Deciphering the antidepressant mechanism of action and neuroplastic effects of psilocybin in mice

Depression is a leading global psychiatric disorder. Conventional antidepressants require chronic administration and frequently fail in treatment-resistant depression. While psilocybin shows promising therapeutic potential, its underlying neurobiological mechanisms remain unclear. Psilocin, its active metabolite, mediates hallucinogenic effects via 5-HT2A receptors but displays higher affinity for other subtypes, including 5-HT2B and 5-HT7. Importantly, 5-HT2B signaling is required for the neurogenic and behavioral effects of classical antidepressants like fluoxetine. In this project, we will investigate the 5-HT2B receptor as a primary candidate mediating psilocybin’s antidepressant action. We will evaluate behavioral responses following acute psilocybin administration at a clinically relevant dose and a non-hallucinogenic microdose to characterize its anti-anhedonic profile. The functional contribution of 5-HT2B receptors will be determined using selective pharmacological antagonists and knockout mouse models. In parallel, we will assess psilocybin and psilocin pharmacokinetics to correlate plasma levels with behavioral outcomes. Finally, we will examine long-term neuroplasticity by measuring hippocampal neurogenesis, neuronal survival, and neurotrophin expression in wild-type and transgenic mice. Unraveling these 5-HT2B-dependent mechanisms will bridge basic and clinical findings, paving the way for targeted therapeutics with enhanced efficacy and reduced adverse effects.