NMDAR-independent, cAMP-dependent antidepressant actions of ketamine.
Nathan H Wray, Jeffrey M Schappi, Harinder Singh, Nicolas B Senese, Mark M Rasenick
Molecular Psychiatry December 2019 DOI: 10.1038/s41380-018-0083-8 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro cell study Peer reviewed |
|---|---|
| Population | C6 glioma cells |
| Interventions | Ketamine (2R 6R)-hydroxynorketamine (HNK) |
| Dose | 10 µM ketamine, 10 µM (2R,6R)-hydroxynorketamine (HNK) |
| Duration | 15 min treatment |
| Topics | Esketamine Ketamine |
| Key points | Ketamine at 10 µM for 15 minutes translocated Gαs from lipid rafts to non-raft domains in C6 glioma cells, increasing Gαs–adenylyl cyclase coupling, intracellular cAMP, CREB phosphorylation, and BDNF expression. The effect occurred independently of the NMDA receptor, and the metabolite (2R,6R)-hydroxynorketamine produced similar changes, whereas another NMDA antagonist did not. The authors propose this as a novel antidepressant mechanism and a possible marker of antidepressant action. |
Abstract
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.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cited by 39
- Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms Pharmacological Reviews June 26, 2018
- Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective Psychiatry and Clinical Neurosciences June 19, 2019
- Ketamine: A tale of two enantiomers Journal of Psychopharmacology November 6, 2020
- Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor Molecular Psychiatry May 7, 2021
- Glutamatergic Neurotransmission: Pathway to Developing Novel Rapid-Acting Antidepressant Treatments The International Journal of Neuropsychopharmacology November 14, 2018
and 34 more in the library
Cites 10
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Translational Psychiatry September 1, 2015
- Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression American Journal of Psychiatry October 1, 2015
and 5 more in the library