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.

Glutamate Signaling in Alcohol Abuse and Dependence

“…Behavioral measures in human alcoholics reveal reduced sensitivity to the perceptual and cognitive disrupting effects of the noncompetitive NMDA antagonist ketamine (Krystal et al, 2003). Human alcoholics also reported less alcohollike effect of the partial glycine agonist D-cycloserine as compared to control subjects, suggesting alterations in glutamatergic signaling in alcohol-dependent individuals (Krystal et al, 2011). Studies of the effects of glutamatergic drugs on drinking in humans are more limited than those in animals due in part to the significant side effects that these agents have.…”

Effects of Augmenting N-Methyl-D-Aspartate Receptor Signaling on Working Memory and Experience-Dependent Plasticity in Schizophrenia: An Exploratory Study Using Acute d-cycloserine

“…DCS has been shown to increase the channel open time at NMDARs containing the NR2C subunit with ~200% efficacy compared to glycine, whereas at NMDARs containing NR2A or 2B subunits, DCS has approximately 50% efficacy compared to glycine. 72 Thus, while DCS is an agonist at NMDARs with NR2C subunits regardless of dose, at NMDARs with NR2B and NR2A subunits, DCS may act as an agonist at low doses (eg, 50-250 mg) by stimulating unoccupied glycine sites, but as an antagonist at high doses (eg 1000 mg) 73 by displacing endogenous glycine. We chose a low DCS dose that was likely to act as an agonist across NMDAR subtypes and we previously found that 100 mg DCS enhanced plasticity in healthy adults.…”

Glycine receptors in nervous tissue and their functional role

“…Глицин (Gly) выполняет в организме целый ряд жизненно важных функций [1][2][3][4][5][6][7][8][9]. Он входит в состав многих белков и биологически активных соединений, из него синтезируются порфириновые кольца гема и пуриновые основания [10].…”

“…Рецепторы к Gly, локализованные во многих участках головного и спинного мозга, оказывают тормозное воздействие на нейроны, уменьшая выделение возбуждающих аминокислот [1][2][3]. В то же время глицин выступает в роли коагониста рецептора g-аминобутирата (GABA-R) и глутаматного рецептора NMDA-R [4][5][6][7][8].…”