Serotonin and psilocybin activate 5-HT1B receptors to suppress cortical signaling through the claustrum
Nature Communications – August 19, 2025
Source: OpenAlex
Summary
The classic hallucinogen psilocybin directly targets the brain's claustrum, a key structure in cortical network states. Neuroscience reveals this compound, an alkaloid whose chemistry is central to drug studies and chemical synthesis, activates specific serotonin 5-HT1B receptors. This neurotransmitter receptor influence on behavior involves suppressing signaling from the anterior cingulate cortex to claustrum neurons. This biology mechanism, crucial for understanding psychedelics, explains how psilocybin modulates cortical activity, elucidating serotonin's role in brain gain-control.
Abstract
Through its widespread reciprocal connections with the cerebral cortex, the claustrum is implicated in sleep and waking cortical network states. Yet, basic knowledge of neuromodulation in this structure is lacking. The claustrum is richly innervated by serotonergic fibers, expresses serotonin receptors, and is suggested to play a role in the ability of psilocybin, which is metabolized to the non-specific serotonin receptor agonist psilocin, to disrupt cortex-wide network states. We therefore addressed the possible role of serotonin, and the classic psychedelic psilocybin, in modulating cortical signaling through the claustrum. We show that serotonin activates 5-HT1B receptors on anterior cingulate cortex inputs - a primary driver of claustrum activity - to suppress signaling to parietal association cortex-projecting claustrum neurons. Additionally, we demonstrate that psilocybin injection also activates anterior cingulate cortex presynaptic 5-HT1B receptors to suppress cortical signaling through the claustrum. Thus, serotonin, via 5-HT1B, may provide gain-control of cortical input to the claustrum, a mechanism that may be directly targeted by psilocybin to modulate downstream cortical network states.