Psilocybin-induced behavioral and cellular effects

Psilocybin, a prominent psychedelic, recently emerged as a potential therapeutic agent for psychiatric disorders, yet the molecular and cellular mechanisms driving its effects remain poorly understood. To address these knowledge gaps, we focused on the nucleus accumbens (NAc), a forebrain region that regulates reward, motivation, and emotion. Systemic administration of psilocybin (3 mg/kg) induced a rapid inhibition of mouse locomotor activities, which was resolved by ∼1 h post-psilocybin treatment. By contrast, psilocybin-induced c-Fos expression in the NAc peaked at ∼6 h in neurons post-treatment and at ∼1.5 h in non-neuronal cells. These temporal profiles suggest that, as an immediate early gene and transcription factor, c-Fos may induce prolonged functional changes in NAc neurons and non-neuronal cells differentially through transcriptional regulation. Finally, to probe for endogenous receptors that may mediate the psilocybin effects, we focused on serotonin 2 A (5-HT2A) and serotonin 2B (5-HT2B) receptors. Inhibition of 5-HT2A receptors (Volinanserin, 0.5 mg/kg) selectively reduced psilocybin-induced c-Fos expression in neurons, whereas inhibition of 5-HT2B receptors (RS 127445, 0.5 mg/kg) reduced psilocybin-induced c-Fos expression in both neurons and non-neuronal cells. These results suggest that 5-HT2B receptors and non-neuronal cells may be key players in the regulation of circuits underlying mood-related disorders.