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

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

doi:10.1126/science.adf0435

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

Science. 2023 Feb 17;379(6633):700-706. doi: 10.1126/science.adf0435. Epub 2023 Feb 16.

Authors

Maxemiliano V Vargas^{1

2}, Lee E Dunlap^#^{2

3}, Chunyang Dong^#⁴, Samuel J Carter^{2

3}, Robert J Tombari^{2

3}, Shekib A Jami⁵, Lindsay P Cameron¹, Seona D Patel³, Joseph J Hennessey⁶, Hannah N Saeger^{2

7}, John D McCorvy⁶, John A Gray^{2

5

8}, Lin Tian^{2

5

9}, David E Olson^{2

3

5

9}

Affiliations

¹ Neuroscience Graduate Program, University of California, Davis, Davis, CA 95618, USA.
² Institute for Psychedelics and Neurotherapeutics, University of California, Davis, Davis, CA 95618, USA.
³ Department of Chemistry, University of California, Davis, Davis, CA 95616, USA.
⁴ Biochemistry, Molecular, Cellular, and Developmental Biology Graduate Program, University of California, Davis, Davis, CA 95616, USA.
⁵ Center for Neuroscience, University of California, Davis, Davis, CA 95618, USA.
⁶ Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
⁷ Pharmacology and Toxicology Graduate Program, University of California, Davis, Davis, CA 95616, USA.
⁸ Department of Neurology, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA.
⁹ Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA.

^# Contributed equally.

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.

MeSH terms

Animals
Antidepressive Agents* / pharmacology
Cerebral Cortex* / drug effects
Cerebral Cortex* / physiology
Hallucinogens* / pharmacology
Mice
Mice, Knockout
Neuronal Plasticity* / drug effects
Receptor, Serotonin, 5-HT2A* / genetics
Receptor, Serotonin, 5-HT2A* / metabolism
Serotonin / pharmacology
Serotonin 5-HT2 Receptor Agonists* / pharmacology
Signal Transduction

Substances

Hallucinogens
Serotonin
Serotonin 5-HT2 Receptor Agonists
Receptor, Serotonin, 5-HT2A
Antidepressive Agents

Abstract

MeSH terms

Substances

Grants and funding