Serotonin 5-HT2A, 5-HT2c and 5-HT1A receptor involvement in the acute effects of psilocybin in mice. In vitro pharmacological profile and modulation of thermoregulation and head-twich response

Psilocybin, a psychedelic drug that activates the 5-HT2A receptor, shows potential for treating neuropsychiatric diseases. In mice, psilocin (the active metabolite) binds with similar affinity to 5-HT2A, 5-HT2C, and 5-HT1A receptors. Psilocybin causes a dose-dependent head-twitch response, a sign of psychosis-like effects, which is blocked by a 5-HT2A antagonist but increased by a 5-HT2C antagonist. Body temperature rises at low doses but falls at higher doses; a 5-HT1A antagonist reverses this drop, causing hyperthermia. These findings clarify the roles of specific serotonin receptors in psilocybin's acute effects, aiding understanding of its therapeutic and side effects.

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Abstract

The psychedelic 5-HT2A receptor (5HT2AR) agonist psilocybin (or the active metabolite psilocin) has emerged as potential useful drug for various neuropsychiatric diseases, with a rapid onset of therapeutic activity. However, the mechanisms responsible for such effects remain incompletely characterized. We aimed to study in vitro pharmacological profile and in vivo acute mechanism of psilocin/psilocybin. Competition binding studies with psilocin were performed in brain and cell cultures. The role of 5HT2AR, 5-HT2C receptors (5HT2CR) and 5-HT1A receptors (5HT1AR) on the psychosis-like head-twitch response (HTR) and on body temperature in mice after psilocybin administration were evaluated. Psilocin showed similar affinities for 5HT2AR (Ki: 120-173 nM), 5HT2CR (Ki: 79-311 nM) and 5-HT1AR (Ki: 152-146 nM) in human and mice brain. Psilocybin induced a dose-dependent HTR (maximal effect 17.07 ± 1.31 at 1 mg/kg i.p.) that was completely suppressed by the 5HT2AR antagonist MDL11939 (1 mg/kg). Higher doses of psilocybin (3 mg/kg) induced lower HTR (9.00 ± 0.53). The 5HT2CR antagonist SB242084 (0.1 mg/kg) increased HTR exerted by psilocybin (3 mg/kg). Psilocybin significantly raised core body temperature at low dose (0.125 mg/kg) (Emax=0.67 ± 0.15 °C), whereas a significant decrease was induced by doses over 1 mg/kg (Emax = -1.31 ± 0.16 °C). Pre-treatment with the 5HT1AR antagonist WAY100635 reversed the decrease of body temperature after psilocybin (1 mg/kg), causing hyperthermia (Emax = 0.94 ± 0.26 °C). The present work provides key findings on the 5HT2AR, 5-HT2CR and 5HT1AR involvement in the acute central effects of psilocybin. The results may be relevant for understanding the mechanism of action underlying the therapeutic effects and side effects of this psychedelic drug.