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.

Introduction: 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. Methods: 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. Results: 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 ( Conclusions: 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.