GABA Mechanisms Underlying the Vulnerability to Alcohol Dependence

Study Overview
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Brief Summary
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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
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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.

Official Title
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Gamma-Aminobutyric Acid (GABA) Mechanisms Underlying the Vulnerability to Alcohol Dependence

Conditions
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Alcoholism

Intervention / Treatment
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* Drug: Thiopental
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female between the ages of 21 and 30 years medically and neurologically healthy on the basis of history, physical examination, Electrocardiogram (EKG), screening laboratories 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: 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) unwillingness to remain alcohol-free for three days prior to each test day; for women, positive pregnancy test at screening or intention to engage in unprotected sex during the study and 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.

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Health Services Research
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Family History Negative for Alcoholism<br>Family History Negative for Alcoholism subjects will receive 2 interventions | Drug: Thiopental<br>* A 2-day test design involving 2 conditions: saline (Placebo) or Thiopental 1.5mg/kg (loading) with a subsequent infusion rate of 40 mcg/kg/minute (60 minute infusion).<br>|
| Placebo Comparator: Family History Positive for Alcoholism<br>Family History Positive for Alcoholism subjects will receive 2 interventions | Drug: Placebo<br>* A 2-day test design involving 2 conditions: saline (Placebo) or Thiopental 1.5mg/kg (loading) with a subsequent infusion rate of 40 mcg/kg/minute (60 minute infusion).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Visual Analog Scales of Similarity to Alcohol - Baseline | Visual Analog Scale of Similarity to Alcohol data using the Likert scale (0 Not at all similar to alcohol - 7 Extremely similar to alcohol) evaluating the similarity of drug effects to alcohol | Baseline | 
| Visual Analog Scales of Similarity to Alcohol - 15 Minutes | Visual Analog Scale of Similarity to Alcohol data using the Likert scale (0 Not at all similar to alcohol - 7 Extremely similar to alcohol) evaluating the similarity of drug effects to alcohol | 15 minutes | 
| Visual Analog Scales of Similarity to Alcohol - 45 Minutes | Visual Analog Scale of Similarity to Alcohol data using the Likert scale (0 Not at all similar to alcohol - 7 Extremely similar to alcohol) evaluating the similarity of drug effects to alcohol | 45 minutes | 
| Visual Analog Scales of Similarity to Alcohol - 80 Minutes | Visual Analog Scale of Similarity to Alcohol data using the Likert scale (0 Not at all similar to alcohol - 7 Extremely similar to alcohol) evaluating the similarity of drug effects to alcohol | 80 minutes | 
| Visual Analog Scales of Similarity to Alcohol - 110 Minutes | Visual Analog Scale of Similarity to Alcohol data using the Likert scale (0 Not at all similar to alcohol - 7 Extremely similar to alcohol) evaluating the similarity of drug effects to alcohol | 110 minutes | 
| Visual Analog Scales of Similarity to Alcohol - 170 Minutes | Visual Analog Scale of Similarity to Alcohol data using the Likert scale (0 Not at all similar to alcohol - 7 Extremely similar to alcohol) evaluating the similarity of drug effects to alcohol | 170 minutes | 
| Visual Analog Scales of Similarity to Alcohol - 230 Minutes | Visual Analog Scale of Similarity to Alcohol data using the Likert scale (0 Not at all similar to alcohol - 7 Extremely similar to alcohol) evaluating the similarity of drug effects to alcohol | 230 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Drinks Felt Consumed at Baseline | The Number of Drinks Scale asks Subjects to report on the number of alcoholic drinks they felt they had consumed. | Baseline | 
| Number of Drinks Felt Consumed - 15 Minutes | The Number of Drinks Scale asks Subjects to report on the number of alcoholic drinks they felt they had consumed. | 15 minutes | 
| Number of Drinks Felt Consumed - 45 Minutes | The Number of Drinks Scale asks Subjects to report on the number of alcoholic drinks they felt they had consumed. | 45 minutes | 
| Number of Drinks Felt Consumed - 80 Minutes | The Number of Drinks Scale asks Subjects to report on the number of alcoholic drinks they felt they had consumed. | 80 minutes | 
| Number of Drinks Felt Consumed - 110 Minutes | The Number of Drinks Scale asks Subjects to report on the number of alcoholic drinks they felt they had consumed. | 110 minutes | 
| Number of Drinks Felt Consumed - 170 Minutes | The Number of Drinks Scale asks Subjects to report on the number of alcoholic drinks they felt they had consumed. | 170 minutes | 
| Number of Drinks Felt Consumed - 230 Minutes | The Number of Drinks Scale asks Subjects to report on the number of alcoholic drinks they felt they had consumed. | 230 minutes | 
| Biphasic Alcohol Effects Scale (BAES) - Subscale Stimulant - Baseline | Self-report rating scale used to measure stimulant effects (0 not at all stimulated - 70 extremely stimulated) | Baseline | 
| Biphasic Alcohol Effects Scale (BAES) - Subscale Stimulant - 15 Minutes | Self-report rating scale used to measure stimulant effects (0 not at all stimulated - 70 extremely stimulated) | 15 minutes | 
| Biphasic Alcohol Effects Scale (BAES) - Subscale Stimulant - 45 Minutes | Self-report rating scale used to measure stimulant effects (0 not at all stimulated - 70 extremely stimulated) | 45 minutes | 
| Biphasic Alcohol Effects Scale (BAES) - Subscale Stimulant - 80 Minutes | Self-report rating scale used to measure stimulant effects (0 not at all stimulated - 70 extremely stimulated) | 80 minutes | 
| Biphasic Alcohol Effects Scale (BAES) - Subscale Stimulant- 110 Minutes | Self-report rating scale used to measure stimulant effects (0 not at all stimulated - 70 extremely stimulated) | 110 minutes | 
| Biphasic Alcohol Effects Scale (BAES) - Subscale Stimulant - 170 Minutes | Self-report rating scale used to measure stimulant effects (0 not at all stimulated - 70 extremely stimulated) | 170 minutes | 
| Biphasic Alcohol Effects Scale (BAES) - Subscale Stimulant - 230 Minutes | Self-report rating scale used to measure stimulant effects (0 not at all stimulated - 70 extremely stimulated) | 230 minutes | 
| Biphasic Alcohol Effects Scale (BAES) - Subscale Sedative Baseline | Self-report rating scale used to measure sedative effects (0 not at all sedated - 70 extremely sedated) | Baseline | 
| Biphasic Alcohol Effects Scale (BAES) - Subscale Sedative - 15 Minutes | Self-report rating scale used to measure sedative effects (0 not at all sedated - 70 extremely sedated) | 15 minutes | 
| Biphasic Alcohol Effects Scale (BAES) - Subscale Sedative - 45 Minutes | Self-report rating scale used to measure sedative effects (0 not at all sedated - 70 extremely sedated) | 45 minutes | 
| Biphasic Alcohol Effects Scale (BAES) - Subscale Sedative - 80 Minutes | Self-report rating scale used to measure sedative effects (0 not at all sedated - 70 extremely sedated) | 80 minutes | 
| Biphasic Alcohol Effects Scale (BAES) - Subscale Sedative - 110 Minutes | Self-report rating scale used to measure sedative effects (0 not at all sedated - 70 extremely sedated) | 110 minutes | 
| Biphasic Alcohol Effects Scale (BAES) - Subscale Sedative - 170 Minutes | Self-report rating scale used to measure sedative effects (0 not at all sedated - 70 extremely sedated) | 170 minutes | 
| Biphasic Alcohol Effects Scale (BAES) - Subscale Sedative - 230 Minutes | Self-report rating scale used to measure sedative effects (0 not at all sedated - 70 extremely sedated) | 230 minutes | 
| Visual Analog Scales (VAS) - High - Baseline | visual analog scale (VAS): self-report scale used to measure high (0 not at all High - 7 extremely High) | Baseline | 
| Visual Analog Scales (VAS) - High - 15 Minutes | visual analog scale (VAS): self-report scale used to measure high (0 not at all High - 7 extremely High) | 15 minutes | 
| Visual Analog Scales (VAS) - High - 45 Minutes | visual analog scale (VAS): self-report scale used to measure high (0 not at all High - 7 extremely High) | 45 minutes | 
| Visual Analog Scales (VAS) - High - 80 Minutes | visual analog scale (VAS): self-report scale used to measure high (0 not at all High - 7 extremely High) | 80 minutes | 
| Visual Analog Scales (VAS) - High - 110 Minutes | visual analog scale (VAS): self-report scale used to measure high (0 not at all High - 7 extremely High) | 110 minutes | 
| Visual Analog Scales (VAS) - High - 170 Minutes | visual analog scale (VAS): self-report scale used to measure high (0 not at all High - 7 extremely High) | 170 minutes | 
| Visual Analog Scales (VAS) - High - 230 Minutes | visual analog scale (VAS): self-report scale used to measure high (0 not at all High - 7 extremely High) | 230 minutes | 
| Visual Analog Scales (VAS) - Buzzed - Baseline | visual analog scale (VAS): self-report scale used to measure buzzed (0 not at all buzzed - 7 extremely buzzed) | Baseline | 
| Visual Analog Scales (VAS) - Buzzed - 15 Minutes | visual analog scale (VAS): self-report scale used to measure buzzed (0 not at all buzzed - 7 extremely buzzed) | 15 minutes | 
| Visual Analog Scales (VAS) - Buzzed - 45 Minutes | visual analog scale (VAS): self-report scale used to measure buzzed (0 not at all buzzed - 7 extremely buzzed) | 45 minutes | 
| Visual Analog Scales (VAS) - Buzzed - 80 Minutes | visual analog scale (VAS): self-report scale used to measure buzzed (0 not at all buzzed - 7 extremely buzzed) . | 80 minutes | 
| Visual Analog Scales (VAS) - Buzzed - 110 Minutes | visual analog scale (VAS): self-report scale used to measure buzzed (0 not at all buzzed - 7 extremely buzzed) | 110 minutes | 
| Visual Analog Scales (VAS) - Buzzed - 170 Minutes | visual analog scale (VAS): self-report scale used to measure buzzed (0 not at all buzzed - 7 extremely buzzed) | 170 minutes | 
| Visual Analog Scales (VAS) - Buzzed - 230 Minutes | visual analog scale (VAS): self-report scale used to measure buzzed (0 not at all buzzed - 7 extremely buzzed) | 230 minutes | 
| Visual Analog Scales (VAS) - Drowsy - Baseline | visual analog scale (VAS): self-report scale used to measure drowsy (0 not at all drowsy - 7 extremely drowsy) | Baseline | 
| Visual Analog Scales (VAS) - Drowsy - 15 Minutes | visual analog scale (VAS): self-report scale used to measure drowsy (0 not at all drowsy - 7 extremely drowsy) | 15 minutes | 
| Visual Analog Scales (VAS) - Drowsy - 45 Minutes | visual analog scale (VAS): self-report scale used to measure drowsy (0 not at all drowsy - 7 extremely drowsy) . | 45 minutes | 
| Visual Analog Scales (VAS) - Drowsy - 80 Minutes | visual analog scale (VAS): self-report scale used to measure drowsy (0 not at all drowsy - 7 extremely drowsy) | 80 minutes | 
| Visual Analog Scales (VAS) - Drowsy - 110 Minutes | visual analog scale (VAS): self-report scale used to measure drowsy (0 not at all drowsy - 7 extremely drowsy) | 110 minutes | 
| Visual Analog Scales (VAS) - Drowsy - 170 Minutes | visual analog scale (VAS): self-report scale used to measure drowsy (0 not at all drowsy - 7 extremely drowsy) | 170 minutes | 
| Visual Analog Scales (VAS) - Drowsy - 230 Minutes | visual analog scale (VAS): self-report scale used to measure drowsy (0 not at all drowsy - 7 extremely drowsy) | 230 minutes | 
| Visual Analog Scales (VAS) - Depressed - Baseline | visual analog scale (VAS): self-report scale used to measure depressed (0 not at all depressed - 7 extremely depressed) | Baseline | 
| Visual Analog Scales (VAS) - Depressed - 15 Minutes | visual analog scale (VAS): self-report scale used to measure depressed (0 not at all depressed - 7 extremely depressed) | 15 minutes | 
| Visual Analog Scales (VAS) - Depressed - 45 Minutes | visual analog scale (VAS): self-report scale used to measure depressed (0 not at all depressed - 7 extremely depressed) | 45 minutes | 
| Visual Analog Scales (VAS) - Depressed - 80 Minutes | visual analog scale (VAS): self-report scale used to measure depressed (0 not at all depressed - 7 extremely depressed) | 80 minutes | 
| Visual Analog Scales (VAS) - Depressed - 110 Minutes | visual analog scale (VAS): self-report scale used to measure depressed (0 not at all depressed - 7 extremely depressed) | 110 minutes | 
| Visual Analog Scales (VAS) - Depressed - 170 Minutes | visual analog scale (VAS): self-report scale used to measure depressed (0 not at all depressed - 7 extremely depressed) | 170 minutes | 
| Visual Analog Scales (VAS) - Depressed - 230 Minutes | visual analog scale (VAS): self-report scale used to measure depressed (0 not at all depressed - 7 extremely depressed) | 230 minutes | 
| Visual Analog Scales (VAS) - Anxious - Baseline | visual analog scale (VAS): self-report scale used to measure anxiety (0 not at all anxious - 7 extremely anxious) | Baseline | 
| Visual Analog Scales (VAS) - Anxious - 15 Minutes | visual analog scale (VAS): self-report scale used to measure anxiety (0 not at all anxious - 7 extremely anxious) | 15 minutes | 
| Visual Analog Scales (VAS) - Anxious - 45 Minutes | visual analog scale (VAS): self-report scale used to measure anxiety (0 not at all anxious - 7 extremely anxious) | 45 minutes | 
| Visual Analog Scales (VAS) - Anxious - 80 Minutes | visual analog scale (VAS): self-report scale used to measure anxiety (0 not at all anxious - 7 extremely anxious) | 80 minutes | 
| Visual Analog Scales (VAS) - Anxious - 110 Minutes | visual analog scale (VAS): self-report scale used to measure anxiety (0 not at all anxious - 7 extremely anxious) | 110 minutes | 
| Visual Analog Scales (VAS) - Anxious - 170 Minutes | visual analog scale (VAS): self-report scale used to measure anxiety (0 not at all anxious - 7 extremely anxious) | 170 minutes | 
| Visual Analog Scales (VAS) - Anxious - 230 Minutes | visual analog scale (VAS): self-report scale used to measure anxiety (0 not at all anxious - 7 extremely anxious) | 230 minutes | 
| Clinician Administered Dissociative Symptoms Scale - Patient Rated - Baseline | Clinician Administered Dissociative Symptoms Scale (CADSS) is a patient and Clinician rated measurement of dissociative states induced by thiopental (0 not at all dissociative - 84 extreme dissociative) | Baseline | 
| Clinician Administered Dissociative Symptoms Scale - Patient Rated - 15 Minutes | Clinician Administered Dissociative Symptoms Scale (CADSS) is a patient and Clinician rated measurement of dissociative states induced by thiopental (0 not at all dissociative - 84 extreme dissociative) | 15 minutes | 
| Clinician Administered Dissociative Symptoms Scale - Patient Rated - 80 Minutes | Clinician Administered Dissociative Symptoms Scale (CADSS) is a patient and Clinician rated measurement of dissociative states induced by thiopental (0 not at all dissociative - 84 extreme dissociative) | 80 minutes | 
| Clinician Administered Dissociative Symptoms Scale - Patient Rated - 110 Minutes | Clinician Administered Dissociative Symptoms Scale (CADSS) is a patient and Clinician rated measurement of dissociative states induced by thiopental (0 not at all dissociative - 84 extreme dissociative) | 110 minutes | 
| Clinician Administered Dissociative Symptoms Scale - Clinician Rated - Baseline | Clinician Administered Dissociative Symptoms Scale (CADSS) is a patient and Clinician rated measurement of dissociative states induced by thiopental (0 not at all dissociative - 20 extreme dissociative) | Baseline | 
| Clinician Administered Dissociative Symptoms Scale - Clinician Rated - 15 Minutes | Clinician Administered Dissociative Symptoms Scale (CADSS) is a patient and Clinician rated measurement of dissociative states induced by thiopental (0 not at all dissociative - 20 extreme dissociative) | 15 minutes | 
| Clinician Administered Dissociative Symptoms Scale - Clinician Rated - 80 Minutes | Clinician Administered Dissociative Symptoms Scale (CADSS) is a patient and Clinician rated measurement of dissociative states induced by thiopental (0 not at all dissociative - 20 extreme dissociative) | 80 minutes | 
| Clinician Administered Dissociative Symptoms Scale - Clinician Rated - 110 Minutes | Clinician Administered Dissociative Symptoms Scale (CADSS) is a patient and Clinician rated measurement of dissociative states induced by thiopental (0 not at all dissociative - 20 extreme dissociative) | 110 minutes | 
| Pegboard Task - Baseline (Dominant Hand) | The pegboard task is a measure of coordination that measures reaction time; how long a subject takes to insert pegs into a pegboard puzzle, first using their dominant hand then using their non-dominant hand. A quicker time indicates greater coordination. Scores are timed in seconds | Baseline | 
| Pegboard Task - 15 Minutes (Dominant Hand) | The pegboard task is a measure of coordination that measures reaction time; how long a subject takes to insert pegs into a pegboard puzzle, first using their dominant hand then using their non-dominant hand. A quicker time indicates greater coordination. Scores are timed in seconds | 15 minutes | 
| Pegboard Task - Baseline (Non-Dominant Hand) | The pegboard task is a measure of coordination that measures reaction time; how long a subject takes to insert pegs into a pegboard puzzle, first using their dominant hand then using their non-dominant hand. A quicker time indicates greater coordination. Scores are timed in seconds. | Baseline | 
| Pegboard Task - 15 Minutes (Non-Dominant Hand) | The pegboard task is a measure of coordination that measures reaction time; how long a subject takes to insert pegs into a pegboard puzzle, first using their dominant hand then using their non-dominant hand. A quicker time indicates greater coordination. Scores are timed in seconds. | 15 minutes | 
| Hopkins Verbal Learning Task (HVLT) - Total Recall | Hopkins Verbal Learning Task (HVLT) - measures verbal memory and hippocampus function based on word recall. (0 = no words recalled - 36 = all words recalled) | 15 minutes | 
| Hopkins Verbal Learning Task (HVLT) - Delayed Recall | Hopkins Verbal Learning Task (HVLT) - measures verbal memory and hippocampus function with word recall at 30 minutes) (0 no words recalled - 12 all words recalled) | 45 minutes | 
| Verbal Fluency | Verbal Fluency Task: requires subjects to generate as many words as possible beginning with a single letter (e.g., H) during a one-minute interval. (total words in one-minute interval) | 15 minutes | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Thiopental, Alcohol, Family History, Vulnerability, GABA