GABA Mechanisms Underlying the Vulnerability to Alcohol Dependence

This project will explore the hypothesis that individuals with a family history positive for
alcohol dependence (FHP) (without any current DSM-IV Axis I disorder, except nicotine
dependence), experience an alteration in the reward "valence" (balance of positive and
negative effects) of the GABA-A receptor agonist barbiturate (thiopental) compared to family
history negative (FHN) age-matched subjects. Further, the effect of variations in genes
important in regulating brain GABA function may alter a component of the discriminative
stimulus effects of ethanol. FHP individuals are defined as individuals with at least one
first-degree relative and another first- or second-degree relatives. Preliminary results
suggest that FHP individuals showed an attenuated response to thiopental as measured by the
descending limb of the BAES during thiopental infusion relative to the FHN group. Further,
preliminary results suggest that variation in genes involved in brain GABA function,
glutamate decarboxylase-65 (GAD65), may influence the risk for alcoholism by altering a
component of the discriminative stimulus effects of ethanol.

We plan to recruit 2 groups of healthy subjects between the ages of 21-30, one with a family
history of alcoholism (family history positive=FHP) and a sex-matched control group without
a family history of alcoholism (family history negative=FHN), to undergo two test days
scheduled 3 days apart, in a randomized double-blind fashion. Test days will involve a
60-minute intravenous infusion of each of 2 conditions: saline or thiopental, in a
randomized order under double-blind conditions. Behavioral ratings include the Biphasic
Alcohol Effects Scale (BAES) and Visual Analog Scales (VAS). Exploratory measures include
event-related potential recordings (ERP) and measures of eye-to-hand coordination. Blood
will be collected for Deoxyribonucleic acid (DNA) extraction and genotyping.

Inclusion Criteria:

1. Male and female between the ages of 21 and 30 years

2. medically and neurologically healthy on the basis of history, physical examination,
Electrocardiogram (EKG), screening laboratories

3. absence of any evidence of substance abuse (with the exception of nicotine
dependence) on the basis of history and drug and ethanol-free at the time of testing
based on urine toxicology and breath alcohol levels at screening and on each test
day.

Exclusion Criteria:

1. Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV) Axis I
psychiatric and substance abuse or dependence diagnosis by history on psychiatric
evaluation that includes a structured diagnostic interview (SCID)

2. unwillingness to remain alcohol-free for three days prior to each test day;

3. for women, positive pregnancy test at screening or intention to engage in unprotected
sex during the study and

4. alcohol naive. For Family History Positive Subjects: 1) Biological father and another
first or second-degree biological relative with history of alcoholism by Family
History Assessment Module (FHAM) developed by COGA.

For Family History Negative Subjects: NO family history of alcoholism in any first or
second-degree relatives. Subjects must reliably report on three first-degree relatives.