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

Jefsen, Oskar Hougaard; Højgaard, Kristoffer; Christiansen, Sofie Laage; Elfving, Betina; Nutt, David; Wegener, Gregers; Müller, Heidi Kaastrup

doi:10.1017/neu.2019.15

Cited by 46 publications

(50 citation statements)

References 45 publications

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“…[13][14][15][16][17][18][19] Additional studies assessing antidepressant-like and anxiolytic-like effects following treatment with 5-HT2AR agonists in rodent behavioral tests like the Forced Swim Test (FST), Open Field Test (OFT), and Elevated Plus Maze (EPM) have also emerged more recently. [19][20][21][22][23][24][25][26] The observed results have sometimes been consistent with interpretations of antidepressant-like or anxiolytic-like activity, such as reductions in FST immobility time and increased open arm time in the EPM. However, there have also been results that are inconsistent with this interpretation, such as a lack of effect on FST in Flinders' Sensitive Rats for up to a week after single or repeated psilocybin dosing.…”

Section: Introductionsupporting

confidence: 74%

“…However, there have also been results that are inconsistent with this interpretation, such as a lack of effect on FST in Flinders' Sensitive Rats for up to a week after single or repeated psilocybin dosing. [25] While differences in dosing strategies, species, strains, and outcome measures certainly account for some of this variability in the observed outcomes of pre-clinical studies to date, the experimental model chosen also likely has a substantial impact. Indeed, no universal animal model exists for MDD or anxiety disorders, and even clinically-validated antidepressants exhibit differing levels and time courses of activity across the various models available.…”

Section: Introductionmentioning

confidence: 99%

“…However, there have also been results that are inconsistent with this interpretation, such as a lack of effect on FST in Flinders’ Sensitive Rats for up to a week after single or repeated psilocybin dosing. [25]…”

Section: Introductionmentioning

confidence: 99%

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Delayed Anxiolytic-Like Effects of Psilocybin in Male Mice Are Supported by Acute Glucocorticoid Release

Jones

Zahid

Grady

et al. 2020

Preprint

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Psilocybin has shown positive preliminary signals in small-scale clinical trials for psychiatric disorders that exhibit maladaptive stress responses as a major component of their presentation. However, there are relatively few assessments of whether an acute administration of psilocybin exhibits reproducible effects in rodent models useful for the study of stress-associated psychiatric disorders. Here, we measured the responses of male C57BL/6J mice to this compound in a battery of relevant behavioral tests. These tests included the open-field test, forced swim test, sucrose preference test, and novelty suppressed feeding test. Furthermore, these tests were presented in either the absence or presence of chronic corticosterone administration, as a chemically induced model of ongoing stress burden. Our results indicate that the effects of psilocybin within these tests are dependent on the chronic hormonal stress burden of the mice: psilocybin alone promotes anxiolytic and hedonic responses, but promotes anxiogenic and anhedonic responses when pre-treated with chronic corticosterone. This identified interaction between stress hormone burden and psilocybin behavioral effects in mice suggests the possibility of further developing rodent behavioral models that can assess additional context-dependent effects of psychedelic administration that are deemed clinically-relevant, but are otherwise difficult to control for, in human studies.

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Section: Introductionsupporting

confidence: 74%

Section: Introductionmentioning

confidence: 99%

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Delayed Anxiolytic-Like Effects of Psilocybin in Male Mice Are Supported by Acute Glucocorticoid Release

Jones

Zahid

Grady

et al. 2020

Preprint

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“…Each FSL or FRL rat was exposed to the FST immediately after the OFT. FST was performed as previously described, using a modified version of the original protocol defined by Porsolt, and used earlier in our laboratory (Jefsen et al, 2019; Liebenberg et al, 2015; Pereira et al, 2019a; Pereira et al, 2019b). Briefly, the animals were exposed to a 10 min test in a Perspex cylinder (height 60 cm, diameter 24 cm) filled with water (25°C), up to a height of 40 cm.…”

Section: Experimental Designmentioning

confidence: 99%

Antidepressant-like effect induced by P2X7 receptor blockade in FSL rats is associated with BDNF signalling activation

et al. 2019

Self Cite

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Background: P2X7 receptors (P2X7R) are ligand-gated ion channels activated by adenosine 5’-triphosphate (ATP), which are involved in processes that are dysfunctional in stress response and depression, such as neurotransmitter release, and neuroimmune response. Genetic and pharmacological inhibition of the P2X7R induce antidepressant-like effects in animals exposed to stress. However, the effect of P2X7R antagonism in an animal model of depression based on selective breeding has not previously been studied, and the mechanism underling the antidepressant-like effect induced by the P2X7R blockade remains unknown. Aims: The present study aimed to: (1) determine whether P2X7R blockade induces antidepressant-like effects in the Flinders Sensitive Line (FSL) rats and, (2) investigate whether brain-derived neurotrophic factor (BDNF) signalling in the frontal cortex and hippocampus is involved in this effect. Methods: FSL and the control Flinders Resistant Line (FRL) rats were treated with vehicle or the P2X7R antagonist A-804598 (3, 10 or 30 mg/Kg/day) for 1 or 7 days before being exposed to the forced swim test (FST). After the behavioural test, animals were decapitated, their brains were removed and the frontal cortex, ventral and dorsal hippocampus were dissected for BDNF signalling analysis. Results: We found that repeated treatment with A-804598 (30 mg/Kg) reduced the immobility time in the FST and activated the BDNF signalling in the ventral hippocampus of FSL rats. Conclusions: P2X7R blockade induces an antidepressant-like effect associated with increased levels of BDNF-AKT-p70 S6 kinase in the ventral hippocampus, which may be mediated by tropomyosin-related kinase B (TRKB) receptor activation supporting the notion of P2X7R antagonism as a potential new antidepressant strategy.

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“…Authors noted that they might have used an inappropriate model-Flinders Sensitive Line, a strain developed for the screening of antidepressant drugs. They further hypothesized that low basal expression of 5-HT 2A R in the frontal cortex and hippocampus in this strain was potentially responsible for negative results [64]. Remarkably, these substances produce positive effects hours to days after administration, despite the fact that they are cleared out in minutes to hours.…”

Section: Animal Studiesmentioning

confidence: 96%

Natural Psychoplastogens As Antidepressant Agents

Vrankova

2020

Molecules

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Increasing prevalence and burden of major depressive disorder presents an unavoidable problem for psychiatry. Existing antidepressants exert their effect only after several weeks of continuous treatment. In addition, their serious side effects and ineffectiveness in one-third of patients call for urgent action. Recent advances have given rise to the concept of psychoplastogens. These compounds are capable of fast structural and functional rearrangement of neural networks by targeting mechanisms previously implicated in the development of depression. Furthermore, evidence shows that they exert a potent acute and long-term positive effects, reaching beyond the treatment of psychiatric diseases. Several of them are naturally occurring compounds, such as psilocybin, N,N-dimethyltryptamine, and 7,8-dihydroxyflavone. Their pharmacology and effects in animal and human studies were discussed in this article.

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

Cited by 46 publications

References 45 publications

Delayed Anxiolytic-Like Effects of Psilocybin in Male Mice Are Supported by Acute Glucocorticoid Release

Delayed Anxiolytic-Like Effects of Psilocybin in Male Mice Are Supported by Acute Glucocorticoid Release

Antidepressant-like effect induced by P2X7 receptor blockade in FSL rats is associated with BDNF signalling activation

Natural Psychoplastogens As Antidepressant Agents

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