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

• 成果类型: Article
• 署名作者: 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.
• 署名单位: University of California System; University of California Davis; University of California System; University of California Davis; University of California System; University of California Davis; University of California System; University of California Davis; University of California System; University of California Davis; Medical College of Wisconsin; University of California System; University of California Davis; University of California System; University of California Davis; University of California System; University of California Davis
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-9897
• DOI: 10.1126/science.adf0435
• 发表日期: 2023-02-17
• 页码: 700-706
• 关键词: serotonin 2a receptor; subcellular-distribution; synaptic plasticity; signaling pathways; hallucinogens; TRAFFICKING; expression; dopamine; stress

摘要

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.