Attenuation of Ketamine Effects by Nimodipine Pretreatment in Recovering Ethanol Dependent Men Psychopharmacologic Implications of the Interaction of NMDA and L-Type Calcium Channel Antagonists

Abstract

Ketamine blocks the calcium channel associated with N-methyl-D-aspartate (NMDA) glutamate receptors. It has transient behavioral effects in healthy humans that resemble aspects of schizophrenia, dissociative disorders, and ethanol intoxication. Ethanol is an antagonist of both NMDA receptors and L-type voltage-sensitive calcium channels (VSCC) and it has minimal psychotogenic activity in humans. A double-blind placebo-controlled study was conducted that evaluated whether pretreatment with the L-type VSCC antagonist, nimodipine, 90 mg D, modulated ketamine response (bolus 0.26 mg/kg, infusion of 0.65 mg/ kg/hr) (Krystal et al. 1999c). In addition, these drugs produce effects in healthy human subjects that resemble aspects of the signs and symptoms of schizophrenia or dissociative disorders (Krystal et al. 25 , NO . 6 Nimodipine-Ketamine Interactions 937 1999a). As a result, ketamine administration may provide a laboratory-based approach that may contribute to the characterization of NMDA receptor contributions to cognitive function and the development of novel pharmacotherapeutic approaches that might ameliorate the consequences of NMDA receptor dysfunction. NMDA receptor antagonists also have ethanol-like behavioral effects in animals and humans (Grant and Colombo 1993;Krystal et al. 1998b;Petrakis et al. 2001). In ethanol dependent patients, ketamine effects were deemed more similar to ethanol effects than they were to the effects of marijuana or cocaine (Krystal et al. 1998b). This observation is consistent with studies indicating that NMDA receptors are among the highest affinity targets of ethanol in the brain, where it produces dose-related uncompetitive antagonism of receptor function (Grant and Lovinger 1995;Lovinger 1997). In animals, the behavioral effects of ethanol have a complex neurobiology, reflecting the interaction of the many component dose-related actions of ethanol in the brain (Green and Grant 1998).Ethanol, relative to the uncompetitive NMDA receptor antagonists phencyclidine and ketamine, has less propensity to produce psychotic symptoms in healthy humans or recovering ethanol-dependent patients (Krystal et al. 1994a;Krystal et al. 1998b;Luby et al. 1959). The limited psychotogenic propensity of ethanol at doses typically associated with human intoxication may reflect the capacity of ethanol facilitation of GABA A receptor function to moderate its NMDA antagonist effects (Grant and Lovinger 1995). Consistent with this hypothesis, some reduction in the perceptual effects of ketamine in healthy human subjects was produced by lorazepam pretreatment (Krystal et al. 1998a). However, preclinical data suggest that the capacity of ethanol to block L-type VSCCs (Crews et al. 1996) may also protect against its psychotogenic potential. In animals, components of the behavioral and discriminative stimulus effects of NMDA antagonists are attenuated by pretreatment with L-type VSCC antagonists (Green and Grant 1999;Green-Jordan and Grant 2000;Popoli et al. 1992;Sukhotina et al. 1999).The current ...

Altered NMDA Glutamate Receptor Antagonist Response in Individuals With a Family Vulnerability to Alcoholism

“…Alternatively, these responses could reflect network consequences of alterations in NMDA receptor function, such as the stimulation of the release of glutamate and dopamine (29). Clinical evidence has shown that drugs that attenuate glutamate release or glutamatergic excitability via blockade of voltage-gated cation channels reduce the dysphoric effects of ketamine and promote the euphoric effects of ketamine in both healthy subjects (30) and recovering ethanol-dependent patients (31). In fact, pretreatment with calcium channel blockers in individuals with no family history of ethanol dependence leads to a ketamine response that is more consistent with that of individuals who have a family history of ethanol dependence (30), suggesting that the alteration reflects dysfunction related to voltage-gated cation channels.…”

Glutamate and GABA systems as targets for novel antidepressant and mood-stabilizing treatments

“…Reductions in membrane depolarization by blockade of voltage-gated ion would be expected to reduce the extent to which these receptors were in the 'active state,' where they were responsive to the binding of glutamate and glycine. 91 Preliminary analyses also suggest that the alpha-2 adrenergic agonist, guanabenz, attenuates the psychotic and cognitive effects of ketamine in healthy subjects. 93 Another alpha-2 agonist, clonidine, has been reported to have some antimanic effects, although perhaps less than lithium.…”

“…For example, lamotrigine and nimodipine attenuate the magnitude of the psychosis, attention impairment and memory impairment produced by ketamine in human subjects. 90,91 In contrast, lamotrigine may have increased the euphoric and stimulatory effects of ketamine. It is not yet clear whether the enhanced euphoric response to ketamine reflects a limitation of lamotrigine in treatment of mania or its prominent antidepressant effects.…”

Altered NMDA Glutamate Receptor Antagonist Response in Recovering Ethanol-Dependent Patients

“…In particular, the changes in ketamine response observed in patients in this study are reminiscent of the impact of pretreatment with an antagonist of voltage-gated cation channels on ketamine response. Both lamotrigine and nimodipine reduce the dysphoric effects of ketamine and preserve or promote its euphoric effects in both healthy subjects (Anand et al, 2000) or recovering ethanol-dependent patients (Krupitsky et al, 2001). The effects of lamotrigine were thought to reflect, in part, its capacity to reduce the stimulatory effects of ketamine on glutamate release.…”