Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors

• Published in: Science (American Association for the Advancement of Science) Vol. 379; no. 6633; pp. 700 - 706
• Main Authors: Vargas, Maxemiliano V, Dunlap, Lee E, Dong, Chunyang, Carter, Samuel J, Tombari, Robert J, Jami, Shekib A, Cameron, Lindsay P, Patel, Seona D, Hennessey, Joseph J, Saeger, Hannah N, McCorvy, John D, Gray, John A, Tian, Lin, Olson, David E
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 17-02-2023
• Subjects: Animals; Antidepressants; Antidepressive Agents - pharmacology; Cerebral Cortex - drug effects; Cerebral Cortex - physiology; Functional plasticity; Hallucinogens - pharmacology; Intracellular; Mice; Mice, Knockout; Neural plasticity; Neuronal Plasticity - drug effects; Psychedelic drugs; Receptor mechanisms; Receptor, Serotonin, 5-HT2A - genetics; Receptor, Serotonin, 5-HT2A - metabolism; Receptors; Serotonin; Serotonin - pharmacology; Serotonin 5-HT2 Receptor Agonists - pharmacology; Serotonin S2 receptors; Signal Transduction; Structure-function relationships
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.adf0435

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.