Background: Ethanol is a glutamate antagonist at the N-methyl-D-aspartate (NMDA) receptor at ethanol levels achieved by human ethanol consumption. Chronic ethanol administration produces a 40-80% increase in NMDA antagonist binding. Clinical studies with the NMDA antagonist, phencyclidine (PCP), initially provided suggestive clinical evidence that this medication produced some subjective effects similar to ethanol. More recently, in a series of studies conducted by the PI with the PCP derivative, ketamine, healthy subjects reported ethanol-like subjective effects. Objectives: l) To rigorously evaluate the extent to which the NMDA antagonist, ketamine, produces ethanol-like effects in healthy subjects and recently detoxified alcoholics, in order to provide clinical data implicating NMDA antagonism in the acute behavioral properties of alcohol in humans; 2) To determine whether ketamine produces craving for alcohol in alcoholics, in order to evaluate whether the shared subjective properties of ethanol and ketamine are relevant to understanding the neurobiology of craving, a significant contributor to relapse in detoxified patients; and 3) to evaluate whether recently detoxified alcoholic and healthy subjects exhibit differential behavioral or neuroendocrine sensitivity to ketamine, consistent with the alteration in NMDA receptor number found in preclinical studies of chronic ethanol effects. Methods: Inpatients meeting DSM-III-R criteria for alcohol dependence who are 10-20 days since their last drink and a matched healthy subject group will complete three test days in a randomized balanced order under double-blind conditions. Test days will involve the 40 minute intravenous infusion of placebo, ketamine 0.1 mg/kg, or ketamine 0.5 mg/kg. Outcome measures include plasma prolactin and cortisol responses, the Brief Psychiatric Rating Scale and the Clinician-Administered Dissociative States Scale to measure perceptual responses to ketamine, visual analog scales for high, similarity to ethanol, and aspects of craving for alcohol, and the Sensation Scale (a validated measure of ethanol-like sensations). Preliminary Findings: To date, 3 recently detoxified -patients completed the protocol, 2/3 reported ethanol-like responses, and increases in craving were observed. No adverse reactions occurred. Over 60 healthy subjects and schizophrenic patients have received ketamine at comparable doses at this Center without adverse reaction, flashbacks, or lingering ketamine responses in studies directed by the PI. These data suggest that ketamine will serve as a safe and informative clinical probe of NMDA function in alcoholism.
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