Activity-dependent brain-derived neurotrophic factor signaling is required for the antidepressant actions of (2 R,6 R)-hydroxynorketamine

Proc Natl Acad Sci U S A. 2019 Jan 2;116(1):297-302. doi: 10.1073/pnas.1814709116. Epub 2018 Dec 17.


Ketamine, a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, produces rapid and long-lasting antidepressant effects in major depressive disorder (MDD) patients. (2R,6R)-Hydroxynorketamine [(2R,6R)-HNK], a metabolite of ketamine, is reported to produce rapid antidepressant effects in rodent models without the side effects of ketamine. Importantly, (2R,6R)-HNK does not block NMDA receptors like ketamine, and the molecular signaling mechanisms for (2R,6R)-HNK remain unknown. Here, we examined the involvement of BDNF/TrkB/mechanistic target of rapamycin complex 1 (mTORC1) signaling in the antidepressant actions of (2R,6R)-HNK. Intramedial prefrontal cortex (intra-mPFC) infusion or systemic (2R,6R)-HNK administration induces rapid and long-lasting antidepressant effects in behavioral tests, identifying the mPFC as a key region for the actions of (2R,6R)-HNK. The antidepressant actions of (2R,6R)-HNK are blocked in mice with a knockin of the BDNF Val66Met allele (which blocks the processing and activity-dependent release of BDNF) or by intra-mPFC microinjection of an anti-BDNF neutralizing antibody. Blockade of L-type voltage-dependent Ca2+ channels (VDCCs), required for activity-dependent BDNF release, also blocks the actions of (2R,6R)-HNK. Intra-mPFC infusion of pharmacological inhibitors of TrkB or mTORC1 signaling, which are downstream of BDNF, also block the actions of (2R,6R)-HNK. Moreover, (2R,6R)-HNK increases synaptic function in the mPFC. These findings indicate that activity-dependent BDNF release and downstream TrkB and mTORC1 signaling, which increase synaptic function in the mPFC, are required for the rapid and long-lasting antidepressant effects of (2R,6R)-HNK, supporting the potential use of this metabolite for the treatment of MDD.

Keywords: (2R,6R)-hydroxynorketamine; BDNF; depression; ketamine; mTORC1.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology*
  • Brain-Derived Neurotrophic Factor / metabolism*
  • Cells, Cultured
  • Depression / drug therapy
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Ketamine / analogs & derivatives*
  • Ketamine / pharmacology
  • Mechanistic Target of Rapamycin Complex 1 / antagonists & inhibitors
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Neurons / drug effects
  • Neurons / metabolism
  • Signal Transduction / drug effects
  • Synaptic Transmission / drug effects


  • Antidepressive Agents
  • Brain-Derived Neurotrophic Factor
  • Ketamine
  • 6-hydroxynorketamine
  • Mechanistic Target of Rapamycin Complex 1