Sex differences and serotonergic mechanisms in the behavioural effects of psilocin

Abstract

Psilocybin has recently attracted a great deal of attention as a clinical research and therapeutic tool. The aim of this paper is to bridge two major knowledge gaps regarding its behavioural pharmacology – sex differences and the underlying receptor mechanisms. We used psilocin (0.25, 1 and 4 mg/kg), an active metabolite of psilocybin, in two behavioural paradigms – the open-field test and prepulse inhibition (PPI) of the acoustic startle reaction. Sex differences were evaluated with respect to the phase of the female cycle. The contribution of serotonin receptors in the behavioural action was tested in male rats with selective serotonin receptor antagonists: 5-HT_1A receptor antagonist (WAY100635 1 mg/kg), 5-HT_2A receptor antagonist (MDL100907 0.5 mg/kg), 5-HT_2B receptor antagonist (SB215505 1 mg/kg) and 5-HT_2C receptor antagonist (SB242084 1 mg/kg). Psilocin induced dose-dependent inhibition of locomotion and suppression of normal behaviour in rats (behavioural serotonin syndrome, impaired PPI). The effects were more pronounced in male rats than in females. The inhibition of locomotion was normalized by 5-HT_1A and 5-HT_2B/C antagonists; however, PPI was not affected significantly by these antagonists. Our findings highlight an important issue of sex-specific reactions to psilocin and that apart from 5-HT_2A-mediated effects 5-HT_1A and 5-HT_2C/B receptors also play an important role. These findings have implications for recent clinical trials.