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 doubleblind 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 firstor 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. Ther e is extensive evidence that a family history of alcoholism is a risk factor for the development of ethanol problems (1). A substantial part of the tendency for ethanol dependence to run in families is attributable to genetic factors (2). Healthy individuals with a family history of ethanol dependence exhibit a relatively lower intensity of subjective intoxication, ataxia, body sway, or flushing to moderate doses of ethanol in a laboratory setting than do healthy individuals with no family history of alcoholism. These findings have clinical importance, since follow-up studies have shown that a reduced sensitivity to the dysphoric or adverse effects of ethanol is the single strongest predictor of the subsequent development of alcoholism (3).Antagonists of the N-methyl-D-aspartate (NMDA) receptor have provided an important mechanism for evaluating the pathophysiology of neuropsychiatric disorders, such as Alzheimer's disease, anxiety, depression, and schizophrenia. For example, administration of the NMDA antagonist ketamine to healthy subjects and the subsequent cognitive deficits (4, 5) and perceptual changes (6-9) have led to further understanding of the pathophysiology of schizophrenia (6-9).NMDA glutamate receptors are among the highest affinity ethanol targets in the brain (10). NMDA receptor antagonists substitute for ethanol ...

Ethanol is an antagonist of the N-methyl-D-aspartate (NMDA) glutamate receptor. Ethanol dependence upregulates NMDA receptors and contributes to crosstolerance with selective NMDA receptor antagonists in animals. This study evaluated whether recovering ethanol-dependent patients show evidence of a reduced level of response to the effects of the NMDA receptor antagonist, ketamine. In this double-blind study, 34 recently detoxified alcohol-dependent patients and 26 healthy comparison subjects completed 3 test days involving a 40-min infusion of saline, ketamine 0.1 mg/kg, or ketamine 0.5 mg/kg in a randomized order. Recovering ethanol-dependent patients showed reduced perceptual alterations, dysphoric mood, and impairments in executive cognitive functions during ketamine infusion relative to the healthy comparison group. No attenuation of ketamine-induced amnestic effects, euphoria, or activation was observed. The alterations in NMDA receptor function observed in recovering ethanol-dependent patients may have important implications for ethanol tolerance, ethanol dependence, and the treatment of alcoholism.

Rationale: Impulsivity and individual differences in subjective response to alcohol are risk factors for alcohol problems and possibly endophenotypes for alcohol dependence. Few prior studies have addressed relationships between the two constructs. Objectives: To predict subjective responses to ethanol, we tested self-reported impulsiveness, ethanol dose condition (high dose, low dose or placebo) and time (7 timepoints) along with interactions among these variables. Methods: The present study is a secondary analysis of data from a within subject, placebo-controlled, dose-ranging ethanol administration study using IV infusion with a clamping technique to maintain steady-state breath alcohol concentration. The sample consisted of healthy, non-alcohol dependent social alcohol drinkers between the ages of 21-30 (N=105). Participants at varying levels of impulsivity were compared with regard to stimulant and subjective responses to three ethanol dose conditions over time. Results: Individuals with higher impulsivity reported stronger stimulant and weaker sedative response to alcohol, particularly at the higher dose. Higher impulsivity was associated with a steeper increase in stimulant effects during the first half of clamped ethanol infusion with the higher dose. Conclusions: These results suggest that impulsive individuals may experience enhanced reinforcing, stimulant effects and relatively muted aversive, sedative effects from alcohol. These subjective responses may relate to enhanced risk of alcohol problems among more impulsive individuals.