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

  • Science. 2023 Feb 17;379(6633):700-706. doi: 10.1126/science.adf0435.
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 Jami  5 ,  Lindsay P Cameron  1 ,  Seona D Patel  3 ,  Joseph J Hennessey  6 ,  Hannah N Saeger  2  7 ,  John D McCorvy  6 ,  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.
PMID: 36795823 DOI: 10.1126/science.adf0435
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.