Distinct 5-HT receptor subtypes regulate claustrum excitability by serotonin and the psychedelic, DOI

Introduction

Psychedelic drugs have shown clinical promise across a range of psychiatric disorders, with their behavioural effects historically attributed to activation of 5-HT2A receptors in the prefrontal cortex, hippocampus, and thalamus. However, psychedelic drugs can be expected to engage 5-HT2A receptors throughout the brain and are also known to act at non-5-HT2A targets, necessitating detailed investigation of serotonergic signalling within discrete brain circuits. The claustrum (CLA) is a particular focus of interest, as autoradiographic studies consistently identify it as the region with the highest density of serotonin receptor binding in the brain, including for psychedelic hallucinogens. Supporting functional relevance, recent fMRI data show altered claustrum activity and connectivity following psilocybin in humans. Despite this, the specific 5-HT receptor subtypes expressed in the claustrum, their cell-type distribution, and their functional impact on claustrum neuron excitability had not been investigated at the time of this study. The researchers aimed to characterise the expression and functional roles of 5-HT receptor subtypes in regulating excitability of claustrum neurons projecting to the anterior cingulate cortex (CLA-ACC neurons), with particular attention to how endogenous serotonin and the serotonergic psychedelic DOI differentially modulate these cells.