Conditions: Alcohol Dependence
Keywords: Alcohol Dependence, Alcoholism, Glycine, D-Cycloserine
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 57
Healthy volunteers: yes

Brief summary:
Question #1: Will glycine ameliorate cognitive deficits? Hypothesis #1: Based on positive findings conducted with glycine and milacemide, a glycine prodrug, in schizophrenia and dementia, we expect that glycine will ameliorate cognitive deficits.

Question #2: Will alcoholic patients show enhanced endocrinal effects to glycine? Hypothesis #2: Based on the dose-related effects of glycine in healthy subjects, we expect that glycine will increase the endocrinal response to glycine in alcoholic patients with, supposedly, dysregulated NMDA receptor function.

Question #3: Will D-cycloserine have ethanol-like effects? Hypothesis #3: If inhibition of NMDA receptor function is fundamental to the subjective effects of ethanol, then the NMDA antagonist properties of D-cycloserine should be recognized as ethanol-like (relative to placebo) in recently detoxified alcoholics and healthy subjects.

Question #4: Will D-cycloserine reverse cognitive benefits of glycine? Hypothesis 4: Based on the dose related NMDA antagonist activity of D-cycloserine, we expect that D-cycloserine will compete with the agonist activity of glycine and therefore it will reverse the cognitive benefits of glycine.

Question #5: Will D-cycloserine inhibit endocrinal effects of glycine? Hypothesis #5: If the agonist activity of glycine is necessary to determine endocrine response, then the dose-related NMDA antagonist properties of D-cycloserine should block these effects.

Detailed description:
The purpose of this study is to investigate the interaction between glycine and D-cycloserine in alcoholic patients and healthy subjects. Preclinical studies have shown that compounds acting at the glycine site of the N-methyl-D-aspartate (NMDA) receptor complex, such as glycine, may reverse the effects of ethanol on the NMDA receptor function (Rabe et al., 1990). The amino acid glycine is a co-agonist of the NMDA receptor complex (Kemp et al., 1993). It binds to the strychnine-insensitive site and positively modulates the NMDA receptor (Mc Donald et al., 1990). Physiologically, the glycine site is not saturated, and administration of glycine can potentiate NMDA receptor mediated responses. In contrast, D-cycloserine (Hood et al., 1989) is a partial-agonist at the glycine site of the NMDA receptor, with dose-dependent NMDA antagonist properties. The NMDA antagonist activity of D-cycloserine should produce ethanol like-effects that can be reversed by the agonist glycine. This study is intended to evaluate possible contributions of the glycine site to the reduction of cognitive deficits of alcoholism and complements the current work at VA Connecticut Healthcare System on the NMDA antagonists in alcoholic and healthy subjects.

Arms:
arm 1: Alcohol dependent patients will receive 4 interventions arm 2: Healthy subjects will receive 4 interventions

Interventions: intervention 1: D-Cycloserine PO and Glycine IV intervention 2: Placebo D-Cycloserine PO and placebo Glycine IV intervention 3: Placebo D-Cycloserine PO and Glycine IV intervention 4: D-Cycloserine PO and placebo Glycine IV
Intervention descriptions: intervention 1: Test days will involve administration of D-Cycloserine in the morning in pill form then 4 hours later a 30 minute infusion of Glycine. intervention 2: Placebo intervention 3: None intervention 4: None

Protocol document: