Abstract
Reduced responses to N-methyl-D-aspartate (NMDA) glutamate receptor antagonists in alcohol-dependent animals and humans provided evidence that chronic alcohol consumption increased NMDA receptor function. To further probe alterations in NMDA glutamate receptor function associated with human alcohol dependence, this study examined the interactive effects of agents acting at the glycineB coagonist site of the NMDA receptor. In doing so, it tested the hypothesis that raising brain glycine concentrations would accentuate the antagonist-like effects of the glycineB partial agonist, D-cycloserine (DCS). Twenty-two alcohol-dependent men and 22 healthy individuals completed 4 test days, during which glycine 0.3 g/kg or saline were administered intravenously and DCS 1000 mg or placebo were administered orally. The study was conducted under double-blind conditions with randomized test day assignment. In this study, DCS produced alcohol-like effects in healthy subjects that were deemed similar to a single standard alcohol drink. The alcohol-like effects of DCS were blunted in alcohol-dependent patients, providing additional evidence of increased NMDA receptor function in this group. Although glycine administration reduced DCS plasma levels, glycine accentuated DCS effects previously associated with the NMDA receptor antagonists, ketamine and ethanol. Thus, this study provided evidence that raising glycine levels accentuated the NMDA receptor antagonist-like effects of DCS and that alcohol-dependent patients showed tolerance to these DCS effects.
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Acknowledgements
This work was generously supported by Department of Veterans Affairs (Merit Review Grant, Alcohol Research Center, Merit Review Grant, National Center for PTSD), the National Institute on Alcohol Abuse and Alcoholism (K05 AA-14906-01, I-P50 AA-12870), and the Yale Center for Clinical Investigation (CTSA). We gratefully acknowledge the critical expert contributions of the research nursing staff of the VA Connecticut Healthcare System Biostudies Unit, Ms Angelina Genovese and Ms Elizabeth O’Donnell.
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During the period 2007–2010, Dr Krystal has served as a scientific consultant to the following companies: Aisling Capital, LLC, AstraZeneca Pharmaceuticals, Brintnall & Nicolini, Cypress Bioscience, Easton Associates, Eli Lilly and Company, F. Hoffmann-La Roche, Forest Laboratories, Gilead Sciences, Glaxo SmithKline, HoustonPharma, Lohocla Research Corporation, Lundbeck Research USA, Merz Pharmaceuticals, MK Medical Communications, Naurex, Pfizer Pharmaceuticals, Schering-Plough Research Institute, SK Holdings, Takeda Industries, Teva Pharmaceutical Industries, and Transcept Pharmaceuticals. Dr Krystal holds less than US$500 in exercisable warrant options with Transcept Pharmaceuticals. He is the principal investigator of a multicenter study in which Janssen Research Foundation has provided drug and some support to the Department of Veterans Affairs. Dr Krystal is a co-sponsor for two patents under review for glutamatergic agents targeting the treatment of depression. Dr D’Souza has been the principal investigator for studies which Yale University School of Medicine receives funding from Pfizer Pharmaceuticals, Cephalon, Abbott Laboratories, Astra Zeneca, Organon/Schering Plough, Sanofi-Aventis, and GlaxoSmithKline in the past 5 years. Dr Ismene Petrakis, Diana Limoncelli, Susan Krasnicki Nappi, Dr Louis Trevisan, and Brian Pittman declare no conflict of interest.
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Krystal, J., Petrakis, I., Limoncelli, D. et al. Characterization of the Interactive Effects of Glycine and D-Cycloserine in Men: Further Evidence for Enhanced NMDA Receptor Function Associated with Human Alcohol Dependence. Neuropsychopharmacol 36, 701–710 (2011). https://doi.org/10.1038/npp.2010.203
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DOI: https://doi.org/10.1038/npp.2010.203
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