Nature Neuroscience
June 1, 2023
Rafael Moliner, Mykhailo Girych, Vera Kovaleva et al.
439 citations
Psychedelics such as LSD and psilocin produce fast and lasting antidepressant effects by directly binding to the TrkB receptor, the receptor for brain-derived neurotrophic factor (BDNF). These compounds bind to TrkB with affinities 1,000 times higher than other antidepressants like fluoxetine and ketamine, and they interact with a distinct but partially overlapping site within the transmembrane domain of TrkB dimers. In mice, the neuroplasticity and antidepressant-like effects of psychedelics depend on TrkB binding and endogenous BDNF signaling, not on serotonin 2A receptor activation. However, LSD-induced head twitching requires serotonin 2A activation and is independent of TrkB binding. This suggests that high-affinity TrkB positive allosteric modulators without serotonin 2A activity could retain antidepressant benefits without hallucinogenic effects.
Trends in neurosciences
November 1, 2024
Cecilia Anna Brunello, Cecilia Cannarozzo, Eero Castrén
29 citations
Antidepressant drugs, including slow-acting types, fast-acting ketamine, and psychedelics, all promote neuronal plasticity through activation of BDNF signaling via its receptor TRKB, though each drug targets different cells. The authors propose that some antidepressants may directly bind to TRKB and allosterically enhance BDNF signaling. Activating TRKB in parvalbumin-containing interneurons disinhibits cortical networks and reopens a juvenile-like window of plasticity. This rewiring of faulty neural circuits, combined with environmental input, may explain clinical antidepressant effects. This hypothesis could guide development of new treatments.
Biological psychiatry
February 1, 2025
Cassiano Ricardo Alves Faria Diniz, Ana Paula Crestani, Plinio Cabrera Casarotto et al.
15 citations
Antidepressants such as fluoxetine and ketamine bind to the p75 neurotrophin receptor (p75NTR) and trigger its proteolysis by α- and γ-secretase, leading to p75NTR nuclear localization. These drugs also enhance brain plasticity and extinction memory in mice and rats, and these effects depend on p75NTR signaling. The authors propose that antidepressants co-opt both the BDNF/TrkB and proBDNF/p75NTR systems to promote activity-dependent synaptic competition and brain remodeling.