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  • Title: AMPA Receptor Activation-Independent Antidepressant Actions of Ketamine Metabolite (S)-Norketamine.
    Author: Yang C, Kobayashi S, Nakao K, Dong C, Han M, Qu Y, Ren Q, Zhang JC, Ma M, Toki H, Yamaguchi JI, Chaki S, Shirayama Y, Nakazawa K, Manabe T, Hashimoto K.
    Journal: Biol Psychiatry; 2018 Oct 15; 84(8):591-600. PubMed ID: 29945718.
    Abstract:
    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.
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