Stress history determines psilocybin’s effects on fear extinction in male adolescent rats

Background: Recent work suggests that psilocybin, a hallucinogenic 5-HT 2A R agonist with rapid and long-lasting anti-depressant actions, facilitates fear extinction retention in adult rodents. However, psilocybin’s effects on adolescent fear extinction are unknown. Further, chronic stress in adolescence predisposes individuals to developing psychopathologies such as anxiety and fear-related disorders, and also reduces the efficacy of several pharmacological adjuncts. Here we examined whether psilocybin enhances fear extinction in adolescent rats, like in adults, and whether chronic stress alters its efficacy.

Methods: Male adolescent rats were given pairings of an innocuous auditory cue with an aversive foot-shock. Study 1 involved non-stressed animals whereas Study 2 involved “stressed” animals (i.e., corticosterone-exposed). Both studies tested whether a single psilocybin dose enhanced fear extinction 24-hours after dosing.

Results: A moderate dose of psilocybin (1.5 mg/kg) impaired both extinction learning and retention in non-stressed adolescent rats, but a higher (3 mg/kg) or lower dose (0.5 mg/kg) had no effect. The opposite pattern was observed in “stressed” adolescents, with both a higher (3 mg/kg) and lower (0.5 mg/kg), but not a moderate (1.5 mg/kg) dose enhancing extinction retention. Extinction learning in stressed adolescents, however, was unaffected by psilocybin.

Conclusions: Our findings suggest that unlike adults, psilocybin impairs extinction in non-stressed male adolescents. However, chronic stress in adolescence alters psilocybin’s effects, resulting in enhanced extinction retention. Taken together, this work suggests that psilocybin could be an effective adjunct to extinction-based therapies for reducing fear in adolescent stress-related disorders but may be prescribed at a different dose to adults.