NMDAR-independent, cAMP-dependent antidepressant actions of ketamine


Ketamine produces rapid and robust antidepressant effects in depressed patients within hours of administration, often when traditional antidepressant compounds have failed to alleviate symptoms. We hypothesized that ketamine would translocate Gαs from lipid rafts to non-raft microdomains, similarly to other antidepressants but with a distinct, abbreviated treatment duration. C6 glioma cells were treated with 10 µM ketamine for 15 min, which translocated Gαs from lipid raft domains to non-raft domains. Other NMDA antagonist did not translocate Gαs from lipid raft to non-raft domains. The ketamine-induced Gαs plasma membrane redistribution allows increased functional coupling of Gαs and adenylyl cyclase to increase intracellular cyclic adenosine monophosphate (cAMP). Moreover, increased intracellular cAMP increased phosphorylation of cAMP response element-binding protein (CREB), which, in turn, increased BDNF expression. The ketamine-induced increase in intracellular cAMP persisted after knocking out the NMDA receptor indicating an NMDA receptor-independent effect. Furthermore, 10 µM of the ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) also induced Gαs redistribution and increased cAMP. These results reveal a novel antidepressant mechanism mediated by acute ketamine treatment that may contribute to ketamine’s powerful antidepressant effect. They also suggest that the translocation of Gαs from lipid rafts is a reliable hallmark of antidepressant action that might be exploited for diagnosis or drug development.

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This research is supported by VA Merit Award BX00149 (MMR) and NIH R01AT009169 (MMR). NHW and JS were supported by T32 MH067631 and HS by an AHA postdoctoral fellowship. (2R,6R)-HNK was gifted by the NIH.

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Correspondence to Mark M. Rasenick.

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MMR has received research support from Eli Lilly and Lundbeck, Inc. and is consultant to Otsuka Pharmaceuticals. He also has ownership in Pax Neuroscience. The remaining authors declare that they have no conflict of interest.

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Wray, N.H., Schappi, J.M., Singh, H. et al. NMDAR-independent, cAMP-dependent antidepressant actions of ketamine. Mol Psychiatry 24, 1833–1843 (2019). https://doi.org/10.1038/s41380-018-0083-8

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