Psychedelics promote plasticity by directly binding to BDNF receptor TrkB

Area of Science:

• Neuroscience
• Pharmacology
• Psychiatry

Background:

• Antidepressants, including fluoxetine and ketamine, act via TrkB receptor binding.
• Psychedelics demonstrate rapid and lasting antidepressant effects, inducing neuroplasticity.
• The precise molecular targets and mechanisms underlying psychedelic antidepressant action remain under investigation.

Purpose of the Study:

• To investigate the direct binding of psychedelics to the TrkB receptor.
• To elucidate the role of TrkB activation in the antidepressant-like effects of psychedelics.
• To differentiate the mechanisms of psychedelic antidepressant effects from their hallucinogenic properties.

Main Methods:

• In vitro binding assays to determine affinity for TrkB receptor.
• Assessment of neurotrophic signaling and plasticity in response to psychedelics and antidepressants.
• Behavioral studies in mice to evaluate antidepressant-like effects.
• Pharmacological manipulations to assess the role of TrkB and serotonin 2A (5-HT2A) receptors.

Main Results:

• Lysergic acid diethylamide (LSD) and psilocin bind directly to TrkB with significantly higher affinity than other antidepressants.
• Psychedelic-induced neuroplasticity and antidepressant-like behaviors in mice are dependent on TrkB activation and BDNF signaling.
• LSD-induced head-twitching behavior is mediated by 5-HT2A receptor activation, independent of TrkB binding.

Conclusions:

• TrkB serves as a common primary target for both psychedelics and traditional antidepressants.
• High-affinity TrkB modulators without 5-HT2A activity could offer antidepressant benefits of psychedelics without hallucinogenic side effects.
• This research identifies TrkB as a key mediator of antidepressant actions, opening avenues for novel therapeutic strategies.