AMPA Receptor Activation-Independent Antidepressant Actions of Ketamine Metabolite (S)-Norketamine

Biol Psychiatry. 2018 Oct 15;84(8):591-600. doi: 10.1016/j.biopsych.2018.05.007. Epub 2018 May 14.


Background: Ketamine, an N-methyl-D-aspartate receptor antagonist, exerts robust antidepressant effects in patients with treatment-resistant depression. The precise mechanisms underlying ketamine's antidepressant actions remain unclear, although previous research suggests that alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) activation plays a role. We investigated whether (S)-norketamine and (R)-norketamine, the two main metabolites of (R,S)-ketamine, also play a significant role in ketamine's antidepressant effects and whether the effects are mediated by AMPAR.

Methods: Cellular mechanisms of antidepressant action of norketamine enantiomers were examined in mice.

Results: (S)-Norketamine had more potent antidepressant effects than (R)-norketamine in inflammation and chronic social defeat stress models. Furthermore, (S)-norketamine induced more beneficial effects on decreased dendritic spine density and synaptogenesis in the prefrontal cortex and hippocampus compared with (R)-norketamine. Unexpectedly, AMPAR antagonists did not block the antidepressant effects of (S)-norketamine. The electrophysiological data showed that, although (S)-norketamine inhibited N-methyl-D-aspartate receptor-mediated synaptic currents, (S)-norketamine did not enhance AMPAR-mediated neurotransmission in hippocampal neurons. Furthermore, (S)-norketamine improved reductions in brain-derived neurotrophic factor-tropomyosin receptor kinase B signaling in the prefrontal cortex of mice susceptible to chronic social defeat stress, whereas the tropomyosin receptor kinase B antagonist and a mechanistic target of rapamycin inhibitor blocked the antidepressant effects of (S)-norketamine. In contrast to (S)-ketamine, (S)-norketamine did not cause behavioral abnormalities, such as prepulse inhibition deficits, reward effects, loss of parvalbumin immunoreactivity in the medial prefrontal cortex, or baseline gamma-band oscillation increase.

Conclusions: Our data identified a novel AMPAR activation-independent mechanism underlying the antidepressant effects of (S)-norketamine. (S)-Norketamine and its prodrugs could be novel antidepressants without the detrimental side effects of (S)-ketamine.

Keywords: AMPAR; Antidepressant; BDNF; Esketamine; NMDAR; Norketamine.

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
  • Dendritic Spines / metabolism
  • Depression / drug therapy*
  • Hippocampus / metabolism*
  • Ketamine / analogs & derivatives*
  • Ketamine / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Prefrontal Cortex / metabolism
  • Receptors, AMPA / metabolism
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Stress, Psychological / drug therapy


  • Antidepressive Agents
  • Brain-Derived Neurotrophic Factor
  • Receptors, AMPA
  • Receptors, N-Methyl-D-Aspartate
  • Ketamine
  • norketamine