Acute but not long-lasting antidepressant-like effect of psilocybin in differential reinforcement of low-rate 72 schedule in rats

Psilocybin, but not LSD, produced an immediate antidepressant-like effect in rats tested on a differential reinforcement of low-rate responding (DRL 72s) schedule, shown by increased reinforced presses and response efficiency. Neither drug showed lasting effects up to four weeks after administration. The DRL 72s test, which reliably distinguishes antidepressants from other psychoactive drugs, detected only acute changes. These results suggest that detecting sustained antidepressant-like effects in rodents may require new behavioral methods, and question whether prolonged efficacy observed in humans depends on the psychotherapy typically paired with psychedelic treatment.

Study at a glance

Abstract

Background: In clinical studies, psychedelics including psilocybin and D-lysergic acid diethylamide (LSD) demonstrate rapid and persistent antidepressant effects. Since the effective treatment with psychedelics is usually provided with psychotherapy, it is debatable whether their prolonged efficacy can be observed in infrahuman species. Preclinical reports on psychedelics’ effects most often address their acute actions, and different tests and models provide inconsistent results. The goal of this study was to examine whether the treatment with psilocybin and/or LSD would demonstrate immediate and/or sustained antidepressant-like effects in the differential reinforcement of low-rate responding (DRL) schedule in rats. In contrast to the antidepressant screening tools, the DRL 72s test is known to detect antidepressants with high predictive validity as it differentiates clinically effective antidepressants from other psychoactive drugs in non-stressed animals. Methods: Adult male Sprague Dawley rats were injected over three consecutive days with psilocybin (1 mg/kg), LSD (0.08 mg/kg), or saline and then tested in DRL 72s for the following 4 weeks. Results: Treatment with psilocybin but not LSD demonstrated an immediate antidepressant-like effect, manifested as an increased number of reinforced presses and response efficiency. By contrast, neither of the drugs showed a long-term (up to 4 weeks following administration) antidepressant-like effect. Conclusions: Using DRL 72s schedule of reinforcement, we demonstrated the acute antidepressant-like effect of psilocybin but not of LSD, and failed to detect their persistent antidepressant-like efficacy. The present study suggests that the detection of long-lasting antidepressant-like activity in rats could be challenging and may require entirely novel behavioral methods.