Adolescent depression is a significant public health concern, yet treatment options remain limited, particularly due to age- and sex-related differences in antidepressant efficacy. This study explored for the first time the potential antidepressant-like response of psilocybin in adolescence by examining acute, repeated and persistent effects in Sprague-Dawley rats of both sexes, as measured under the stress of the forced-swim test. As compared to other studies, we relied on a more translational approach by administering psilocybin orally (oral gavage, o.g.), while elucidating its hallucinogenic-like potential through head-twitch responses. Finally, hippocampal neurogenesis markers were evaluated as potential biomarkers of psilocybin's antidepressant-like responses in adolescence (1- and 16-days post-treatment). The main results showed that: (1) acute psilocybin (1 mg/kg, 30 min) induced subjective hallucinogenic effects, as measured by head-twitch responses, independently of the route of administration (i.p. vs. o.g.), and without changing locomotor activity; (2) acute psilocybin (0.3 and 1 mg/kg, o.g., 30 min) exerted a rapid antidepressant-like response that coincided with the course of hallucinogenic-like responses; (3) repeated psilocybin (0.3 and 1 mg/kg, 7 days, 1 dose/day, o.g.) induced an antidepressant-like response while increased several hippocampal neurogenesis markers (Ki-67: cell proliferation, NeuroD1: neural progenitors and BrdU: cell survival) as measured 1-day post-treatment; and (4) the long-lasting antidepressant-like effects of psilocybin (observed up to 15-days post-treatment) paralleled hippocampal NeuroD1 regulation. Interestingly these effects were observed for rats independently of sex (mixed-sex cohort). To the best of our knowledge, these results are the first ones to underscore oral psilocybin's potential as a fast-acting and long-lasting antidepressant during adolescence, a developmental stage marked by high vulnerability to depression and reduced response to conventional treatments, while also proposing NeuroD1 as a putative biomarker of its long-term plasticity.
