Altered NMDA Glutamate Receptor Antagonist Response in Individuals With a Family Vulnerability to Alcoholism

A family history of alcoholism is linked to differences in how the brain responds to a drug that blocks NMDA glutamate receptors. Healthy young adults with at least two relatives who had ethanol dependence received intravenous infusions of a low or high dose of ketamine, an NMDA receptor antagonist, or a placebo. Compared to those with no family history of alcoholism, individuals with a family history reported fewer perceptual changes and less dysphoric mood during ketamine infusion. These findings suggest that inherited alterations in NMDA receptor function may influence the subjective effects of alcohol and contribute to the risk of developing alcoholism.

Study at a glance

Abstract

OBJECTIVE: A family history of alcoholism is a risk factor for the development of ethanol dependence. Ethanol is an antagonist of the N-methyl-d-aspartate (NMDA) glutamate receptor, and alterations in NMDA receptor function are thought to be involved in ethanol abuse and dependence. The purpose of this study was to determine in healthy individuals with no ethanol dependence whether response to the NMDA receptor antagonist ketamine would differentiate those with a family history of ethanol dependence from those without such a family history. METHOD: Healthy subjects between the ages of 21 and 30 received 40-minute intravenous infusions of saline, low-dose ketamine (0.1 mg/kg), and high-dose ketamine (0.5 mg/kg) on three separate test days in a randomized order under double-blind conditions. The healthy individuals with at least one first-degree relative and another first- or second-degree relative with ethanol dependence (N=16) were compared with those who had no family history of ethanol dependence in any first- or second-degree relative (N=29). Outcome measures included the Brief Psychiatric Rating Scale, Clinician-Administered Dissociative States Scale, verbal fluency, Hopkins Verbal Learning Test, a biphasic alcohol effects scale, visual analog scales of mood states, and ketamine levels. RESULTS: During ketamine infusion, individuals with a family history of ethanol dependence showed an attenuated response in terms of perceptual alterations and dysphoric mood relative to those without such a family history. CONCLUSIONS: These data suggest that alterations in NMDA receptor function may contribute to subjective response to ethanol and therefore also to the risk of developing alcoholism.