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| Sponsor: | University of Connecticut Health Center |
|---|---|
| Collaborators: |
National Institutes of Health (NIH) National Institute on Alcohol Abuse and Alcoholism (NIAAA) |
| Information provided by: | University of Connecticut Health Center |
| ClinicalTrials.gov Identifier: | NCT00734656 |
Purpose
This study will explore the hypothesis that effects of alcohol are in part mediated by increased production of neuroactive steroids, which interact with GABAA-receptors. We propose to study non-dependent drinkers using a 4-session within-subjects design in which alcohol / placebo is paired with dutasteride / placebo pretreatment. Dutasteride is a 5-alpha steroid reductase (5AR) inhibitor that limits the production of dihydrotestosterone and the 5a-reduced neuroactive steroids allopregnanolone, pregnanolone and 3a,5a-THDOC. This work continues our pilot studies in this area in which we demonstrated that both an alcohol-dependence associated GABRA2 allele and inhibition of 5AR reduce the subjective response to alcohol. We will extend work in this area by 1) examining a larger group of subjects that includes both light and heavy drinkers balanced on GABRG1-GABRA2 genotype, 2) include objective measures of alcohol's effects, 3) measure plasma concentrations of neuroactive steroids and their adrenal steroid hormone precursors at several time points following alcohol administration, 4) examine effects of a more potent and specific inhibitor of 5a-reductase (to validate and clarify the relationship of neuroactive steroids to alcohol effects), and 5) examine the effects of natural variation in other genes, particularly those encoding in steroid 5a-reductase, m-opioid receptor, GABA and glutamate receptor subunits, serotoninergic genes and those involved in the biology of stress responses, on the between subject differences in acute alcohol effects. Aim 1. Examine the effect of GABRG1-GABRA2 genotype on multiple responses to alcohol in 80 healthy human subjects. Aim 2. Examine the effects of dutasteride pre-treatment on alcohol-induced increases in circulating neuroactive steroid levels and on the subjective, motor and cognitive effects of acute alcohol consumption. In addition, we will examine the interactive effects of GABRG1-GABRA2 genotype and dutasteride on the response to alcohol.Aim 3. Examine the impact of genetic variation in the 5a-reductase and m-opioid receptor genes on alcohol-induced neuroactive steroid signaling as well as the effect of natural variation in GABA and glutamate receptor subunits, serotoninergic genes and those involved in the biology of stress responses, on the between subject differences in acute alcohol effects. Aim 4. Conduct an optional sub-study to examine alcohol induced changes in neuroactive steroid metabolism in vitro using neural cultures generated from skin biopsies obtained from study participants.This aim is an in vitro sub-study that will allow comparison of subjective and behavioral effects of alcohol measured in Aims 1-3 of the main study with and alcohol induced changes in neuroactive steroid metabolism directly in neural cells derived in vitro from induced pluripotent stem cells generated from skin biopsies obtained for Aim 4 from study participants.
| Condition | Intervention |
|---|---|
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Alcohol Related Disorders Alcoholism Alcohol Abuse |
Drug: Dutasteride Drug: Alcohol beverage Drug: Placebo pill Drug: Placebo alcohol beverage Procedure: Skin Biopsy |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Pharmacodynamics Study Intervention Model: Crossover Assignment Masking: Double Blind (Subject, Caregiver) |
| Official Title: | Subjective and Physiological Effects of Alcohol: Role of Genetic Variation and Adrenal Hormones |
| Estimated Enrollment: | 180 |
| Study Start Date: | March 2007 |
| Estimated Study Completion Date: | May 2011 |
| Estimated Primary Completion Date: | May 2011 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: 1
Light Drinkers: 1-3 drinks, 1-3 times a week (up to 5 drinks per week on average) with no more than one episode of heavy drinking in the past two months
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Drug: Dutasteride
During the pre-laboratory visits subjects will randomly be given the medication at 4mg at two of the four visits, and subjects will be provided with written instructions for medication self administration.
Other Name: Another name for Dutasteride is Avodart.
Drug: Alcohol beverage
Subjects will randomly ingest three 0.8g/kg of vodka alcohol at two of the four laboratory visits. Vodka alcohol beverages are prepared by pharmacy and given to subject by Research Nurse. Vodka alcohol will be consumed within a 36 minute period. Behavioral effects of acute alcohol in laboratory setting will be observed.
Other Name: Smirnoff Triple Distilled Vodka
Drug: Placebo pill
During the pre-laboratory visits subjects will randomly be given the placebo at two of the four visits. Pharmacy dispenses placebo and and subjects will be provided with written instructions for placebo self administration.
Other Name: sugar pill
Drug: Placebo alcohol beverage
Subjects will randomly ingest three placebo alcohol beverage at two of the four laboratory. Placebo beverages are prepared by pharmacy and given to subject by Research Nurse. Placebo beverage will be consumed within a 36 minute period. Behavioral effects of acute alcohol in laboratory setting will be observed.
Other Name: Contains 1 ml of vokda alcohol layered on surface as a taste mask
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Experimental: 2
Heavy Drinkers: At least 10 drinks per week , with at least one episode per week of heavy drinking.
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Drug: Dutasteride
During the pre-laboratory visits subjects will randomly be given the medication at 4mg at two of the four visits, and subjects will be provided with written instructions for medication self administration.
Other Name: Another name for Dutasteride is Avodart.
Drug: Alcohol beverage
Subjects will randomly ingest three 0.8g/kg of vodka alcohol at two of the four laboratory visits. Vodka alcohol beverages are prepared by pharmacy and given to subject by Research Nurse. Vodka alcohol will be consumed within a 36 minute period. Behavioral effects of acute alcohol in laboratory setting will be observed.
Other Name: Smirnoff Triple Distilled Vodka
Drug: Placebo pill
During the pre-laboratory visits subjects will randomly be given the placebo at two of the four visits. Pharmacy dispenses placebo and and subjects will be provided with written instructions for placebo self administration.
Other Name: sugar pill
Drug: Placebo alcohol beverage
Subjects will randomly ingest three placebo alcohol beverage at two of the four laboratory. Placebo beverages are prepared by pharmacy and given to subject by Research Nurse. Placebo beverage will be consumed within a 36 minute period. Behavioral effects of acute alcohol in laboratory setting will be observed.
Other Name: Contains 1 ml of vokda alcohol layered on surface as a taste mask
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Experimental: 3
Skin biopsy: 3.5 millimeter punch biopsy of skin from the upper arm will be obtained by subjects who consent to participating to this sub-study.
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Procedure: Skin Biopsy
A 3.5 mm punch biopsy of skin from the upper arm will be obtained from subjects. Biopsies will be minced into 6-8 pieces and placed in culture. Primary fibroblasts cultures will be obtained by expansion of fibroblast cells growing out of skin explants after 7-14 days by repeated passage 1-2 times per week in Dulbecco's Modified Eagle Medium supplemented with 10% fetal bovine serum and 0.5% penicillin and streptomycin. Frozen stocks of fibroblasts for each subject will be prepared at passage 4-6. Initially, fibroblasts from a selected subset of study participants will be used to generate iPS cells, specifically those from 3-5 heavy drinkers and 3-5 light drinkers including subjects who exhibited suppression of alcohol subjective effects by dutasteride pretreatment as well as those who did not. Fibroblasts from other participants will be de-identified and retained for potential use in generating iPS cells in subsequently funded investigations.
Other Names:
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Alcohol has multiple pharmacological effects, though which of these effects relate to the risk of alcohol dependence is not clear. Family-based and case-control genetic studies of alcohol dependence indicate that genetic variations of the adjacent GABAA g1- and a2-subunit genes, GABRG1 and GABRA2, influence the risk of developing alcohol dependence. Preliminary results from our alcohol laboratory studies in humans suggest that variation in GABRA2 influences the subjective effects of alcohol. Animal studies indicate that the neuroactive steroid allopregnanolone is an alcohol-modulated endogenous agonist at GABAA receptors and that genetic variation in steroid 5a-reductase type I gene which generates neuroactive steroids, may moderate alcohol effects. Studies in humans have identified a functional m-opioid receptor polymorphism (Asn40Asp) that moderates the feedback regulation of the HPA axis and may be associated with variation in the neurosteroid response to acute alcohol. To better define the role of GABRA2 gene variation, neuroactive steroids and genetic variants of 5a-reductase and m-opioid receptor genes on the acute effects of alcohol in humans, we propose to conduct a laboratory study of non-alcohol dependent drinkers using a 4-session design in which alcohol/placebo beverage is paired with dutasteride/placebo pretreatment. Dutasteride, an inhibitor of both type I and type II 5a-reductase enzymes, blocks the production of 5a-reduced neuroactive steroids. This study will extend our preliminary findings with finasteride by including a) a placebo control for alcohol, b) a more specific inhibitor of both 5a-reductase isoenzymes, c) a larger group of subjects (including both light and heavy drinkers), d) quantitative tests of static ataxia and response inhibition, e) plasma concentrations of neuroactive steroids and their adrenal steroid hormone precursors at several time points following alcohol administration, and f) the effects of polymorphisms in steroid 5a-reductase enzymes and m-opioid receptor genes on acute alcohol effects (including changes in levels of neuroactive steroids).
Correlation of in vitro effects of alcohol on neural tissue for defined biological process with subjective and behavioral effects of alcohol in human subjects offers the potential to better understand natural variation between subjects in alcohol effects and risk of alcohol use disorders. Recent descriptions of methods to reprogram human post-natal and adult somatic cells into pluripotent stem cells (induced pluripotent stem cells or iPS cells) in vitro (Takahashi, Tanabe et al. 2007; Lowry, Richter et al. 2008; Nakagawa, Koyanagi et al. 2008; Park, Zhao et al. 2008) may now allow examination of correlations between subject variation in alcohol response and the direct effects of alcohol on neural tissue in vitro. In this sub-study we propose to demonstrate use of this technology by conducting a parallel examination of between subject differences in a) alcohol effects and their modulation by a pharmacologic probe of neuroactive steroid production in human volunteers (main study aims 1-3), and b) alcohol induced changes in neuroactive steroid metabolism in vitro using neural cultures generated from these same subjects (this sub-study). Aim 1. Generate frozen stocks of adult primary fibroblast cultures from study participants enrolled in our ongoing dutasteride/alcohol human laboratory study. Aim 2. Generate induced pluripotent stem (iPS) cell lines from each of 8-10 participants (3-5 heavy drinkers and 3-5 light drinkers) with at least one from each group who show either robust or minimal effect of dutasteride pretreatment on acute alcohol subjective effects. Aim 3. Examine the effect of short term exposure of neural cells generated by differentiation of subject specific iPS cells, to 25, 50 or 100 mM (0.115 to 0.460 %) ethanol on the production of the neuroactive steroid allopregnanolone and of type I and II 5a-reductase protein and mRNA produced by these cells.
140 subjects will be recruited for the main study and 70 subjects in the substudy will be subjects who have, or are participating, in the above main study.
Eligibility| Ages Eligible for Study: | 21 Years to 45 Years |
| Genders Eligible for Study: | Male |
| Accepts Healthy Volunteers: | Yes |
Inclusion Criteria:
Exclusion Criteria:
Contacts and Locations| United States, Connecticut | |
| University of Connecticut Health Center | |
| Farmington, Connecticut, United States, 06030 | |
| Principal Investigator: | Jonathan Covault, MD, PhD | University of Connecticut Health Center |
More Information
| Responsible Party: | Jonathan Covault, M.D., Ph.D., University of Connecticut Health Center |
| ClinicalTrials.gov Identifier: | NCT00734656 History of Changes |
| Other Study ID Numbers: | 06-218S-2, 619, 5R01AA015606-02 |
| Study First Received: | July 31, 2008 |
| Last Updated: | February 21, 2011 |
| Health Authority: | United States: Food and Drug Administration |
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steroid 5AReductase genetic polymorphism GABA receptor pluripotent stem (iPS) cell lines |
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Alcoholism Alcohol-Related Disorders Substance-Related Disorders Mental Disorders Ethanol Dutasteride Anti-Infective Agents, Local Anti-Infective Agents |
Therapeutic Uses Pharmacologic Actions Central Nervous System Depressants Physiological Effects of Drugs Central Nervous System Agents 5-alpha Reductase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action |
