Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors
The study shows that psychedelics promote cortical neuroplasticity by selectively activating intracellular 5-HT2A receptors rather than surface receptors, explaining why serotonin does not elicit the same growth effects. This identifies location-biased 5-HT2A signalling as a therapeutic target and raises the possibility that serotonin may not be the endogenous ligand for intracellular 5-HT2ARs.
Authors
- David Olson
- John McCorvy
- Lindsay Cameron
Published
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.
Research Summary of 'Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors'
Introduction
Dysregulation of the cortex, including reduced dendritic arbor complexity and lower dendritic spine density, is implicated in several neuropsychiatric disorders and is a target for therapeutics that promote structural plasticity. Psychoplastogens such as ketamine and serotonergic psychedelics produce rapid and sustained increases in cortical structural and functional plasticity; for psychedelics this effect requires activation of 5-hydroxytryptamine 2A receptors (5-HT2ARs). However, a puzzling observation is that some 5-HT2AR agonists promote cortical neuroplasticity while others, including endogenous serotonin, do not, despite serotonin being a potent, balanced 5-HT2AR agonist in canonical signalling assays. The physicochemical differences between ligands led the investigators to consider location bias — the idea that receptor signalling differs depending on whether ligands access plasma-membrane versus intracellular receptor pools — as a possible explanation. Vargas and colleagues set out to test whether activation of an intracellular population of 5-HT2ARs is necessary for psychedelics to induce cortical structural plasticity and related antidepressant-like behavioural responses. To do so they combined in vivo pharmacology and genetics (including 5-HT2AR knockout mice and viral expression of transporters), in vitro neuronal culture assays and structure–activity studies of tryptamine analogues, fluorescence- and biophysical-reporter assays of receptor conformation and signalling, subcellular localisation experiments, and chemical modification of ligands to alter membrane permeability.
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Study Details
- Study Typeindividual
- Journal
- Topics
- Authors
- APA Citation
Vargas, M. V., Dunlap, L. E., Dong, C., Carter, S. J., Tombari, R. J., Jami, S. A., Cameron, L. P., Patel, S. D., Hennessey, J. J., Saeger, H. N., McCorvy, J. D., Gray, J. A., Tian, L., & Olson, D. E. (2023). Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors. Science, 379(6633), 700-706. https://doi.org/10.1126/science.adf0435
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