NMDAR-independent, cAMP-dependent antidepressant actions of ketamine

• Published in: Molecular psychiatry Vol. 24; no. 12; pp. 1833 - 1843
• Main Authors: Wray, Nathan H., Schappi, Jeffrey M., Singh, Harinder, Senese, Nicolas B., Rasenick, Mark M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.12.2019; Nature Publishing Group
• Subjects: 13/1; 13/89; 13/95; 14/19; 14/35; 42/109; 631/378; 692/53/2423; 82/80; Adenylate cyclase; AMP; Antidepressants; Antidepressants, Tricyclic; Antidepressive Agents - pharmacology; Behavioral Sciences; Biological Psychology; Brain-derived neurotrophic factor; Brain-Derived Neurotrophic Factor - metabolism; Cell Line; Cyclic adenylic acid; Cyclic AMP - metabolism; Cyclic AMP response element-binding protein; Cyclic AMP Response Element-Binding Protein - metabolism; Depression - drug therapy; Drug development; Drug therapy; Ethylenediaminetetraacetic acid; Glioma; Glioma - metabolism; Glioma cells; Gliomas; Glutamic acid receptors (ionotropic); Humans; Intracellular; Ketamine; Ketamine - pharmacology; Lipid rafts; Lipids; Medicine; Medicine & Public Health; Membrane Microdomains - drug effects; Metabolites; N-Methyl-D-aspartic acid receptors; Neurosciences; Pharmacotherapy; Phosphorylation; Protein binding; Psychiatry; Receptors, N-Methyl-D-Aspartate - metabolism
• ISSN: 1359-4184; 1476-5578; 1476-5578
• DOI: 10.1038/s41380-018-0083-8

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 Gα s 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 Gα s from lipid raft domains to non-raft domains. Other NMDA antagonist did not translocate Gα s from lipid raft to non-raft domains. The ketamine-induced Gα s plasma membrane redistribution allows increased functional coupling of Gα s 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 Gα s 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 Gα s from lipid rafts is a reliable hallmark of antidepressant action that might be exploited for diagnosis or drug development.