Clinical trial NCT00611767: GABA Mechanisms Underlying the Vulnerability to Alcohol Dependence
Official title: Gamma-Aminobutyric Acid (GABA) Mechanisms Underlying the Vulnerability to Alcohol Dependence
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Alcoholism
Keywords: Thiopental
Alcohol
Family History
Vulnerability
GABA
Lead sponsor: Yale University
Sponsor class: OTHER
Collaborators: name: VA Connecticut Healthcare System
First posted: 2008-02-11
Enrollment: 73
Sex: ALL
Minimum age (years): 21
Maximum age (years): 30
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: HEALTH_SERVICES_RESEARCH

Brief summary: 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.

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.

Eligibility 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 The Collaborative Study on the Genetics of Alcoholism (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.

Primary outcomes:
measure: Visual Analog Scales of Similarity to Alcohol - Baseline
timeFrame: Baseline
measure: Visual Analog Scales of Similarity to Alcohol - 15 Minutes
timeFrame: 15 minutes
measure: Visual Analog Scales of Similarity to Alcohol - 45 Minutes
timeFrame: 45 minutes
measure: Visual Analog Scales of Similarity to Alcohol - 80 Minutes
timeFrame: 80 minutes
measure: Visual Analog Scales of Similarity to Alcohol - 110 Minutes
timeFrame: 110 minutes
measure: Visual Analog Scales of Similarity to Alcohol - 170 Minutes
timeFrame: 170 minutes
measure: Visual Analog Scales of Similarity to Alcohol - 230 Minutes
timeFrame: 230 minutes
Secondary outcomes:
measure: Number of Drinks Felt Consumed at Baseline
timeFrame: Baseline
measure: Number of Drinks Felt Consumed - 15 Minutes
timeFrame: 15 minutes
measure: Number of Drinks Felt Consumed - 45 Minutes
timeFrame: 45 minutes
measure: Number of Drinks Felt Consumed - 80 Minutes
timeFrame: 80 minutes
measure: Number of Drinks Felt Consumed - 110 Minutes
timeFrame: 110 minutes
measure: Number of Drinks Felt Consumed - 170 Minutes
timeFrame: 170 minutes
measure: Number of Drinks Felt Consumed - 230 Minutes
timeFrame: 230 minutes
measure: Biphasic Alcohol Effects Scale (BAES) - Subscale Stimulant - Baseline
timeFrame: Baseline
measure: Biphasic Alcohol Effects Scale (BAES) - Subscale Stimulant - 15 Minutes
timeFrame: 15 minutes
measure: Biphasic Alcohol Effects Scale (BAES) - Subscale Stimulant - 45 Minutes
timeFrame: 45 minutes
measure: Biphasic Alcohol Effects Scale (BAES) - Subscale Stimulant - 80 Minutes
timeFrame: 80 minutes
measure: Biphasic Alcohol Effects Scale (BAES) - Subscale Stimulant- 110 Minutes
timeFrame: 110 minutes
measure: Biphasic Alcohol Effects Scale (BAES) - Subscale Stimulant - 170 Minutes
timeFrame: 170 minutes
measure: Biphasic Alcohol Effects Scale (BAES) - Subscale Stimulant - 230 Minutes
timeFrame: 230 minutes
measure: Biphasic Alcohol Effects Scale (BAES) - Subscale Sedative Baseline
timeFrame: Baseline
measure: Biphasic Alcohol Effects Scale (BAES) - Subscale Sedative - 15 Minutes
timeFrame: 15 minutes
measure: Biphasic Alcohol Effects Scale (BAES) - Subscale Sedative - 45 Minutes
timeFrame: 45 minutes
measure: Biphasic Alcohol Effects Scale (BAES) - Subscale Sedative - 80 Minutes
timeFrame: 80 minutes
measure: Biphasic Alcohol Effects Scale (BAES) - Subscale Sedative - 110 Minutes
timeFrame: 110 minutes
measure: Biphasic Alcohol Effects Scale (BAES) - Subscale Sedative - 170 Minutes
timeFrame: 170 minutes
measure: Biphasic Alcohol Effects Scale (BAES) - Subscale Sedative - 230 Minutes
timeFrame: 230 minutes
measure: Visual Analog Scales (VAS) - High - Baseline
timeFrame: Baseline
measure: Visual Analog Scales (VAS) - High - 15 Minutes
timeFrame: 15 minutes
measure: Visual Analog Scales (VAS) - High - 45 Minutes
timeFrame: 45 minutes
measure: Visual Analog Scales (VAS) - High - 80 Minutes
timeFrame: 80 minutes
measure: Visual Analog Scales (VAS) - High - 110 Minutes
timeFrame: 110 minutes
measure: Visual Analog Scales (VAS) - High - 170 Minutes
timeFrame: 170 minutes
measure: Visual Analog Scales (VAS) - High - 230 Minutes
timeFrame: 230 minutes
measure: Visual Analog Scales (VAS) - Buzzed - Baseline
timeFrame: Baseline
measure: Visual Analog Scales (VAS) - Buzzed - 15 Minutes
timeFrame: 15 minutes
measure: Visual Analog Scales (VAS) - Buzzed - 45 Minutes
timeFrame: 45 minutes
measure: Visual Analog Scales (VAS) - Buzzed - 80 Minutes
timeFrame: 80 minutes
measure: Visual Analog Scales (VAS) - Buzzed - 110 Minutes
timeFrame: 110 minutes
measure: Visual Analog Scales (VAS) - Buzzed - 170 Minutes
timeFrame: 170 minutes
measure: Visual Analog Scales (VAS) - Buzzed - 230 Minutes
timeFrame: 230 minutes
measure: Visual Analog Scales (VAS) - Drowsy - Baseline
timeFrame: Baseline
measure: Visual Analog Scales (VAS) - Drowsy - 15 Minutes
timeFrame: 15 minutes
measure: Visual Analog Scales (VAS) - Drowsy - 45 Minutes
timeFrame: 45 minutes
measure: Visual Analog Scales (VAS) - Drowsy - 80 Minutes
timeFrame: 80 minutes
measure: Visual Analog Scales (VAS) - Drowsy - 110 Minutes
timeFrame: 110 minutes
measure: Visual Analog Scales (VAS) - Drowsy - 170 Minutes
timeFrame: 170 minutes
measure: Visual Analog Scales (VAS) - Drowsy - 230 Minutes
timeFrame: 230 minutes
measure: Visual Analog Scales (VAS) - Depressed - Baseline
timeFrame: Baseline
measure: Visual Analog Scales (VAS) - Depressed - 15 Minutes
timeFrame: 15 minutes
measure: Visual Analog Scales (VAS) - Depressed - 45 Minutes
timeFrame: 45 minutes
measure: Visual Analog Scales (VAS) - Depressed - 80 Minutes
timeFrame: 80 minutes
measure: Visual Analog Scales (VAS) - Depressed - 110 Minutes
timeFrame: 110 minutes
measure: Visual Analog Scales (VAS) - Depressed - 170 Minutes
timeFrame: 170 minutes
measure: Visual Analog Scales (VAS) - Depressed - 230 Minutes
timeFrame: 230 minutes
measure: Visual Analog Scales (VAS) - Anxious - Baseline
timeFrame: Baseline
measure: Visual Analog Scales (VAS) - Anxious - 15 Minutes
timeFrame: 15 minutes
measure: Visual Analog Scales (VAS) - Anxious - 45 Minutes
timeFrame: 45 minutes
measure: Visual Analog Scales (VAS) - Anxious - 80 Minutes
timeFrame: 80 minutes
measure: Visual Analog Scales (VAS) - Anxious - 110 Minutes
timeFrame: 110 minutes
measure: Visual Analog Scales (VAS) - Anxious - 170 Minutes
timeFrame: 170 minutes
measure: Visual Analog Scales (VAS) - Anxious - 230 Minutes
timeFrame: 230 minutes
measure: Clinician Administered Dissociative Symptoms Scale - Patient Rated - Baseline
timeFrame: Baseline
measure: Clinician Administered Dissociative Symptoms Scale - Patient Rated - 15 Minutes
timeFrame: 15 minutes
measure: Clinician Administered Dissociative Symptoms Scale - Patient Rated - 80 Minutes
timeFrame: 80 minutes
measure: Clinician Administered Dissociative Symptoms Scale - Patient Rated - 110 Minutes
timeFrame: 110 minutes
measure: Clinician Administered Dissociative Symptoms Scale - Clinician Rated - Baseline
timeFrame: Baseline
measure: Clinician Administered Dissociative Symptoms Scale - Clinician Rated - 15 Minutes
timeFrame: 15 minutes
measure: Clinician Administered Dissociative Symptoms Scale - Clinician Rated - 80 Minutes
timeFrame: 80 minutes
measure: Clinician Administered Dissociative Symptoms Scale - Clinician Rated - 110 Minutes
timeFrame: 110 minutes
measure: Pegboard Task - Baseline (Dominant Hand)
timeFrame: Baseline
measure: Pegboard Task - 15 Minutes (Dominant Hand)
timeFrame: 15 minutes
measure: Pegboard Task - Baseline (Non-Dominant Hand)
timeFrame: Baseline
measure: Pegboard Task - 15 Minutes (Non-Dominant Hand)
timeFrame: 15 minutes
measure: Hopkins Verbal Learning Task (HVLT) - Total Recall
timeFrame: 15 minutes
measure: Hopkins Verbal Learning Task (HVLT) - Delayed Recall
timeFrame: 45 minutes
measure: Verbal Fluency
timeFrame: 15 minutes
Other outcomes:
Locations:
city: West Haven
country: United States
facility: VA Connecticut Healthcare System
state: Connecticut
Study officials:
affiliation: Yale University
name: Ismene L Petrakis, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Petrakis IL, Kerfoot K, Pittman B, Perrino A, Koretski J, Newcomb J, Limoncelli D, Acampora G, Ralevski E. Subjective Effects of Thiopental in Young Adults with and without a Family History of Alcoholism. J Addict Res Ther. 2012 May 14;Suppl 7(2):6336. doi: 10.4172/2155-6105.S7-002.