Distinct 5-HT receptor subtypes regulate claustrum excitability by serotonin and the psychedelic, DOI
Anderson, T. L., Asadipooya, A., Keady, J. V., Neeley, R. E., Ortinski, P. I., Songrady, J., Tavakoli, N. S., Turner, J. R.
This cell-based study investigates the role of serotonin receptors in the claustrum's response to psychedelic drugs. It finds that the claustrum is rich in 5-HT2C receptors on glutamatergic neurons and that serotonin and the psychedelic DOI have opposite effects on synaptic signalling, both mediated by 5-HT2C receptors rather than 5-HT2A receptors as previously thought.
Abstract
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.