Characterization of the interactive effects of glycine and D-cycloserine in men: further evidence for enhanced NMDA receptor function associated with human alcohol dependence.
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 glycine(B) 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 glycine(B) 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.
Department of Psychiatry, NIAAA Center for the Translational Neuroscience of Alcoholism, Yale University School of Medicine, New Haven, CT 06511, USA. john.krystal@yale.edu
John H
JH
Krystal
Ismene L
IL
Petrakis
Diana
D
Limoncelli
Susan Krasnicki
SK
Nappi
Louis
L
Trevisan
Brian
B
Pittman
Deepak C
DC
D'Souza
Raymond F
RF
Suckow
D000328:Adult; D000437:Alcoholism / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology; D000647:Amnesia / Q000139:chemically induced; D000963:Antimetabolites / Q000008:administration & dosage* / Q000097:blood; D001143:Arousal / Q000187:drug effects; D002853:Chromatography, Liquid / Q000379:methods; D003071:Cognition / Q000187:drug effects; D003523:Cycloserine / Q000008:administration & dosage* / Q000097:blood; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004347:Drug Interactions; D000431:Ethanol / Q000009:adverse effects; D005998:Glycine / Q000008:administration & dosage* / Q000097:blood; D006801:Humans; D008297:Male; D011939:Mental Recall / Q000187:drug effects; D008875:Middle Aged; D009483:Neuropsychological Tests; D012720:Severity of Illness Index; D013997:Time Factors
D000963:Antimetabolites; D000431:Ethanol; D003523:Cycloserine; D005998:Glycine