Differential contributions of serotonin receptors to the behavioral effects of indoleamine hallucinogens in mice

Psilocin, the active metabolite of psilocybin, acts as an agonist at 5-HT1A, 5-HT2A, and 5-HT2C receptors. In mice, psilocin induced head twitch response (HTR) via 5-HT2A receptors, as effects were absent in mice lacking that gene. In the behavioral pattern monitor (BPM), psilocin decreased locomotor activity, holepoking, and time in the chamber center; these effects were blocked by the 5-HT1A antagonist WAY-100635 but not by 5-HT2C antagonism or 5-HT2A gene deletion. 5-MeO-DMT produced similar BPM effects attenuated by WAY-100635. Psilocin and 5-MeO-DMT decreased path linearity via 5-HT2C and 5-HT1A receptors, respectively. 1-methylpsilocin induced HTR via 5-HT2A but was inactive in the BPM, suggesting greater pharmacological selectivity and potential as a therapeutic alternative to psilocybin.

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Abstract

Psilocin (4-hydroxy- N, N-dimethyltryptamine) is a hallucinogen that acts as an agonist at 5-HT 1A , 5-HT 2A , and 5-HT 2C receptors. Psilocin is the active metabolite of psilocybin, a hallucinogen that is currently being investigated clinically as a potential therapeutic agent. In the present investigation, we used a combination of genetic and pharmacological approaches to identify the serotonin (5-HT) receptor subtypes responsible for mediating the effects of psilocin on head twitch response (HTR) and the behavioral pattern monitor (BPM) in C57BL/6J mice. We also compared the effects of psilocin with those of the putative 5-HT 2C receptor-selective agonist 1-methylpsilocin and the hallucinogen and non-selective serotonin receptor agonist 5-methoxy- N, N-dimethyltryptamine (5-MeO-DMT). Psilocin, 1-methylpsilocin, and 5-MeO-DMT induced the HTR, effects that were absent in mice lacking the 5-HT 2A receptor gene. When tested in the BPM, psilocin decreased locomotor activity, holepoking, and time spent in the center of the chamber, effects that were blocked by the selective 5-HT 1A antagonist WAY-100635 but were not altered by the selective 5-HT 2C antagonist SB 242,084 or by 5-HT 2A receptor gene deletion. 5-MeO-DMT produced similar effects when tested in the BPM, and the action of 5-MeO-DMT was significantly attenuated by WAY-100635. Psilocin and 5-MeO-DMT also decreased the linearity of locomotor paths, effects that were mediated by 5-HT 2C and 5-HT 1A receptors, respectively. In contrast to psilocin and 5-MeO-DMT, 1-methylpsilocin (0.6–9.6 mg/kg) was completely inactive in the BPM. These findings confirm that psilocin acts as an agonist at 5-HT 1A , 5-HT 2A , and 5-HT 2C receptors in mice, whereas the behavioral effects of 1-methylpsilocin indicate that this compound is acting at 5-HT 2A sites but is inactive at the 5-HT 1A receptor. The fact that 1-methylpsilocin displays greater pharmacological selectivity than psilocin indicates that 1-methylpsilocin represents a potentially useful alternative to psilocybin for development as a potential therapeutic agent.