Abstract
Ethanol is an antagonist of the N-methyl-D-aspartate (NMDA) glutamate receptor. Ethanol dependence upregulates NMDA receptors and contributes to crosstolerance with selective NMDA receptor antagonists in animals. This study evaluated whether recovering ethanol-dependent patients show evidence of a reduced level of response to the effects of the NMDA receptor antagonist, ketamine. In this double-blind study, 34 recently detoxified alcohol-dependent patients and 26 healthy comparison subjects completed 3 test days involving a 40-min infusion of saline, ketamine 0.1 mg/kg, or ketamine 0.5 mg/kg in a randomized order. Recovering ethanol-dependent patients showed reduced perceptual alterations, dysphoric mood, and impairments in executive cognitive functions during ketamine infusion relative to the healthy comparison group. No attenuation of ketamine-induced amnestic effects, euphoria, or activation was observed. The alterations in NMDA receptor function observed in recovering ethanol-dependent patients may have important implications for ethanol tolerance, ethanol dependence, and the treatment of alcoholism.
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Acknowledgements
This research was supported by Grants 1R01 AA10121-01, RO1 AA12308-01, KO2 AA 00261-01, and P50 AA12870-01 from the National Institute on Alcohol Abuse and Alcoholism (Bethesda, MD) (Drs Krystal, Petrakis), and the Department of Veterans Affairs (Washington, DC) through funding of the Department of Veterans Affairs Alcohol Research Center and a Merit Review Grant (Drs Krystal, Petrakis). We wish to acknowledge the critical contributions to this research made by the clinical and research staff of the Biostudies Unit and Substance Abuse Treatment Unit of the VA Connecticut Healthcare System (West Haven, CT). We also thank Robert Gibbons, PhD for his consultation to the data analysis plan.
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Krystal, J., Petrakis, I., Limoncelli, D. et al. Altered NMDA Glutamate Receptor Antagonist Response in Recovering Ethanol-Dependent Patients. Neuropsychopharmacol 28, 2020–2028 (2003). https://doi.org/10.1038/sj.npp.1300252
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DOI: https://doi.org/10.1038/sj.npp.1300252
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