Psychedelics promote plasticity by directly binding to BDNF receptor TrkB

Nat Neurosci. 2023 Jun;26(6):1032-1041. doi: 10.1038/s41593-023-01316-5. Epub 2023 Jun 5.

Abstract

Psychedelics produce fast and persistent antidepressant effects and induce neuroplasticity resembling the effects of clinically approved antidepressants. We recently reported that pharmacologically diverse antidepressants, including fluoxetine and ketamine, act by binding to TrkB, the receptor for BDNF. Here we show that lysergic acid diethylamide (LSD) and psilocin directly bind to TrkB with affinities 1,000-fold higher than those for other antidepressants, and that psychedelics and antidepressants bind to distinct but partially overlapping sites within the transmembrane domain of TrkB dimers. The effects of psychedelics on neurotrophic signaling, plasticity and antidepressant-like behavior in mice depend on TrkB binding and promotion of endogenous BDNF signaling but are independent of serotonin 2A receptor (5-HT2A) activation, whereas LSD-induced head twitching is dependent on 5-HT2A and independent of TrkB binding. Our data confirm TrkB as a common primary target for antidepressants and suggest that high-affinity TrkB positive allosteric modulators lacking 5-HT2A activity may retain the antidepressant potential of psychedelics without hallucinogenic effects.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation
  • Animals
  • Antidepressive Agents* / metabolism
  • Binding Sites
  • Brain-Derived Neurotrophic Factor / metabolism
  • Embryo, Mammalian / cytology
  • Female
  • HEK293 Cells
  • Hallucinogens* / metabolism
  • Humans
  • Lysergic Acid Diethylamide* / chemistry
  • Lysergic Acid Diethylamide* / metabolism
  • Lysergic Acid Diethylamide* / pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Molecular Dynamics Simulation
  • Neuronal Plasticity / drug effects
  • Neurons / drug effects
  • Psilocybin* / chemistry
  • Psilocybin* / metabolism
  • Psilocybin* / pharmacology
  • Receptor, trkB* / metabolism
  • Signal Transduction

Substances

  • Hallucinogens
  • tropomyosin-related kinase-B, human
  • Brain-Derived Neurotrophic Factor
  • Receptor, trkB
  • Antidepressive Agents
  • Lysergic Acid Diethylamide
  • psilocin
  • Psilocybin