The capacity of ethanol to block N-methyl-D-aspartate (NMDA) glutamate receptors contributes to its behavioral effects in animals and humans. Recent preclinical data indicate that NMDA receptors and u opiate receptors are co-localized and have opposing actions in several brain regions involved in reward, such as the nucleus accumbens, the amygdala, and the raphe nucleus. These finds lead to the prediction that the mu receptor antagonist, naltrexone, would block the rewarding effects of NMDA antagonists, such as ketamine and ethanol. The capacity of naltrexone to attenuate the rewarding effects of ethanol contributes to its capacity to prevent episodes of drinking from becoming relapses to alcohol abuse. Similarly, our pilot data suggest that naltrexone reduces the euphoric and ethanol-like effects of subperceptual doses of ketamine. However, the mechanisms underlying the interactions of ethanol and naltrexone are not well understood. It is timely to explore the interactions of human opiate and glutamate receptor systems. Acamprostate, another promising pharmacotherapy for alcoholism, may act, in part, via glutamate receptor systems. The NIAAA multicenter study, Project COMBINE, will test the interactive effects of naltrexone and acamprostate. Better understanding of the interactions of opiate and glutamate systems may provide insights into findings from this study. In this application, we test the hypothesis that naltrexone attenuates the euphoric and ethanol-like effects of the NMDA antagonist, ketamine. We propose to examine the interactive effects of naltrexone and ketamine in 36 healthy human subjects using a randomized, balanced, placebo-controlled, within subjects design. The primary outcome measures include the visual analog scale measuring similarity to ethanol and the visual analog scale measuring """"""""high."""""""" In our previous studies, we found that the rewarding effects of ketamine were remarkably resistant to antagonism by pretreatment with haloperidol or facilitation by pretreatment with lorazepam or amphetamine. We hypothesize that ketamine may mimic some aspects of the actions of ethanol at the NMDA receptor. Thus, the blockade of the rewarding effects of ketamine by naltrexone may provide insight into an important mechanism underlying the psychopharmacology of ethanol and the treatment of alcoholism.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Alcohol and Toxicology Subcommittee 4 (ALTX)
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Witt, Ellen
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Yale University
Schools of Medicine
New Haven
United States
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Krystal, John H; Madonick, Steven; Perry, Edward et al. (2006) Potentiation of low dose ketamine effects by naltrexone: potential implications for the pharmacotherapy of alcoholism. Neuropsychopharmacology 31:1793-800
Petrakis, Ismene L; Limoncelli, Diana; Gueorguieva, Ralitza et al. (2004) Altered NMDA glutamate receptor antagonist response in individuals with a family vulnerability to alcoholism. Am J Psychiatry 161:1776-82
Krystal, John H; Petrakis, Ismene L; Limoncelli, Diana et al. (2003) Altered NMDA glutamate receptor antagonist response in recovering ethanol-dependent patients. Neuropsychopharmacology 28:2020-8