Inhibition by ketamine of muscarinic acetylcholine receptor function.
M E Durieux
Anesthesia and analgesia July 1, 1995 DOI: 10.1097/00000539-199507000-00012 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro study using recombinant receptor expression in Xenopus oocytes Peer reviewed |
|---|---|
| Population | Xenopus oocytes expressing recombinant m1 muscarinic receptors or AT1A angiotensin receptors |
| Interventions | Ketamine Angiotensin II |
| Dose | MCh 10(-6)M; ketamine approximately 200 microM for complete inhibition, IC50 5.7 microM (1.56 micrograms/mL); ketamine 365 microM in the angiotensin II experiments; angiotensin II 10(-6) M |
| Measures | Charge movement through Ca(2+)-activated Cl- channels (intracellular Ca2+ release), currents induced by angiotensin II |
| Topics | Ketamine Esketamine |
| Keywords | Oocytes Animals Xenopus Methacholine chloride Muscarine Biphenyl compounds Losartan Tetrazoles Imidazoles Angiotensin ii Calcium channels Chloride channels Receptors, muscarinic Receptors, n-methyl-d-aspartate Receptors, phencyclidine Muscarinic antagonists Signal transduction Recombination, genetic Membrane potentials Female Angiotensin receptor antagonists |
| Key points | Ketamine inhibited m1 muscarinic receptor-mediated calcium signaling in Xenopus oocytes with an IC50 of 5.7 microM and complete inhibition at about 200 microM, a range the authors describe as clinically relevant. Ketamine (365 microM) did not inhibit angiotensin II-induced currents, suggesting the effect is specific to muscarinic signaling. The authors propose this may explain some anticholinergic effects of ketamine. |
Abstract
Although ketamine's primary site of action appears to be the phencyclidine receptor on the N-methyl-D-aspartate (NMDA) receptor complex, additional activity on opiate and quisqualate receptors is suggested. Some phencyclidines have been shown to interact with muscarinic receptors, but this has not been determined for ketamine. We studied the interaction between ketamine and the m1 muscarinic receptor, the most prominent subtype in cortex and hippocampus. Receptors were expressed recombinantly in Xenopus oocytes, and intracellular Ca2+ release in response to the agonist acetyl-beta-methylcholine (MCh, 10(-6)M) was assessed by measuring charge movement through Ca(2+)-activated Cl- channels. Average responses to MCh were 4.1 +/- 0.7 microC. Ketamine inhibited responses to MCh, with complete inhibition at approximately 200 microM ketamine. The IC50 was 5.7 microM, (1.56 micrograms/mL), well within the clinically relevant concentration range. To demonstrate that intracellular signaling pathways and the Ca2+ activated Cl- channel were not affected by ketamine, we tested the effect of ketamine (365 microM) on currents induced by angiotensin II (10(-6) M) in oocytes expressing the AT1A angiotensin receptor. No inhibitory effect was noted. In summary, ketamine profoundly inhibits muscarinic signaling. This effect might explain some of the anticholinergic clinical effects of ketamine, both central (effects on memory and consciousness) and peripheral (prominent sympathetic tone, bronchodilation, mydriasis).
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
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