GABA Mechanisms Underlying the Vulnerability to Alcohol Dependence

Condition(s) targeted: Alcoholism

Intervention: Thiopental (Drug); Placebo (Drug)

Phase: N/A

Status: Recruiting

Sponsored by: Yale University

Official(s) and/or principal investigator(s):
Ismene L Petrakis, MD, Principal Investigator, Affiliation: Yale University

This Project will explore the hypothesis that individuals with a family history positive for alcohol dependence (without any current Axis I disorder, except nicotine dependence), experience an alteration in the reward "valence" (balance of positive and negative effects) of the GABAA receptor agonist barbiturate (thiopental) compared to family history negative age-matched subjects. Further, variation in genes involved in brain GABA function may influence the risk for alcoholism by altering a component of the discriminative stimulus effects of ethanol.

Official title: GABA Mechanisms Underlying the Vulnerability to Alcohol Dependence

Study design: Allocation: Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Outcomes Assessor), Primary Purpose: Health Services Research

Primary outcome: Biphasic Alcohol Effects Scale, confirmed with other measures such as the Visual Analog Scales

Secondary outcome: potential response P300 measurements, grooved pegboard test

Detailed description: 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.

Minimum age: 21 Years. Maximum age: 30 Years. Gender(s): Both.

Criteria:

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.

VA Connecticut Healthcare System, West Haven, Connecticut 06516, United States; Recruiting
Diana D Limoncelli, BA, Phone: 203-932-5711, Ext: 5217, Email: arc1@yale.edu

Starting date: November 2005
Last updated: February 8, 2008