title: Effects of Ketamine and Ketamine Metabolites on Evoked Striatal Dopamine Release, Dopamine Receptors, and Monoamine Transporters.
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.
authors.affiliation: Department of Psychiatry (A.C., P.Z., J.F.C., D.O.F., T.D.G.), Department of Pharmacology (D.O.F, T.D.G), and Department of Anatomy and Neurobiology (J.F.C, T.D.G), University of Maryland School of Medicine, Baltimore, Maryland; Department of Psychology, Notre Dame of Maryland University, Baltimore, Maryland (A.C.); Biomedical Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland (R.M., K.S.S.D., I.W.W.); National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology, University of North Carolina Chapel Hill Medical School, Chapel Hill, North Carolina (H.J.K., X.-P.H.); and Mitchell Woods Pharmaceuticals, Shelton, Connecticut (I.W.W.).
authors.forename: Adem
authors.initials: A
authors.lastname: Can
authors.affiliation: Department of Psychiatry (A.C., P.Z., J.F.C., D.O.F., T.D.G.), Department of Pharmacology (D.O.F, T.D.G), and Department of Anatomy and Neurobiology (J.F.C, T.D.G), University of Maryland School of Medicine, Baltimore, Maryland; Department of Psychology, Notre Dame of Maryland University, Baltimore, Maryland (A.C.); Biomedical Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland (R.M., K.S.S.D., I.W.W.); National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology, University of North Carolina Chapel Hill Medical School, Chapel Hill, North Carolina (H.J.K., X.-P.H.); and Mitchell Woods Pharmaceuticals, Shelton, Connecticut (I.W.W.).
authors.forename: Panos
authors.identifier: 0000-0002-1968-8648
authors.initials: P
authors.lastname: Zanos
authors.affiliation: Department of Psychiatry (A.C., P.Z., J.F.C., D.O.F., T.D.G.), Department of Pharmacology (D.O.F, T.D.G), and Department of Anatomy and Neurobiology (J.F.C, T.D.G), University of Maryland School of Medicine, Baltimore, Maryland; Department of Psychology, Notre Dame of Maryland University, Baltimore, Maryland (A.C.); Biomedical Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland (R.M., K.S.S.D., I.W.W.); National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology, University of North Carolina Chapel Hill Medical School, Chapel Hill, North Carolina (H.J.K., X.-P.H.); and Mitchell Woods Pharmaceuticals, Shelton, Connecticut (I.W.W.).
authors.forename: Ruin
authors.identifier: 0000-0002-6812-0127
authors.initials: R
authors.lastname: Moaddel
authors.affiliation: Department of Psychiatry (A.C., P.Z., J.F.C., D.O.F., T.D.G.), Department of Pharmacology (D.O.F, T.D.G), and Department of Anatomy and Neurobiology (J.F.C, T.D.G), University of Maryland School of Medicine, Baltimore, Maryland; Department of Psychology, Notre Dame of Maryland University, Baltimore, Maryland (A.C.); Biomedical Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland (R.M., K.S.S.D., I.W.W.); National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology, University of North Carolina Chapel Hill Medical School, Chapel Hill, North Carolina (H.J.K., X.-P.H.); and Mitchell Woods Pharmaceuticals, Shelton, Connecticut (I.W.W.).
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Kang
authors.affiliation: Department of Psychiatry (A.C., P.Z., J.F.C., D.O.F., T.D.G.), Department of Pharmacology (D.O.F, T.D.G), and Department of Anatomy and Neurobiology (J.F.C, T.D.G), University of Maryland School of Medicine, Baltimore, Maryland; Department of Psychology, Notre Dame of Maryland University, Baltimore, Maryland (A.C.); Biomedical Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland (R.M., K.S.S.D., I.W.W.); National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology, University of North Carolina Chapel Hill Medical School, Chapel Hill, North Carolina (H.J.K., X.-P.H.); and Mitchell Woods Pharmaceuticals, Shelton, Connecticut (I.W.W.).
authors.forename: Katinia S S
authors.initials: KS
authors.lastname: Dossou
authors.affiliation: Department of Psychiatry (A.C., P.Z., J.F.C., D.O.F., T.D.G.), Department of Pharmacology (D.O.F, T.D.G), and Department of Anatomy and Neurobiology (J.F.C, T.D.G), University of Maryland School of Medicine, Baltimore, Maryland; Department of Psychology, Notre Dame of Maryland University, Baltimore, Maryland (A.C.); Biomedical Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland (R.M., K.S.S.D., I.W.W.); National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology, University of North Carolina Chapel Hill Medical School, Chapel Hill, North Carolina (H.J.K., X.-P.H.); and Mitchell Woods Pharmaceuticals, Shelton, Connecticut (I.W.W.).
authors.forename: Irving W
authors.initials: IW
authors.lastname: Wainer
authors.affiliation: Department of Psychiatry (A.C., P.Z., J.F.C., D.O.F., T.D.G.), Department of Pharmacology (D.O.F, T.D.G), and Department of Anatomy and Neurobiology (J.F.C, T.D.G), University of Maryland School of Medicine, Baltimore, Maryland; Department of Psychology, Notre Dame of Maryland University, Baltimore, Maryland (A.C.); Biomedical Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland (R.M., K.S.S.D., I.W.W.); National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology, University of North Carolina Chapel Hill Medical School, Chapel Hill, North Carolina (H.J.K., X.-P.H.); and Mitchell Woods Pharmaceuticals, Shelton, Connecticut (I.W.W.).
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Cheer
authors.affiliation: Department of Psychiatry (A.C., P.Z., J.F.C., D.O.F., T.D.G.), Department of Pharmacology (D.O.F, T.D.G), and Department of Anatomy and Neurobiology (J.F.C, T.D.G), University of Maryland School of Medicine, Baltimore, Maryland; Department of Psychology, Notre Dame of Maryland University, Baltimore, Maryland (A.C.); Biomedical Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland (R.M., K.S.S.D., I.W.W.); National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology, University of North Carolina Chapel Hill Medical School, Chapel Hill, North Carolina (H.J.K., X.-P.H.); and Mitchell Woods Pharmaceuticals, Shelton, Connecticut (I.W.W.).
authors.forename: Douglas O
authors.initials: DO
authors.lastname: Frost
authors.affiliation: Department of Psychiatry (A.C., P.Z., J.F.C., D.O.F., T.D.G.), Department of Pharmacology (D.O.F, T.D.G), and Department of Anatomy and Neurobiology (J.F.C, T.D.G), University of Maryland School of Medicine, Baltimore, Maryland; Department of Psychology, Notre Dame of Maryland University, Baltimore, Maryland (A.C.); Biomedical Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland (R.M., K.S.S.D., I.W.W.); National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology, University of North Carolina Chapel Hill Medical School, Chapel Hill, North Carolina (H.J.K., X.-P.H.); and Mitchell Woods Pharmaceuticals, Shelton, Connecticut (I.W.W.).
authors.forename: Xi-Ping
authors.initials: XP
authors.lastname: Huang
authors.affiliation: Department of Psychiatry (A.C., P.Z., J.F.C., D.O.F., T.D.G.), Department of Pharmacology (D.O.F, T.D.G), and Department of Anatomy and Neurobiology (J.F.C, T.D.G), University of Maryland School of Medicine, Baltimore, Maryland; Department of Psychology, Notre Dame of Maryland University, Baltimore, Maryland (A.C.); Biomedical Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland (R.M., K.S.S.D., I.W.W.); National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology, University of North Carolina Chapel Hill Medical School, Chapel Hill, North Carolina (H.J.K., X.-P.H.); and Mitchell Woods Pharmaceuticals, Shelton, Connecticut (I.W.W.) gouldlab@me.com.
authors.forename: Todd D
authors.initials: TD
authors.lastname: Gould
mesh_terms: D000818:Animals; D004298:Dopamine / Q000378:metabolism*; D007649:Ketamine / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017072:Neostriatum / Q000187:drug effects* / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism*; D011954:Receptors, Dopamine / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*
chemical_list: D050484:Norepinephrine Plasma Membrane Transport Proteins; D011954:Receptors, Dopamine; D050486:Serotonin Plasma Membrane Transport Proteins; D007649:Ketamine; D004298:Dopamine