GABA Mechanisms Underlying the Vulnerability to Alcohol Dependence

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

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.

Study Overview

• Status: Completed
• Conditions: Alcoholism
• Intervention / Treatment: Drug: Thiopental; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 73
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • West Haven, Connecticut, United States, 06516
      • VA Connecticut Healthcare System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 30 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: HEALTH_SERVICES_RESEARCH
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Family History Negative for Alcoholism; Family History Negative for Alcoholism subjects will receive 2 interventions	Drug: Thiopental; 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).
PLACEBO_COMPARATOR: Family History Positive for Alcoholism; Family History Positive for Alcoholism subjects will receive 2 interventions	Drug: Placebo; 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).

What is the study measuring?

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
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 - 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
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 - 170 Minutes	Self-report rating scale used to measure stimulant effects (0 not at all stimulated - 70 extremely stimulated)	170 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 - 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
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 - 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 - 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 - 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
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 - 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 - 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

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: VA Connecticut Healthcare System

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: November 1, 2005
• Primary Completion (ACTUAL): April 1, 2012
• Study Completion (ACTUAL): April 1, 2012

Study Registration Dates

• First Submitted: December 27, 2007
• First Submitted That Met QC Criteria: February 8, 2008
• First Posted (ESTIMATE): February 11, 2008

Study Record Updates

• Last Update Posted (ACTUAL): March 17, 2017
• Last Update Submitted That Met QC Criteria: January 24, 2017
• Last Verified: November 1, 2016

More Information

Terms related to this study

• Keywords: Alcohol; GABA; Family History; Vulnerability; Thiopental
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Alcohol-Related Disorders; Substance-Related Disorders; Alcoholism; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Hypnotics and Sedatives; GABA Modulators; GABA Agents; Anticonvulsants; Thiopental
• Other Study ID Numbers: 0510000664; VA Merit Grant (VA Merit Grant)