Psilocybin's persisting clinical effects are commonly attributed to activation of the serotonin 2A receptor, but its active metabolite binds to many serotonin receptor subtypes, including the serotonin 1B receptor (5-HT1BR). In mice, 5-HT1BR expression influenced brain-wide activity after psilocybin administration, measured by differences in c-Fos patterns across regions involved in emotional processing and cognitive function, including the amygdala and prefrontal cortex. 5-HT1BR mediated some acute and persisting behavioral effects: mice lacking 5-HT1BRs showed attenuated hypolocomotion to psilocybin, and both transgenic and pharmacological loss-of-function models indicated 5-HT1B involvement in decreased anhedonia and reduced anxiety-like behavior. The research implicates 5-HT1BR as a mediator of psilocybin's behavioral and neural effects in mice.
Psilocybin's persisting antidepressant-like effects in mice involve not only the serotonin 2A receptor but also the serotonin 1B receptor (5-HT1BR). Mice lacking 5-HT1BR showed altered brain-wide neural activity after psilocybin, measured by c-Fos expression in emotion- and cognition-related regions such as the amygdala. While the acute head twitch response was unaffected, 5-HT1BR absence reduced psilocybin-induced hypolocomotion. Longer-term effects on anhedonia and anxiety-like behavior depended on 5-HT1BR, with influences from sex and stress. Network analysis identified circuits through which 5-HT1BR may modulate psilocybin's effects. The findings suggest 5-HT1BR contributes to psilocybin's enduring antidepressant-like actions in mice.
Research in mice implicates the 5-HT1BR, a nonhallucinogenic serotonin receptor, as a potential mediator of the behavioral and neural effects of psilocybin. The 5-HT1BR influences brain-wide neural changes following psilocybin administration and may contribute to its enduring antidepressant-like effects in mice. However, the data do not address whether 5-HT1BR is sufficient for these effects.