Absence of significant interactive effects of high-dose D-cycloserine and ethanol in healthy human subjects: preliminary insights into ethanol actions at the glycine B site of NMDA glutamate receptors.
BACKGROUND
Ethanol reduces N-methyl-d-aspartate (NMDA) glutamate receptor function via multiple cellular targets. It is not yet clear whether direct ethanol antagonism of the glycine(B) co-agonist site of NMDA receptors is relevant to this effect. The purpose of this study was to evaluate whether ethanol effects at the glycine(B) co-agonist site was clinically relevant by evaluating some aspects of the psychopharmacologic interactions between the glycine(B) partial agonist, D-cycloserine (DCS), and ethanol in healthy human subjects.


METHODS
All subjects completed 4 test days under double-blind conditions in which DCS or placebo was administered orally prior to ethanol or an ethanol-tainted placebo drink. Two groups of healthy subjects were studied. A first group of subjects (n = 25) were pretreated orally with DCS 500 mg or placebo 4 hours prior to ethanol (0.8 g/kg, p.o. or placebo) administration. A second group of subjects (n = 20) were pretreated with DCS 1000 mg or placebo prior to ethanol administration. Outcomes included subjective and cognitive responses to the experimental interventions.


RESULTS
Predictable ethanol responses were observed in both groups of subjects, although the response to ethanol and the breath alcohol levels, but not plasma alcohol levels, were slightly but significantly lower in the group that received the higher DCS dose. DCS produced mild sedative effects that were greater for the lower than the higher dose. It also produced a mild impairment of verbal fluency without impairing attention. No statistically significant interactions between ethanol and DCS emerged in analyses. However, the combination of ethanol and DCS produced significantly greater impairment than both ethanol or DCS administered alone on a test of verbal fluency and aspects of memory function.


CONCLUSIONS
DCS and ethanol both produced sedative and cognitive effects, consistent with their ability to reduce NMDA receptor function. However, the absence of interactive effects observed in this study raises questions about the clinical significance of the glycine(B) site as a target for ethanol in the brain at levels of ethanol intoxication associated with social drinking. However, it should be noted that this conclusion is limited to the dependent measures evaluated and the doses of ethanol and DCS studied.
Trevisan
Louis
L
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA.
Petrakis
Ismene L
IL
Pittman
Brian
B
Gueorguieva
Ralitza
R
D'Souza
D Cyril
DC
Perry
Edward
E
Limoncelli
Diana
D
Krystal
John H
JH
D000328:Adult; D000435:Alcoholic Intoxication / Q000188:drug therapy*; D001944:Breath Tests; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D003071:Cognition / Q000187:drug effects*; D003523:Cycloserine / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D000431:Ethanol / Q000097:blood / Q000494:pharmacology*; D005260:Female; D005998:Glycine / Q000378:metabolism; D006801:Humans; D008297:Male; D011939:Mental Recall / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists* / Q000378:metabolism; D013060:Speech / Q000187:drug effects
D002492:Central Nervous System Depressants; D016194:Receptors, N-Methyl-D-Aspartate; D000431:Ethanol; D003523:Cycloserine; D005998:Glycine