Open AccessPsychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors
Author(s) -
Maxemiliano V. Vargas,
Lee E. Dunlap,
Chunyang Dong,
Samuel J. Carter,
Robert J. Tombari,
Shekib A. Jami,
Lindsay P. Cameron,
Seona D. Patel,
Joseph J. Hennessey,
Hannah N. Saeger,
John D. McCorvy,
J.A. Gray,
Lin Tian,
David E. Olson
Publication year - 2023
Publication title -
science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 12.556
H-Index - 1186
eISSN - 1095-9203
pISSN - 0036-8075
DOI - 10.1126/science.adf0435
Subject(s) - neuroplasticity , intracellular , neuroscience , serotonin , receptor , cortical neurons , cortex (anatomy) , plasticity , biology , psychology , microbiology and biotechnology , biochemistry , physics , thermodynamics
Decreased dendritic spine density in the cortex is a hallmark of several neuropsychiatric diseases, and the ability to promote cortical neuron growth has been hypothesized to underlie the rapid and sustained therapeutic effects of psychedelics. Activation of 5-hydroxytryptamine (serotonin) 2A receptors (5-HT2ARs) is essential for psychedelic-induced cortical plasticity, but it is currently unclear why some 5-HT2AR agonists promote neuroplasticity, whereas others do not. We used molecular and genetic tools to demonstrate that intracellular 5-HT2ARs mediate the plasticity-promoting properties of psychedelics; these results explain why serotonin does not engage similar plasticity mechanisms. This work emphasizes the role of location bias in 5-HT2AR signaling, identifies intracellular 5-HT2ARs as a therapeutic target, and raises the intriguing possibility that serotonin might not be the endogenous ligand for intracellular 5-HT2ARs in the cortex.
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