TY - JOUR
T1 - Distinct 5-HT receptor subtypes regulate claustrum excitability by serotonin and the psychedelic, DOI
AU - Anderson, Tanner L.
AU - Keady, Jack V.
AU - Songrady, Judy
AU - Tavakoli, Navid S.
AU - Asadipooya, Artin
AU - Neeley, Ryson E.
AU - Turner, Jill R.
AU - Ortinski, Pavel I.
N1 - Publisher Copyright:
© 2024 Elsevier Ltd
PY - 2024/9
Y1 - 2024/9
N2 - 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.
AB - 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.
KW - 2,5-dimethoxy-4-iodoamphetamine (DOI)
KW - 5-HT2A
KW - 5-HT2C
KW - Claustrum
KW - Electrophysiology
KW - Psychedelics
KW - Serotonin
UR - http://www.scopus.com/inward/record.url?scp=85202916410&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85202916410&partnerID=8YFLogxK
U2 - 10.1016/j.pneurobio.2024.102660
DO - 10.1016/j.pneurobio.2024.102660
M3 - Article
C2 - 39218140
AN - SCOPUS:85202916410
SN - 0301-0082
VL - 240
JO - Progress in Neurobiology
JF - Progress in Neurobiology
M1 - 102660
ER -