Norketamine, the main metabolite of ketamine, is a non-competitive NMDA receptor antagonist in the rat cortex and spinal cord

Ebert, Bjarke; Mikkelsen, Søren; Thorkildsen, Christian; Borgbjerg, Finn Molke

doi:10.1016/s0014-2999(97)01116-3

Cited by 224 publications

(177 citation statements)

References 27 publications

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“…Ketamine is a noncompetitive N-methyl-D-aspartate glutamate receptor (NMDAR) antagonist [K i 5 0.2-1.6 mM, with (S)-ketamine approximately 4-fold more potent than (R)-ketamine] (Parsons et al, 1995;Ebert et al, 1997;Moaddel et al, 2013). (S)-and (R)-norketamine are less potent NMDAR antagonists (K i 5 1.7-2.25 and 13-26 mM, (n = 9; three independent experiments and three replicates per experiment).…”

Section: Lack Of Direct Effects Of Ketamine On Daergic Functionmentioning

confidence: 99%

Effects of Ketamine and Ketamine Metabolites on Evoked Striatal Dopamine Release, Dopamine Receptors, and Monoamine Transporters

Can

Zanos

Moaddel³

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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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 Nmethyl-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 (D 1 -D 5 ) 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 mM). 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.

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Section: Lack Of Direct Effects Of Ketamine On Daergic Functionmentioning

confidence: 99%

Effects of Ketamine and Ketamine Metabolites on Evoked Striatal Dopamine Release, Dopamine Receptors, and Monoamine Transporters

Can

Zanos

Moaddel³

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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“…First, because NBQX does not block N-methyl-D-aspartate (NMDA)-type glutamate receptors, which are present in the IO (Petralia et al 1994), it is possible that the remaining spontaneous CS activity may have been in response to NMDA-mediated excitation. However, this possibility is unlikely because of several reasons discussed previously (Lang 2001), including the voltage dependence of NMDA channels, the loss of glutamate-mediated, stimulus-evoked CSs with intra-IO injections of NBQX, and the fact that the anesthetic that was used, ketamine, is an NMDA channel blocker (Ebert et al 1997) and was likely present in concentrations well above those needed to block NMDA receptors. Second, other transmitters found within the IO can influence the excitability of IO neurons and may be capable of triggering spike activity.…”

Section: Origin and Modulation Of Spontaneous Olivocerebellar Activitymentioning

confidence: 99%

GABAergic and Glutamatergic Modulation of Spontaneous and Motor-Cortex-Evoked Complex Spike Activity

Lang

2002

Journal of Neurophysiology

109

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Lang, Eric J. GABAergic and glutamatergic modulation of spontaneous and motor-cortex-evoked complex spike activity. J Neurophysiol 87: 1993Neurophysiol 87: -2008Neurophysiol 87: , 2002 10.1152/jn.00477.2001. Olivocerebellar activity is organized such that synchronous complex spikes occur primarily among Purkinje cells located within the same parasagittally oriented strip of cortex. Previous findings have shown that this synchrony distribution is modulated by the release of GABA and glutamate within the inferior olive, which probably act by controlling the efficacy of the electrotonic coupling between olivary neurons. The relative strengths of these two neurotransmitters in modulating the patterns of synchrony were compared by obtaining multiple electrode recordings of spontaneous crus 2a complex spike activity during intraolivary injection of solutions containing a GABA A (picrotoxin) and/or AMPA [1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide disodium (NBQX)] receptor antagonist. Injection of either antagonist led to increased synchrony between cells located within the same parasagittally oriented Ϸ250-m-wide cortical strip. Picrotoxin also increased complex spike synchrony among cells located in different cortical strips, leading to a less prominent banding pattern, whereas injections of NBQX tended to decrease complex spike synchrony among such cells, enhancing the banding pattern. The relative strength of these two classes of olivary afferents was assessed by first injecting one of the antagonists alone and then in combination with the other. The enhanced banding pattern of complex spike synchrony following injection of NBQX alone remained during the subsequent combined injection of both antagonists. Furthermore, the widespread synchronization of complex spike activity following injection of picrotoxin alone was partially or completely reversed by combined injection of picrotoxin and NBQX. Changes in the climbing fiber reflex induced by the intraolivary injections paralleled the changes observed for spontaneous complex spike activity, indicating that the effects of picrotoxin and NBQX on the synchrony distribution reflect changes in the pattern of effective coupling of inferior olivary neurons and demonstrating that synchronous complex spike activity does not require simultaneous excitatory input to olivary cells. Finally the pattern of synchrony during motor cortical stimulation was examined. It was found that the patterns of synchrony for motor-cortex-evoked complex spike activity were similar to those of spontaneous activity, indicating an important role for electrotonic coupling in determining the response of the olivocerebellar system to afferent input. Moreover, intraolivary injections of picrotoxin increased the spatial distribution of the evoked response. In sum, the results provide evidence for the hypothesis that electrotonic coupling of inferior olivary neurons via gap junctions is the mechanism underlying complex spike synchrony and that this coupling plays an important ...

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“…(S)-Ketamine has an approximately 5-fold greater N-methyl-D-aspartate affinity and 4-fold greater analgesic potency, compared with (R)-ketamine, and is associated with less psychotomimetic effects (White et al, 1980;Mathisen et al, 1995;Ebert et al, 1997). Furthermore, the plasma clearance of (S)-ketamine is approximately 22% faster in vivo (White et al, 1985).…”

Section: Introductionmentioning

confidence: 99%

TheCYP2B6*6Allele Significantly Alters theN-Demethylation of Ketamine Enantiomers In Vitro

Coller

Hutchinson

et al. 2013

Drug Metab Dispos

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Ketamine is primarily metabolized to norketamine by hepatic CYP2B6 and CYP3A4-mediated N-demethylation. However, the relative contribution from each enzyme remains controversial. The CYP2B6*6 allele is associated with reduced enzyme expression and activity that may lead to interindividual variability in ketamine metabolism. We examined the N-demethylation of individual ketamine enantiomers using human liver microsomes (HLMs) genotyped for the CYP2B6*6 allele, insect cell-expressed recombinant CYP2B6 and CYP3A4 enzymes, and COS-1 cell-expressed recombinant CYP2B6.1 and CYP2B6.6 protein variant. Effects of CYP-selective inhibitors on norketamine formation were also determined in HLMs. The two-enzyme Michaelis-Menten model best fitted the HLM kinetic data. The Michaelis-Menten constants (K m ) for the highaffinity enzyme and the low-affinity enzyme were similar to those for the expressed CYP2B6 and CYP3A4, respectively. The intrinsic clearance for both ketamine enantiomers by the high-affinity enzyme in HLMs with CYP2B6*1/*1 genotype were at least 2-fold and 6-fold higher, respectively, than those for CYP2B6*1/*6 genotype and CYP2B6*6/*6 genotype. The V max and K m values for CYP2B6.1 were approximately 160 and 70% of those for CYP2B6.6, respectively. N,N9N9-triethylenethiophosphoramide (thioTEPA) (CYP2B6 inhibitor, 25 mM) and the monoclonal antibody against CYP2B6 but not troleandomycin (CYP3A4 inhibitor, 25 mM) or the monoclonal antibody against CYP3A4 inhibited ketamine N-demethylation at clinically relevant concentrations. The degree of inhibition was significantly reduced in HLMs with the CYP2B6*6 allele (genedose P < 0.05). These results indicate a major role of CYP2B6 in ketamine N-demethylation in vitro and a significant impact of the CYP2B6*6 allele on enzyme-ketamine binding and catalytic activity.

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Norketamine, the main metabolite of ketamine, is a non-competitive NMDA receptor antagonist in the rat cortex and spinal cord

Cited by 224 publications

References 27 publications

Effects of Ketamine and Ketamine Metabolites on Evoked Striatal Dopamine Release, Dopamine Receptors, and Monoamine Transporters

Effects of Ketamine and Ketamine Metabolites on Evoked Striatal Dopamine Release, Dopamine Receptors, and Monoamine Transporters

GABAergic and Glutamatergic Modulation of Spontaneous and Motor-Cortex-Evoked Complex Spike Activity

TheCYP2B6*6Allele Significantly Alters theN-Demethylation of Ketamine Enantiomers In Vitro

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