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 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.

Mechanisms of ketamine action as an antidepressant

“…Indeed, a net result of all these processes is a sustained potentiation of excitatory synapses in cortico-mesolimbic brain circuits involved in the maintenance of mood and stress-reactivity 190 . Additional mechanisms, not discussed in the present review, include ketamine’s effects on the monoaminergic systems 191–194 , as well as its anti-inflammatory actions, which are postulated to be involved in the mechanisms underlying its antidepressant actions; the reader is directed to reviews by Sleigh et al (2014) 195 and Loix et al (2011) 196 .…”

Convergent Mechanisms Underlying Rapid Antidepressant Action

“…Notably, it was recently demonstrated that higher brain levels of the ( 2S,6S;2R,6R )-HNK metabolite of ketamine in female mice might be associated with these enhanced antidepressant behavioral actions of ketamine in female compared to male mice [45]. ( 2S,6S;2R,6R )-HNK is the most prominent HNK metabolite present in the plasma and brain of mice [45, 102] and the plasma of treatment-resistant patients with depression [103] following a single ketamine administration. Similar to the preclinical findings, higher levels of this metabolite have been measured in the plasma of female patients compared with male patients following a single infusion of ketamine, but this difference was not associated with any significantly different antidepressant responses in these patients [103].…”

Ketamine and its metabolite (2R,6R)-hydroxynorketamine induce lasting alterations in glutamatergic synaptic plasticity in the mesolimbic circuit

“…Indeed, ketamine and its metabolites, in particular (2R,6R)-HNK, are still present in plasma and brain 30-60 min after their injection. 29 We did not examine the effect of chronic administration of ketamine or (2R,6R)-HNK, because antidepressant actions are observed following a single injection and chronic ketamine treatment has no effect on depression-like behavior. 30 We measured fEPSP/PSs mediated by AMPARs in the core region of the NAc in brain slices as described previously 28 ( Supplementary Figure 1).…”