Serotonin 1B receptors expressed on forebrain excitatory neurons mediate the post-acute anxiolytic response to psilocybin in mice.

Abstract

Psilocybin can produce rapid and sustained antidepressant-like and anxiolytic effects, yet the receptor and circuit mechanisms underlying these behavioral changes remain unclear. While the serotonin 2A receptor mediates psilocybin's acute psychedelic effects, psilocin (the active metabolite of psilocybin) binds many serotonin receptor subtypes. Our prior work has identified the serotonin 1B receptor (5-HT1BR) as being necessary for the post-acute pro-hedonic and anxiolytic effects of psilocybin in mice. 5-HT1BRs are widely expressed throughout the brain on many different neuron subtypes. In order to assess the role of 5-HT1BR expression on terminals of forebrain excitatory neurons in the response to psilocybin, we used a conditional genetic approach to selectively eliminate expression of htr1b in forebrain excitatory neurons using the Emx1 promoter. We examined acute behavioral responses, post-acute anxiolytic effects, and brain-wide neural activation to a single high dose of psilocybin in male and female mice. The absence of 5-HT1BR expression on Emx1+ neurons did not alter psilocybin's acute behavioral effects, including head twitch responding and hyperlocomotion. However, psilocybin's post-acute anxiolytic effects in the elevated plus maze (EPM) and novelty suppressed feeding (NSF) assays were strongly attenuated in mice lacking these receptors. Whole-brain c-Fos mapping across 190 regions revealed that psilocybin produced robust activation across the brain in both genotypes, including prefrontal cortices, corticolimbic structures, and sensory cortices. Network-level analyses revealed that psilocybin drove broad inter-regional decorrelation in control mice but increased synchronization in knockouts, with thalamic, prefrontal, and amygdala circuits most strongly affected. These findings implicate 5-HT1BRs expressed on terminals of forebrain excitatory neurons as a potential circuit-level excitatory gating mechanism. Overall, these receptors may be important for a coordinated network reorganization following psilocybin that contributes to the anxiolytic behavioral effects.

In the evidence

This study is part of the evidence base for 3 syntheses in the library. Here is how each one recorded it.

• State of the evidence: Psilocybin for anxiety ↑Supports

  Mice lacking 5-HT1B receptors on forebrain excitatory neurons showed strongly attenuated post-acute anxiolytic effects of psilocybin, implicating these receptors in its anxiety-reducing action.

  Synthesized October 22, 2026

• State of the evidence: Anxiety ↑Supports

  Psilocybin's post-acute anxiolytic effects in elevated plus maze and novelty suppressed feeding assays were strongly attenuated in mice lacking serotonin 1B receptors on forebrain excitatory neurons.

  Synthesized October 19, 2026

• State of the evidence: Serotonin ↑Supports

  Loss of 5-HT1B receptors on forebrain excitatory neurons did not alter psilocybin's acute effects but strongly attenuated its post-acute anxiolytic effects.

  Synthesized October 19, 2026

Comparable studies

Other preclinical and animal studies on psilocybin for anxiety, most cited first.