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
Science February 16, 2023 DOI: 10.1126/science.adf0435 (opens in new tab) via OpenAlex
Summary
AI-generated from the abstractDecreased 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-HT2ARs is essential for psychedelic-induced cortical plasticity, but it is unclear why some 5-HT2AR agonists promote neuroplasticity while others do not. Using molecular and genetic tools, the authors demonstrate that intracellular 5-HT2ARs mediate the plasticity-promoting properties of psychedelics, explaining why serotonin does not engage similar plasticity mechanisms. This work emphasizes location bias in 5-HT2AR signaling, identifies intracellular 5-HT2ARs as a therapeutic target, and raises the possibility that serotonin might not be the endogenous ligand for intracellular 5-HT2ARs in the cortex.
Study at a glance
| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | In vitro and in vivo (rodent) models |
| Citations | 467 |
| Key finding | Intracellular 5-HT2ARs, not cell-surface ones, mediate the plasticity-promoting effects of psychedelics, explaining why serotonin does not engage similar plasticity mechanisms. |
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.