This (rat) 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 of 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.”
Authors: Tanner L. Anderson, Jack V. Keady, Judy Songrady, Navid S. Tavakoli, Artin Asadipooya, Ryson E. Neeley, Jill R. Turner & Pavel I. Ortinski
Summary of Distinct 5-HT receptor subtypes regulate claustrum excitability by serotonin and the psychedelic, DOI
The introduction discusses the promising results of psychedelic drugs in preclinical and clinical studies for treating various psychiatric disorders, including treatment-resistant depression, post-traumatic stress disorder, and substance use disorders. While the behavioural effects of psychedelics have long been attributed to serotonin 2A receptors (5-HT2ARs), particularly in brain regions like the prefrontal cortex, hippocampus, midbrain and thalamus, psychedelic drugs can activate 5-HT2ARs in other brain regions and have been shown to bind to non-5-HT2A receptors or act via signaling pathways outside of the 5-HT receptor family.
The researchers highlight that autoradiography studies have found the highest density of binding of radiolabelled serotonin receptor ligands, including psychedelic hallucinogens, in the claustrum (CLA), a subcortical brain region wedged between the external capsule and the insula. Recent fMRI data in humans show altered CLA activity and functional connectivity after systemic administration of psilocybin, supporting a role for CLA as central to the effect of psychedelics.
The CLA is densely innervated by serotonin fibre afferents from the raphe nuclei and expresses subtypes for 5-HT1, 5-HT2, and 5-HT3 receptors. However, expression of other 5-HT receptors, their relative abundance, cell-type localisation, and 5-HT receptor impact on neuronal excitability within the CLA remain completely unknown. The researchers aim to address these gaps in knowledge through their study.
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https://doi.org/10.1016/j.pneurobio.2024.102660
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Cite this paper (APA)
Anderson, T. L., Keady, J. V., Songrady, J., Tavakoli, N. S., Asadipooya, A., Neeley, R. E., ... & Ortinski, P. I. (2024). Distinct 5-HT receptor subtypes regulate claustrum excitability by serotonin and the psychedelic, DOI. Progress in Neurobiology, 102660.
