Activity-dependent brain-derived neurotrophic factor signaling is required for the antidepressant actions of (2 R ,6 R )-hydroxynorketamine
Proceedings of the National Academy of Sciences December 17, 2018 Kenichi Fukumoto, Manoela V. Fogaça, Rong-Jian Liu et al. 191 citations
A metabolite of ketamine, (2R,6R)-hydroxynorketamine [(2R,6R)-HNK], produces rapid and sustained antidepressant effects in animal models without the side effects of ketamine and without blocking the NMDA receptor. The antidepressant effects require activity-dependent release of BDNF, mediated by stimulation of voltage-dependent Ca2+ channels. Increased BDNF release activates downstream TrkB and mechanistic target of rapamycin complex 1 signaling, which increases synaptic function of pyramidal neurons in the medial prefrontal cortex. Stimulation of BDNF release and increased synaptic function block or reverse the detrimental effects of stress and depression.