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 et al. · 2023 · 468 citationsRead the paper
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.
3 ideas Seedlabs derived from this research
A small-molecule drug designed to trigger rapid antidepressant effects by acting as a positive allosteric modulator of the TrkB receptor. By targeting the transmembrane domain of TrkB without activating 5-HT2A receptors, the drug aims to provide the neuroplasticity benefits of psychedelics without inducing hallucinations.
AI score 87/100A preclinical assay service that distinguishes between compounds activating cell-surface versus intracellular 5-HT2A receptors. This allows drug developers to isolate neuroplasticity-promoting effects from hallucinogenic activity, targeting a specific subcellular receptor pool.
AI score 87/100A new class of neuroplasticity-promoting drugs that specifically target intracellular 5-HT2A receptors to treat neuropsychiatric diseases without triggering standard surface-receptor signaling.
AI score 76/100