Characterization of the interactive effects of glycine and D-cycloserine in men: further evidence for enhanced NMDA receptor function associated with human alcohol dependence

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 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.

Figures

Figure 1

Similarity to alcohol. DCS was administered at 240 min before the infusion of glycine or saline.

Figure 2

Number of Drinks Scale (NDS). DCS was administered at 240 min before the infusion of glycine or saline.

Figure 3

Biphasic Alcohol Effects Scale (BAES) Sedative Subscale. DCS was administered at 240 min before the infusion of glycine or saline.

Figure 4

Likert scale ‘High'. DCS was administered at 240 min before the infusion of glycine or saline.

Figure 5

Continuous performance task of vigilance, A' score. -Cycloserine (DCS) was administered at 240 min before the infusion of glycine or saline.

Figure 6

Immediate recall Hopkins Verbal Learning Task (HVLT) scores. DCS was administered at 240 min before the infusion of glycine or saline.

Figure 7

Total delayed recall Hopkins Verbal Learning Task (HVLT) scores by treatment and diagnosis. DCS was administered at 240 min before the infusion of glycine or saline.

Figure 8

Plasma levels of -cycloserine (DCS), glycine, and /-serine. (a) Plasma DCS levels over time by treatment. (b) Plasma glycine levels over time by treatment. (c) Plasma /-serine levels over time by treatment. /-serine+glycine. DCS was administered at 240 min before the infusion of glycine or saline.