Preadministration of Lorazepam Negates the Long-Term Antidepressant-Like Effects of Psilocybin in Male Wistar Kyoto Rats

Introduction:Psilocybin, a classical psychedelic, has shown to produce persistent antidepressant effects, including in patients with treatment-resistant depression. In clinical practice, it is common to coprescribe benzodiazepines (BZDs) alongside antidepressants. However, our preliminary study indicated that preadministration of lorazepam diminished the antidepressant-like efficacy and longevity of psilocin. These results raise concern about the potential reduction of therapeutic benefits in psilocybin-assisted therapy for patients concurrently prescribed BZDs. The current study aimed to confirm these results while exploring psilocybin’s long-term effects on neuroplasticity-related gene expression in the medial prefrontal cortex. Methods:Male Wistar Kyoto rats were given saline (S/S), lorazepam (L/S), psilocybin (S/P), or lorazepam followed by psilocybin (L/P). Treatments were delivered as two intraperitoneal injections separated by 30 min. Rats were tested in the forced swim test at 3, 5, 7, 9, and 11 weeks post-treatment. Tissue punches from the anterior cingulate cortex, prelimbic cortex (PL), and infralimbic cortex were collected for quantitative PCR analysis of 17 targets normalized to Ywhaz. Results:S/P rats exhibited sustained antidepressant-like effects for up to 9 weeks compared with control (S/S). L/P rats did not exhibit antidepressant-like effects at any time point, similarly to S/S. Lorazepam was associated with a decrease in Gria3 expression, and psilocybin was associated with an increase in Gria4 expression at 12 weeks post-treatment in the PL. Conclusions:Psilocybin produced long-lasting antidepressant-like effects, and administration of a BZD prior to psilocybin prevented these effects. Two genes were altered in response to treatment; however, their implications in antidepressant-like effects remain elusive.