Abstract
Following administration at subanesthetic doses, (R,S)-ketamine (ketamine) induces rapid and robust relief from symptoms of depression in treatment-refractory depressed patients. Previous studies suggest that ketamine’s antidepressant properties involve enhancement of dopamine (DA) neurotransmission. Ketamine is rapidly metabolized to (2S,6S)- and (2R,6R)-hydroxynorketamine (HNK), which have antidepressant actions independent of N-methyl-d-aspartate glutamate receptor inhibition. These antidepressant actions of (2S,6S;2R,6R)-HNK, or other metabolites, as well as ketamine’s side effects, including abuse potential, may be related to direct effects on components of the dopaminergic (DAergic) system. Here, brain and blood distribution/clearance and pharmacodynamic analyses at DA receptors (D1–D5) and the DA, norepinephrine, and serotonin transporters were assessed for ketamine and its major metabolites (norketamine, dehydronorketamine, and HNKs). Additionally, we measured electrically evoked mesolimbic DA release and decay using fast-scan cyclic voltammetry following acute administration of subanesthetic doses of ketamine (2, 10, and 50 mg/kg, i.p.). Following ketamine injection, ketamine, norketamine, and multiple hydroxynorketamines were detected in the plasma and brain of mice. Dehydronorketamine was detectable in plasma, but concentrations were below detectable limits in the brain. Ketamine did not alter the magnitude or kinetics of evoked DA release in the nucleus accumbens in anesthetized mice. Neither ketamine’s enantiomers nor its metabolites had affinity for DA receptors or the DA, noradrenaline, and serotonin transporters (up to 10 μM). These results suggest that neither the side effects nor antidepressant actions of ketamine or ketamine metabolites are associated with direct effects on mesolimbic DAergic neurotransmission. Previously observed in vivo changes in DAergic neurotransmission following ketamine administration are likely indirect.
Footnotes
- Received June 14, 2016.
- Accepted July 27, 2016.
↵1 A.C. and P.Z. contributed equally to the manuscript.
This study was supported by the Intramural Research Program of the National Institutes of Health National Institute of Mental Health [Grant MH107615 to T.D.G.] and the National Institute on Aging. Receptor binding profiles, Ki determinations, and functional assays (H.J.K. and X.-P.H.) were supported by the National Institute of Mental Health Psychoactive Drug Screening Program [Contract # HHSN-271-2008-025C to Bryan L. Roth, University of North Carolina] in conjunction with Jamie Driscoll (National Institute of Mental Health, Bethesda, MD).
Ruin Moaddel and Irving W. Wainer are listed as coinventors on a patent for the use of (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydro- and hydroxylated metabolites of (R,S)-ketamine metabolites in the treatment of depression and neuropathic pain. Panos Zanos, Ruin Moaddel, Irving W. Wainer, and Todd D. Gould are listed as coinventors on a patent application for the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorders. Ruin Moaddel and Irving W. Wainer have assigned their patent rights to the U.S. government but will share a percentage of any royalties that may be received by the government. Panos Zanos and Todd D. Gould have assigned their patent rights to the University of Maryland, Baltimore, but will share a percentage of any royalties that may be received by the University of Maryland Baltimore. All other authors declare no competing interests.
- U.S. Government work not protected by U.S. copyright
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