Faculty Collaboration Database

Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors. Science 2023 Feb 17;379(6633):700-706

Date

02/17/2023

Pubmed ID

36795823

Pubmed Central ID

PMC10108900

DOI

10.1126/science.adf0435

Scopus ID

2-s2.0-85148258353 (requires institutional sign-in at Scopus site)   82 Citations

Abstract

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.

Author List

Vargas MV, Dunlap LE, Dong C, Carter SJ, Tombari RJ, Jami SA, Cameron LP, Patel SD, Hennessey JJ, Saeger HN, McCorvy JD, Gray JA, Tian L, Olson DE

Author

John McCorvy PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Antidepressive Agents
Cerebral Cortex
Hallucinogens
Mice
Mice, Knockout
Neuronal Plasticity
Receptor, Serotonin, 5-HT2A
Serotonin
Serotonin 5-HT2 Receptor Agonists
Signal Transduction