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

Recent evidence indicates that neuronal activity within the claustrum (CLA) may be central to cellular and behavioral responses to psychedelic hallucinogens. The CLA prominently innervates many cortical targets and displays exceptionally high levels of serotonin (5-HT) binding. However, the influence of serotonin receptors, prime targets of psychedelic drug action, on CLA activity remains unexplored. We characterize the CLA expression of all known 5-HT subtypes and contrast the effects of 5-HT and the psychedelic hallucinogen, 2,5-dimethoxy-4-iodoamphetamine (DOI), on excitability of cortical-projecting CLA neurons. We find that the CLA is particularly enriched with 5-HT2C receptors, expressed predominantly on glutamatergic neurons. Electrophysiological recordings from CLA neurons that project to the anterior cingulate cortex (ACC) indicate that application of 5-HT inhibits glutamate receptor-mediated excitatory postsynaptic currents (EPSCs). In contrast, application of DOI stimulates EPSCs. We find that the opposite effects of 5-HT and DOI on synaptic signaling can both be reversed by inhibition of the 5-HT2C, but not 5-HT2A, receptors. We identify specific 5-HT receptor subtypes as serotonergic regulators of the CLA excitability and argue against the canonical role of 5-HT2A in glutamatergic synapse response to psychedelics within the CLA-ACC circuit. •The claustrum is enriched with 5-HT2A and 5-HT2C receptor mRNA.•Claustrum 5-HT2 receptors are more prominent in glutamatergic than in GABAergic neuron population.•Synaptic and intrinsic excitability of CLA-ACC neurons are inhibited by serotonin through the 5-HT1A and 5-HT2C receptors.•The psychedelic drug, DOI, increases post-synaptic responses to glutamate via the 5-HT2C, but not the canonical 5-HT2A, pathways.