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.

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.

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).

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).

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

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

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

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

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

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

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

The Number of Drinks Scale asks Subjects to report on the number of alcoholic drinks they felt they had consumed.

The Number of Drinks Scale asks Subjects to report on the number of alcoholic drinks they felt they had consumed.

The Number of Drinks Scale asks Subjects to report on the number of alcoholic drinks they felt they had consumed.

The Number of Drinks Scale asks Subjects to report on the number of alcoholic drinks they felt they had consumed.

The Number of Drinks Scale asks Subjects to report on the number of alcoholic drinks they felt they had consumed.

The Number of Drinks Scale asks Subjects to report on the number of alcoholic drinks they felt they had consumed.

The Number of Drinks Scale asks Subjects to report on the number of alcoholic drinks they felt they had consumed.

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

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

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

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

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

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

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

Self-report rating scale used to measure sedative effects (0 not at all sedated - 70 extremely sedated)

Self-report rating scale used to measure sedative effects (0 not at all sedated - 70 extremely sedated)

Self-report rating scale used to measure sedative effects (0 not at all sedated - 70 extremely sedated)

Self-report rating scale used to measure sedative effects (0 not at all sedated - 70 extremely sedated)

Self-report rating scale used to measure sedative effects (0 not at all sedated - 70 extremely sedated)

Self-report rating scale used to measure sedative effects (0 not at all sedated - 70 extremely sedated)

Self-report rating scale used to measure sedative effects (0 not at all sedated - 70 extremely sedated)

visual analog scale (VAS): self-report scale used to measure high (0 not at all High - 7 extremely High)

visual analog scale (VAS): self-report scale used to measure high (0 not at all High - 7 extremely High)

visual analog scale (VAS): self-report scale used to measure high (0 not at all High - 7 extremely High)

visual analog scale (VAS): self-report scale used to measure high (0 not at all High - 7 extremely High)

visual analog scale (VAS): self-report scale used to measure high (0 not at all High - 7 extremely High)

visual analog scale (VAS): self-report scale used to measure high (0 not at all High - 7 extremely High)

visual analog scale (VAS): self-report scale used to measure high (0 not at all High - 7 extremely High)

visual analog scale (VAS): self-report scale used to measure buzzed (0 not at all buzzed - 7 extremely buzzed)

visual analog scale (VAS): self-report scale used to measure buzzed (0 not at all buzzed - 7 extremely buzzed)

visual analog scale (VAS): self-report scale used to measure buzzed (0 not at all buzzed - 7 extremely buzzed)

visual analog scale (VAS): self-report scale used to measure buzzed (0 not at all buzzed - 7 extremely buzzed) .

visual analog scale (VAS): self-report scale used to measure buzzed (0 not at all buzzed - 7 extremely buzzed)

visual analog scale (VAS): self-report scale used to measure buzzed (0 not at all buzzed - 7 extremely buzzed)

visual analog scale (VAS): self-report scale used to measure buzzed (0 not at all buzzed - 7 extremely buzzed)

visual analog scale (VAS): self-report scale used to measure drowsy (0 not at all drowsy - 7 extremely drowsy)

visual analog scale (VAS): self-report scale used to measure drowsy (0 not at all drowsy - 7 extremely drowsy)

visual analog scale (VAS): self-report scale used to measure drowsy (0 not at all drowsy - 7 extremely drowsy) .

visual analog scale (VAS): self-report scale used to measure drowsy (0 not at all drowsy - 7 extremely drowsy)

visual analog scale (VAS): self-report scale used to measure drowsy (0 not at all drowsy - 7 extremely drowsy)

visual analog scale (VAS): self-report scale used to measure drowsy (0 not at all drowsy - 7 extremely drowsy)

visual analog scale (VAS): self-report scale used to measure drowsy (0 not at all drowsy - 7 extremely drowsy)

visual analog scale (VAS): self-report scale used to measure depressed (0 not at all depressed - 7 extremely depressed)

visual analog scale (VAS): self-report scale used to measure depressed (0 not at all depressed - 7 extremely depressed)

visual analog scale (VAS): self-report scale used to measure depressed (0 not at all depressed - 7 extremely depressed)

visual analog scale (VAS): self-report scale used to measure depressed (0 not at all depressed - 7 extremely depressed)

visual analog scale (VAS): self-report scale used to measure depressed (0 not at all depressed - 7 extremely depressed)

visual analog scale (VAS): self-report scale used to measure depressed (0 not at all depressed - 7 extremely depressed)

visual analog scale (VAS): self-report scale used to measure depressed (0 not at all depressed - 7 extremely depressed)

visual analog scale (VAS): self-report scale used to measure anxiety (0 not at all anxious - 7 extremely anxious)

visual analog scale (VAS): self-report scale used to measure anxiety (0 not at all anxious - 7 extremely anxious)

visual analog scale (VAS): self-report scale used to measure anxiety (0 not at all anxious - 7 extremely anxious)

visual analog scale (VAS): self-report scale used to measure anxiety (0 not at all anxious - 7 extremely anxious)

visual analog scale (VAS): self-report scale used to measure anxiety (0 not at all anxious - 7 extremely anxious)

visual analog scale (VAS): self-report scale used to measure anxiety (0 not at all anxious - 7 extremely anxious)

visual analog scale (VAS): self-report scale used to measure anxiety (0 not at all anxious - 7 extremely anxious)

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)

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)

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)

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)

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)

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)

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)

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)

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

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

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.

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.

Hopkins Verbal Learning Task (HVLT) - measures verbal memory and hippocampus function based on word recall. (0 = no words recalled - 36 = all words recalled)

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)

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)

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.

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.