The proposed study is the first to explore the contribution of brain glutamate systems, a
major target of ethanol in the brain, to the vulnerability to develop alcoholism. This
study may lead to an enhanced understanding of the underlying neurobiological mechanism in
high risk individuals that may lead to the transition from moderate to excessive use of
Males and females with a paternal family history of alcoholism have a high risk for
developing alcoholism. These individuals have been shown to have decreased dysphoric
responses to alcohol self-administration that may promote the excessive use of alcohol.
Ethanol has been shown to be an antagonist at the N-methyl-D-aspartate (NMDA) glutamate
receptor. We have recently shown that sober alcoholics have decreased dysphoric response to
the NMDA antagonist, ketamine. We propose to test the hypothesis that this characteristic
exists as a vulnerability factor in those individuals susceptible to develop alcoholism.
Specifically, the objective is to determine whether individuals with a family history
positive (FHP) for alcoholism will experience less dysphoric, anxiogenic, and psychotogenic
effects to alcohol infusion when compared to family history negative (FHN) control subjects.
Male and female subjects, FHP (biological father and one other first degree relative)
between the ages of 21-30, and matched controls (FHN) will complete 3 test days in a
randomized balanced order under double-blind conditions. Test days will involve
administration of placebo or one of two ethanol doses (target BrAc=40mg%, or target
BrAc=100mg%) intravenously for 20 minutes, until the target BrAc is achieved. Once BrAc is
achieved (40mg% or 100mg%) it will be maintained using a clamp procedure for over 60
minutes. Outcome measures include the Positive and Negative Symptom Scale, visual analog
scales of mood state, (i.e. anxiety) and the Clinician-Administered Dissociative States
Scale (CADSS) to measure perceptual responses to alcohol. Secondary measures include visual
analog scales for high, similarity to ethanol, Mini Mental Status Examination (MMSE),
Placement of electrodes, Biphasic Alcohol Effects Scale, Hopkins Verbal Learning, and number
of drinks scale, aspects of craving for alcohol and tests of cognitive impairment.
1. Male and female between the ages of 21 and 30 years;
2. medically and neurologically healthy on the basis of history, physical examination,
EKG, Screening laboratories absence of current and/or past substance abuse on the
basis of history and urine toxicology and breath alcohol levels at screening and on
each test day.
For Family History Positive (FHP) Subjects: 1) Biological father and another first or
second-degree biological relative with history of alcoholism by FHAM-Family History
Assessment Module developed by COGA.
1. DSM-IV psychiatric and substance abuse (excluding alcohol abuse) diagnosis by history
on psychiatric evaluation that includes a structured diagnostic interview (Structured
Clinical Interview for DSM-IV Axis I Disorders: SCID)
2. Subjects who meet criteria for alcohol abuse and express an interest in stopping
alcohol use and/or express an interest in treatment or are currently enrolled in
treatment for alcoholism, or have sought treatment in the last 6 months.
3. history of counseling or psychotherapy; except family therapy centered around another
4. extended unwillingness to remain alcohol-free for 48 hours prior to test days;
5. for women: positive pregnancy test at screening or intention to engage in unprotected
sex during the study
6. alcohol naïve
7. Adoptee and no contact with family members.