Psychedelics promote plasticity by directly binding to BDNF receptor TrkB
This mice study investigated the antidepressant and neuroplastic effects of psychedelics, specifically lysergic acid diethylamide (LSD) and psilocin. The trial centres around their high-affinity binding to TrkB, a BDNF receptor implicated in antidepressant mechanisms. These substances bind to TrkB with affinities 1,000-fold higher than other antidepressants (SSRIs), and their effects on neurotrophic signalling, plasticity, and antidepressant-like behaviour in mice depend on this TrkB binding and promotion of endogenous BDNF signalling. Interestingly, these effects are independent of serotonin (5-HT) 2A receptor activation, suggesting that TrkB is a primary target for antidepressants.
Authors
- Moliner, R.
- Girych, M.
- Brunello, C. A.
Published
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.
Research Summary of 'Psychedelics promote plasticity by directly binding to BDNF receptor TrkB'
Introduction
Depression incidence has risen substantially, and there is a pressing need for faster, more effective treatments. Preliminary clinical trials suggest that psychedelics such as lysergic acid diethylamide (LSD) and psilocybin (via its metabolite psilocin, PSI) can produce rapid and sustained antidepressant effects; however, their acute hallucinogenic effects mediated by serotonin 2A receptors (5-HT2A) limit clinical use. Earlier work showed that diverse antidepressants, including fluoxetine and ketamine, can bind to TrkB, the receptor for brain-derived neurotrophic factor (BDNF), and thereby potentiate neurotrophic signalling that underpins plasticity and therapeutic actions of antidepressants. Moliner and colleagues set out to determine whether psychedelics directly bind to TrkB and whether such binding mediates their plasticity-promoting and antidepressant-like effects. The study aims to localise the binding site, characterise binding affinities and structural consequences for TrkB, and test whether psychedelic-induced neurotrophic signalling, synaptic plasticity and behavioural effects depend on TrkB binding and BDNF signalling or on 5-HT2A activation. This work combines biochemical binding assays, structural NMR and atomistic molecular dynamics (MD) simulations, cellular imaging and electrophysiological assays, and in vivo behavioural and plasticity paradigms using wild-type and TrkB TMD mutant mice.
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Study Details
- Study Typeindividual
- Journal
- Compounds
- Topic
- APA Citation
Moliner, R., Girych, M., Brunello, C. A., Kovaleva, V., Biojone, C., Enkavi, G., Antenucci, L., Kot, E. F., Goncharuk, S. A., Kaurinkoski, K., Kuutti, M., Fred, S. M., Elsilä, L. V., Sakson, S., Cannarozzo, C., Diniz, C. R. A. F., Seiffert, N., Rubiolo, A., Haapaniemi, H., . . . Castrén, E. (2023). Psychedelics promote plasticity by directly binding to BDNF receptor TrkB. Nature Neuroscience, 26(6), 1032-1041. https://doi.org/10.1038/s41593-023-01316-5
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