One Dose of Psilocybin in Late Adolescence Mitigates Deleterious Effects of Developmental Stress on Cognition and Behavioral Despair in Adult Female Rats

Introduction: Psilocybin (PSI) has persistent antidepressant efficacy in human trials. We have shown one dose of PSI to significantly decrease depressive‐like behavior in male Wistar‐Kyoto (WKY) rats for at least five weeks without losing efficacy. However, the outcome assay we used to evaluate depressive‐like behavior, the forced swim test (FST), has been criticized for not providing circuit‐specific endpoint data. Further, rodent strains like WKY selectively bred for face validity in modeling depression have lower translational value than chronic/developmental stress models. Pattern separation is a function of the dentate gyrus (DG) and CA3 region of the hippocampus. Pattern separation deficits are measurable in a number of psychological and neurological disorders where the DG‐CA3 circuit is impaired, including major depressive disorder, schizophrenia, and age‐related dementias. The object pattern separation (OPS) task is a new paradigm to measure DG‐CA3 function in rodents, proposed as a cognitive‐based outcome measure for depression‐like phenotypes, but so far only used in healthy male animals. Whether OPS performance correlates with established measures of behavioral despair, or can be normalized by human pharmacotherapies, is unknown.

Objectives: Evaluate long‐term antidepressant‐like effects of PSI in the stress‐based adolescent chronic restraint stress (aCRS) model for depression, establish face and predictive validity of the OPS task, and determine whether OPS correlates with FST immobility in aCRS rats.

Methods: Adolescent female Sprague Dawley rats were assigned to groups: not restrained‐saline (NRS), not restrained‐PSI (NRP), restrained‐saline (RS), and restrained‐PSI (RP). RS and RP rats were restrained 1 hr/day post‐natal days (PND) 32–45. Rats received IP PSI (1 mg/kg) or saline PND 52. The OPS task was performed nightly PND 82 (0 cm) – 86 (24 cm) in a 66 cm diameter arena containing two identical objects, one of which was moved from 0 cm to 6, 12, 18, and 24 cm from 0 following an hour intertrial interval. FST was performed PND 89–90.

Results: Significant discrimination in the OPS at 24 cm was observed in NRS ( p <0.001), NRP ( p <0.0001), and RP ( p <0.01), but RS rats were unable to discriminate between moved and stationary objects. RS rats were significantly more immobile in the FST than NRS rats ( p <0.0001). No differences were observed between NRS, NRP, and RP rats. Immobility in the FST was inversely correlated to discrimination in the OPS at 24 cm (r=−0.402, p =0.023).

Conclusions: The OPS is a translationally relevant outcome with face and predictive validity, correlates with an established measure of depressive‐like behavior, and can be used in female rats. One dose of PSI in late adolescence mitigates cognitive and behavioral deficiencies characteristic of the developmentally‐stressed adult aCRS rat model for depression. Our aCRS model is uniquely suitable for elucidating the antidepressant mechanisms of PSI, which has translationally relevant antidepressant‐like effects that can be measured using the OPS task, many weeks after administration. Support or Funding Information This work supported by Eleusis, PBC.