AMPA receptor activation-independent antidepressant actions of ketamine metabolite ( S )-norketamine. Yang, C., Kobayashi, S., Nakao, K., Dong, C., Han, M., Qu, Y., Ren, Q., Zhang, J., C., Ma, M., Toki, H., Yamaguchi, J., Chaki, S., Shirayama, Y., Nakazawa, K., Manabe, T., & Hashimoto, K. Biological Psychiatry, 5, 2018.
AMPA receptor activation-independent antidepressant actions of ketamine metabolite ( S )-norketamine [link]Website  abstract   bibtex   
BACKGROUND Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, exerts robust antidepressant effects in treatment-resistant depressed patients. The precise mechanisms underlying ketamine’s antidepressant actions remain unclear, although previous research suggests that α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) activation plays a role. Here, 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 The 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 (CSDS) models. Furthermore, (S)-norketamine induced more beneficial effects on decreased dendritic spine density and synaptogenesis in the prefrontal cortex (PFC) 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 NMDAR-mediated synaptic currents, (S)-norketamine did not enhance AMPAR-mediated neurotransmission in hippocampal neurons. Furthermore, (S)-norketamine improved the reductions in brain-derived neurotrophic factor (BDNF)–tropomyosin-related kinase B (TrkB) signaling in the PFC of CSDS susceptible mice, whereas the TrkB antagonist and a mechanistic target of rapamycin (mTOR) inhibitor blocked the antidepressant effects of (S)-norketamine. Unlike (S)-ketamine, (S)-norketamine did not cause behavioral abnormalities, such as prepulse inhibition deficits, reward effects, loss of parvalbumin immunoreactivity in the medial PFC, or baseline γ-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.
@article{
 title = {AMPA receptor activation-independent antidepressant actions of ketamine metabolite ( S )-norketamine},
 type = {article},
 year = {2018},
 identifiers = {[object Object]},
 websites = {http://linkinghub.elsevier.com/retrieve/pii/S000632231831521X},
 month = {5},
 id = {dfc70139-9bf2-31df-8907-0e6e758d5933},
 created = {2018-05-20T13:47:18.086Z},
 accessed = {2018-05-20},
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 profile_id = {48f1fda5-0084-39cd-8cc7-68fcbd29ae85},
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 last_modified = {2019-10-23T13:46:50.267Z},
 tags = {CA},
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 starred = {false},
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 citation_key = {Yang2018a},
 notes = {FL},
 private_publication = {false},
 abstract = {BACKGROUND
Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, exerts robust antidepressant effects in treatment-resistant depressed patients. The precise mechanisms underlying ketamine’s antidepressant actions remain unclear, although previous research suggests that α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) activation plays a role. Here, 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
The 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 (CSDS) models. Furthermore, (S)-norketamine induced more beneficial effects on decreased dendritic spine density and synaptogenesis in the prefrontal cortex (PFC) 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 NMDAR-mediated synaptic currents, (S)-norketamine did not enhance AMPAR-mediated neurotransmission in hippocampal neurons. Furthermore, (S)-norketamine improved the reductions in brain-derived neurotrophic factor (BDNF)–tropomyosin-related kinase B (TrkB) signaling in the PFC of CSDS susceptible mice, whereas the TrkB antagonist and a mechanistic target of rapamycin (mTOR) inhibitor blocked the antidepressant effects of (S)-norketamine. Unlike (S)-ketamine, (S)-norketamine did not cause behavioral abnormalities, such as prepulse inhibition deficits, reward effects, loss of parvalbumin immunoreactivity in the medial PFC, or baseline γ-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.},
 bibtype = {article},
 author = {Yang, Chun and Kobayashi, Shizuka and Nakao, Kazuhito and Dong, Chao and Han, Mei and Qu, Youge and Ren, Qian and Zhang, Ji Chun and Ma, Min and Toki, Hidetoh and Yamaguchi, Jun-ichi and Chaki, Shigeyuki and Shirayama, Yukihiko and Nakazawa, Kazu and Manabe, Toshiya and Hashimoto, Kenji},
 journal = {Biological Psychiatry}
}
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