The non-hallucinogenic serotonin 1B receptor is necessary for the antidepressant-like effects of psilocybin in mice

Recent studies highlight the promising use of psychedelic therapies for psychiatric disorders, including depression. The persisting clinical effects of psychedelics such as psilocybin are commonly attributed to activation of the serotonin 2A receptor (5-HT2AR) based on its role in the acute hallucinatory effects. However, the active metabolite of psilocybin binds to many serotonin receptor subtypes, including the serotonin 1B receptor (5-HT1BR). Given the known role of 5-HT1BR in mediating depressive phenotypes and promoting neural plasticity, we hypothesized that it mediates the effects of psilocybin on neural activity and behavior. We first examined the acute neural response to psilocybin in mice lacking 5-HT1BR. We found that 5-HT1BR expression influenced brain-wide activity following psilocybin administration, measured by differences in the patterns of the immediate early gene c-Fos, across regions involved in emotional processing and cognitive function, including the amygdala and prefrontal cortex. Functionally, we demonstrated that 5-HT1BR is necessary for the acute and persisting behavioral effects of psilocybin. Although there was no effect of 5-HT1BR expression on the acute head twitch response, mice lacking 5-HT1BRs had attenuated hypolocomotor responses to psilocybin. We also measured the persisting antidepressant-like effects of psilocybin using transgenic and pharmacological 5-HT1BR loss-of-function models and found that 5-HT1B was required for the decreased anhedonia and reduced anxiety-like behavior. Finally, using a network analysis, we identified neural circuits through which 5-H1BR may modulate the response to psilocybin. Overall, our research implicates the 5-HT1BR, a non-hallucinogenic serotonin receptor, as a critical mediator of the behavioral and neural effects of psilocybin in mice.