The capacity of ethanol to block N-methyl-D-aspartate (NMDA) glutamate receptors contributes to its behavioral effects in animals and humans. Data comparing alcoholics and healthy subjects has furthermore suggested that ethanol dependence is associated with dysregulation of the NMDA receptor and NMDA receptor-related factors may play a role in alcohol use and misuse. Studies conducted by our group and other investigators have shown that alcoholics appear to be less sensitive to the aversive effects of NMDA antagonists, such as ketamine (specifically dissociated and psychotogenic effects). Additionally, alcoholics continue to experience the rewarding effects of NMDA antagonists when they show evidence of cross-tolerance to many other aspects of NMDA antagonist response. Altered sensitivity to ketamine may be state-or-trait dependent. Individuals with a paternal family history of alcoholism have a higher risk for developing alcoholism and are less sensitive to the effects of alcohol ingestion in a laboratory setting (i.e. less subjective intoxication), than healthy subjects without a family history of alcoholism. These and other data have suggested that these individuals may lack the warning signs to stop drinking when consuming modest alcoholism will experience less dysphoric, anxiogenic and psychotogenic effects to ketamine infusion when compared to family history negative (FHN) age- matched control subjects. All subjects will complete 3 test days (placebo, ketamine 0.1 mg/kg, or ketamine 0.5 mg/kg) in a randomized, balanced order under double-blind conditions. Primary outcome measures include the Biphasic Alcohol Effects Scale (BAES), Visual Analog Scales (VAS) for high, and similarity to ethanol and mood states, the Sensation Scale (ethanol-like sensations), Brief Psychiatric Rating Scale (BPRS) for psychosis, and the Clinician Administered Dissociative States Scale (CADS) to measure perceptual responses to ketamine. NMDA dysregulation associated with alcoholism may represent and underlying vulnerability, and individuals with this vulnerability may experience a blunting of the dysphoric and psychotogenic effects of alcohol, which in turn contributes to alcohol misuse and to the transition from moderate alcohol use to excessive drinking.
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