Psychedelics Promote Neuroplasticity Through the Activation of Intracellular 5-HT2A Receptors

Overview

Journal Science

Specialty Science

Date 2023 Feb 16

PMID 36795823

Authors

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

John A Gray

Lin Tian

David E Olson

Affiliations

Soon will be listed here.

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.

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