaluate the differential response between the two sexes. Notably, while in most cases animal models successfully mimic drug response in both sexes, test parameters and treatment-sensitive behavioral indexes are not always the same for male and female rodents. Thus, there is an increasing need to validate animal models for both sexes and use std. procedures across different labs. Linked Articles : This article is part of a themed section on Animal Models in Psychiatry Research. To view the other articles in this section visit.

      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1Sqtr3K&md5=3c51690f5b89e3b7f93f2d973d86a405

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      Dalla, C. , Pitychoutis, P. M. , Kokras, N. , and Papadopoulou-Daifoti, Z. (2010) Sex Differences in Animal Models of Depression and Antidepressant Response. Basic Clin. Pharmacol. Toxicol. 106 , 226– 233,  DOI: 10.1111/j.1742-7843.2009.00516.x

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      Sex differences in animal models of depression and antidepressant response

      Dalla, Christina; Pitychoutis, Pothitos M.; Kokras, Nikolaos; Papadopoulou-Daifoti, Zeta

      Basic & Clinical Pharmacology & Toxicology (2010), 106 (3), 226-233CODEN: BCPTBO; ISSN:1742-7835. (Wiley-Blackwell)

      A review. Many stress-related mental disorders, including depression and post-traumatic stress disorder occur more often in women than in men. While social and cultural factors certainly contribute to these differences, neurobiol. sex differences seem to also play an important role. A rapidly burgeoning literature from basic and clin. research documents sex differences in brain anatomy, chem. and function, as well as in stress and drug responses. For example, some clin. studies have reported that women may have a better outcome when treated with selective serotonin re-uptake inhibitors, in comparison to tricyclic antidepressants. Furthermore, relatively limited basic research has been devoted to developing animal models and consequently describing drug treatments which are sensitive to sex differences. In this MiniReview, we discuss sex differences in behavioral aspects, as well as neurochem., neurobiol. and pharmacol. findings that we have collected from several different animal models and tests of depression. These are the forced swim test, the chronic mild stress and the learned helplessness models, the Flinders sensitive line rats, which is a genetic model of depression and the lipopolysaccharide-induced sickness behavior, a putative inflammatory model of depression. Collectively, our data have shown that in all animal models assayed, serotonergic neurochem. responses were differently affected in males and females, ultimately producing sex-dependent behavioral effects. In addn., Flinders sensitive line rats exhibited a sexually dimorphic response to chronic antidepressant treatment. These sex-differentiated neurochem. and behavioral alterations lend support to a major role of serotonin in the mediation of sexually dimorphic responses.

      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXivVShtbk%253D&md5=530cad79456109d2ba080f73fd37cf4c

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      Brenes Sáenz, J. C. , Villagra, O. R. , and Fornaguera Trías, J. (2006) Factor analysis of Forced Swimming test, Sucrose Preference test and Open Field test on enriched, social and isolated reared rats. Behav. Brain Res. 169 , 57– 65,  DOI: 10.1016/j.bbr.2005.12.001

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      Factor analysis of Forced Swimming test, Sucrose Preference test and Open Field test on enriched, social and isolated reared rats

      Brenes Saenz Juan Carlos; Villagra Odir Rodriguez; Fornaguera Trias Jaime

      Behavioural brain research (2006), 169 (1), 57-65 ISSN:0166-4328.

      Developmental and social factors are known to play a crucial role in the pathogenesis of affective disorders. Although it has been demonstrated that early life aversive experiences can be a risk factor in the development of human depression, most of the investigation in animals that try to model depression do not include postnatal manipulations. Since housing represents a fundamental ethological factor which modifies behavior and brain development, this study aimed to investigate the impact of different social and structural housing conditions on the development of a depressive-like syndrome in the behavioral despair paradigm and an anxiety-like syndrome in the unconditioned anxiety paradigm. The present study uses several multivariate analyses to study the impact of housing conditions in animal models of depression and anxiety. In this study, social isolation was able to reproduce the effects found in other animals models based on stress, suggesting that only 2 months of social isolation are enough to produce effects that can be useful as behavioral model of depression. Moreover, environmental enrichment showed an antidepressive and anxiolytic like effect in animal models of depression and anxiety. This effect, which has not been reported in earlier studies, suggests that stimulation during the first stages of growth might play a "protective" role on behavior and brain development.

      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD287hs1Cjuw%253D%253D&md5=c5518c89a4965051914d869c93645af4

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      Hibicke, M. , Graham, M. A. , and Hayslett, R. L. (2017) Adolescent chronic restraint stress (aCRS) elicits robust depressive-like behavior in freely cycling, adult female rats without increasing anxiety-like behaviors. Exp. Clin. Psychopharmacol. 25 , 74– 83,  DOI: 10.1037/pha0000119

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      Adolescent chronic restraint stress (aCRS) elicits robust depressive-like behavior in freely cycling, adult female rats without increasing anxiety-like behaviors

      Hibicke, Meghan; Graham, Martha A.; Hayslett, Renee L.

      Experimental and Clinical Psychopharmacology (2017), 25 (2), 74-83CODEN: ECLPES; ISSN:1936-2293. (American Psychological Association)

      Stress during times of rapid development is a risk factor for Major Depressive Disorder, a mood disorder that disproportionately affects women. We developed an adolescent chronic restraint stress (aCRS) protocol using female rats to address the impact of adolescent stress on female adult depressive-like behavior. Animals were divided into 4 treatment groups: not restrained:saline (NRSAL), not restrained: desipramine (NRDES), restrained:saline (RSAL), and restrained:desipramine (RDES). NRSAL and NRDES rats were housed in a sep. colony room from RSAL and RDES rats. All animals were weighed and handled daily. Beginning postnatal day (PND) 34(±1), RSAL and RDES rats were restrained for 1 h daily for 14 consecutive days. Beginning PND 55(±1), NRDES and RDES rats were given s.c. desipramine (5 mg/kg), which served as a pos. control, daily for 14 consecutive days. During that same time period, NRSAL and RSAL rats were given s.c. saline daily. aCRS (RSAL and RDES) rats showed significantly attenuated wt. gain compared with nonrestrained (NRSAL and NRDES) rats during the restraint period. Wt. gain normalized after the final restraint session. Behavioral testing took place PND 68-69(±1), and included open field testing, the elevated plus maze, locomotor activity, and the forced swim test (FST). RSAL rats showed significantly more immobility in the FST vs. all other groups, indicating depressive-like behavior. No differences between groups were obsd. in the other behavioral measures. These results indicate that aCRS elicits depressive-like behavioral characteristics in adult female rats without increasing anxiety-like behaviors.

      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsFCmt7%252FP&md5=c98cc433f495c4cb7173fbcc3bf833f3

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      Hibicke, M. (2017) Development and Evaluation of an Adolescent Chronic Restraint Stress (ACRS) Protocol to Model Adult Depression in Female Rats. Ph.D. Thesis, Mercer University.

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      Kandi, P. , Hibicke, M. , and Hayslett, R. L. (2015) Acute Cytisine and Diarylpropionitrile Independently and Additively Reduce Depressive-Like Behavior in Female Ovariectomized Rats. J. Pharm. Sci. Pharmacol 2 , 250– 258,  DOI: 10.1166/jpsp.2015.1064

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      Mezadri, T. J. , Batista, G. M. , Portes, A. C. , Marino-Neto, J. , and Lino-de-Oliveira, C. (2011) Repeated rat-forced swim test: reducing the number of animals to evaluate gradual effects of antidepressants. J. Neurosci. Methods 195 , 200– 205,  DOI: 10.1016/j.jneumeth.2010.12.015

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      Repeated rat-forced swim test: Reducing the number of animals to evaluate gradual effects of antidepressants

      Mezadri, T. J.; Batista, G. M.; Portes, A. C.; Marino-Neto, J.; Lino-de-Oliveira, C.

      Journal of Neuroscience Methods (2011), 195 (2), 200-205CODEN: JNMEDT; ISSN:0165-0270. (Elsevier B.V.)

      The forced swim test (FST) is a pre-clin. test to short and long term treatment with antidepressant drugs (ADT), which requires between-subject designs. Herein a modified protocol of the FST using within-subject design (repeated rat-FST) was evaluated. Male Wistar rats were submitted to 15 min of swimming (Day 1: pretest) followed by three subsequent 5 min-swimming tests one week apart (Day 2: test, Day 7: retest 1, Day 14: retest 2). To det. the temporal and factorial characteristics of the variables scored in the repeated rat-FST, the protocol was carried out in untreated animals (E1). To validate the method, daily injections of Fluoxetine (FLX, 2.5 mg/kg, i.p.) or saline were given over a 2-wk period (E2). Tests and retests have been videotaped for further register of the latency, frequency and duration of behaviors. Over retesting the latency to immobility decreased whereas duration of immobility tended to increase. Factorial anal. revealed that the test, the retest 1 as well as the retest 2 have variables suitable to detection of antidepressant-like effects of ADT. Compared to saline, FLX chronically administrated reduced duration of immobility whereas increased duration of swimming in retest 2. The data suggest that repeated rat-FST detected the gradual increase in the efficacy of low doses of FLX over time. Therefore, repeated rat-FST seemed suitable to detect short and long term effects of selective serotonin reuptake inhibitors, or other ADT, thus reducing the no. of animals used in the screenings of this type of compds.

      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtVKlsrY%253D&md5=689fced471a4fa4ec1c0a68818b3f7b3

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      Sengupta, P. (2013) The Laboratory Rat: Relating Its Age With Human's. Int. J. Prev. Med. 4 , 624– 630

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      The Laboratory Rat: Relating Its Age With Human's

      Sengupta Pallav

      International journal of preventive medicine (2013), 4 (6), 624-30 ISSN:2008-7802.

      By late 18(th) or early 19(th) century, albino rats became the most commonly used experimental animals in numerous biomedical researches, as they have been recognized as the preeminent model mammalian system. But, the precise correlation between age of laboratory rats and human is still a subject of debate. A number of studies have tried to detect these correlations in various ways, But, have not successfully provided any proper association. Thus, the current review attempts to compare rat and human age at different phases of their life. The overall findings indicate that rats grow rapidly during their childhood and become sexually mature at about the sixth week, but attain social maturity 5-6 months later. In adulthood, every day of the animal is approximately equivalent to 34.8 human days (i.e., one rat month is comparable to three human years). Numerous researchers performed experimental investigations in albino rats and estimated, in general, while considering their entire life span, that a human month resembles every-day life of a laboratory rat. These differences signify the variations in their anatomy, physiology and developmental processes, which must be taken into consideration while analyzing the results or selecting the dose of any research in rats when age is a crucial factor.

      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3sfot1Kltg%253D%253D&md5=f2f301068ed0c0bf70c630355f374dcb

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      Walf, A. A. and Frye, C. A. (2007) The use of the elevated plus maze as an assay of anxiety-related behavior in rodents. Nat. Protoc. 2 , 322– 328,  DOI: 10.1038/nprot.2007.44

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      The use of the elevated plus maze as an assay of anxiety-related behavior in rodents

      Walf, Alicia A.; Frye, Cheryl A.

      Nature Protocols (2007), 2 (2), 322-328CODEN: NPARDW; ISSN:1750-2799. (Nature Publishing Group)

      The elevated plus maze is a widely used behavioral assay for rodents and it has been validated to assess the anti-anxiety effects of pharmacol. agents and steroid hormones, and to define brain regions and mechanisms underlying anxiety-related behavior. Briefly, rats or mice are placed at the junction of the four arms of the maze, facing an open arm, and entries/duration in each arm are recorded by a video-tracking system and observer simultaneously for 5 min. Other ethol. parameters (i.e., rears, head dips and stretched-attend postures) can also be obsd. An increase in open arm activity (duration and/or entries) reflects anti-anxiety behavior. In our lab., rats or mice are exposed to the plus maze on one occasion; thus, results can be obtained in 5 min per rodent.

      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtFGntbvP&md5=fa92de73215d02cdbfda885e84d985a8

• Supporting Information

  Supporting Information

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  The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acschemneuro.9b00493.

  • Open field locomotor activity (PDF)

  • Summary of significant results from relevant comparisons made during the four experiments presented (PDF)

  • cn9b00493_liveslides.mp4 (7.15 MB)
  • cn9b00493_si_001.pdf (937.27 kb)
  • cn9b00493_si_002.pdf (71.22 kb)

  
  

  Terms & Conditions

  Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

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Source: https://pubs.acs.org/doi/10.1021/acschemneuro.9b00493

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