A Single Administration of Psilocybin Persistently Rescues Cognitive Deficits Caused by Adolescent Chronic Restraint Stress Without Long-Term Changes in Synaptic Protein Gene Expression in a Rat Experimental System with Translational Relevance to Depression.
Meghan Hibicke, Hannah M. Kramer, Charles D. Nichols
Psychedelic Medicine March 1, 2023 DOI: 10.1089/psymed.2022.0012 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized controlled trial Peer reviewed |
|---|---|
| Population | Adult female rats subjected to adolescent chronic restraint stress |
| Intervention | Psilocybin |
| Duration | 14-day restraint period, single administration on day 21, behavioral testing on days 51-58, sacrifice on day 63 |
| Topics | Depression Psilocybin |
| Keywords | Adolescent stress Pattern separation Psychedelics Psychedelic medicine Hallucinogens Behavioral therapy Psychiatric care Cognitive function memory Brain function Stress disorders trauma |
| Citations | 25 |
| Key findings | A single psilocybin administration rescued cognitive function and reduced passive coping in stressed rats for at least five weeks without altering synaptic plasticity gene expression. |
Abstract
Psilocybin has shown long-lasting antidepressant effects in preclinical and clinical trials, but the mechanisms responsible are unclear. As both passive coping strategies and pattern separation deficits are characteristics of major depression, we used adult female rats subjected to adolescent chronic restraint stress (aCRS) to investigate the effects of psilocybin on forced swim test (FST) and object pattern separation (OPS) behaviors 5 weeks after a single administration. Adolescent rats were randomly assigned to one of four treatment groups-not restrained/saline, not restrained/psilocybin, restrained/saline, and restrained/psilocybin. Restrained group rats were restrained for 1 h daily from day 1 through day 14. Saline and psilocybin were administered on day 21, OPS was evaluated on days 51-55, forced swim behavior was evaluated on day 57 or 58, and animals were sacrificed on day 63. Brains were removed and the medial prefrontal cortex, dorsal dentate gyrus, dorsal CA3 hippocampal area, and ventral hippocampus were microdissected out and prepared for mRNA analysis of a panel of genes relevant to synaptic plasticity using quantitative polymerase chain reaction. Psilocybin rescued cognitive function in aCRS rats in both assays, but did not affect either measure in nonstressed rats. Immobility in the FST was correlated with impaired discrimination ability in the OPS. No differences in mRNA expression for a panel of genes related to structural synaptic proteins were observed between groups, although stress was a significant contributor to variability of the gene for glutamate metabotropic receptor 2 (Grm2) in two hippocampal regions. Our data indicate that aCRS and OPS represent a powerful system with translational relevance to study depression, and that a single treatment with psilocybin has long-lasting antidepressant-like effects without long-term alterations of mRNA related to synaptic density in brain areas relevant to depression.
Comparable studies
Other preclinical and animal studies on psilocybin for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psychedelics, but Not Ketamine, Produce Persistent Antidepressant-like Effects in a Rodent Experimental System for the Study of Depression Rats | 2020 | Preclinical study | |
| 5-HT2ARs Mediate Therapeutic Behavioral Effects of Psychedelic Tryptamines. Rodents | 2023 | Experimental study | |
| Psilocybin lacks antidepressant-like effect in the Flinders Sensitive Line rat Flinders Sensitive Line rats and Flinders Resistant Line rats | 2019 | Experimental study | |
| Psilocybin Facilitates Fear Extinction: Importance of Dose, Context, and Serotonin Receptors Male and female mice | 2024 | Experimental study | |
| Rapid-acting antidepressant drugs modulate affective bias in rats Rats | 2024 | Experimental animal study |
Citations in the library
Cited by 24
- Therapeutic mechanisms of psychedelics and entactogens. Neuropsychopharmacology July 24, 2023
- Preclinical perspectives on the mechanisms underlying the therapeutic actions of psilocybin in psychiatric disorders Neuropharmacology March 13, 2023
- Epigenetic mechanisms of rapid-acting antidepressants Translational Psychiatry September 4, 2024
- Unraveling psilocybin's therapeutic potential: behavioral and neuroplasticity insights in Wistar-Kyoto and Wistar male rat models of treatment-resistant depression. Psychopharmacology July 4, 2024
- Psilocybin as a lead candidate molecule in preclinical therapeutic studies of psychiatric disorders: A systematic review Journal of Neurochemistry November 29, 2023
and 19 more in the library
Cites 30
- Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial Journal of Psychopharmacology November 30, 2016
- Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. The Lancet Psychiatry May 17, 2016
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial Psychological Medicine June 15, 2018
- Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms. Scientific Reports October 13, 2017
and 25 more in the library