My lab is devoted to understanding the biological and psychological characteristics of persons at risk for alcoholism. Alcohol addiction is a behavioral disorder with both genetic and environmental contributions. Persons with a positive family history of alcoholism are 4 – 6 times as likely to develop an alcohol use disorder as persons with no such history. Our guiding hypothesis is that a genetic predisposition toward alcohol and other substance-use disorders involves altered function of brain regions regulating reward motivation. We are studying four domains of function related to prefrontal cortex and limbic system regulation of motivated behavior: 1) Behavioral under control: the person's temperamental balance of positive to negative affect should be less stable and weighted toward dysphoria. 2) Cognitive processing on tests or working memory. 3) Decision-making during a reward based delay discounting calling for choices between immediate, but small rewards vs. waiting over a time delay to gain a larger reward. 4) Visceral responses to psychological stress using the stress hormone, cortisol, and autonomic control of the heart.
We have found so far that persons with a positive family history of alcoholism are more antisocial and under-controlled on paper and pencil personality tests along with having more negative emotional experiences. They are behaviorally more impulsive and have mild working memory deficits. That is, they show faster delay discounting of future rewards. They also have modestly diminished physiological stress responses. This pattern of results indicates the likelihood of altered interactions between the prefrontal cortex, ventral striatum, and limbic system, in which the prefrontal cortex may exert less control over cognition, motivated behavior, and processes stressors as less threatening. We are therefore carrying out neuroimaging of these brain structures under appropriate task conditions.
The primary brain neurochemical systems that we believe are involved in these altered behavioral and physiological phenotypes are the central opioid, dopaminergic, and the serotonergic systems. We have banked and stored DNA on 320 of our volunteers since the inception of the project using the Oragene kit. We are collaborating with the National Institutes of Health, Laboratory of Neurogenetics at the National Institute on Alcohol and Alcoholism and will soon begin a genome-wide association scan (GWAS) of this set of DNA samples.
The depth and breadth of this phenotypic information provides an invaluable opportunity to examine these several domains of existing data with respect to:
- genetic polymorphisms thought to predispose to substance abuse risk
- Carry out exploratory analyses across a much wider range of genetic polymorphisms using a 770,000 SNP genotyping array suitable for GWAS as well as candidate gene analyses.
We will also capture of information from 130 genes and ancestry informative markers previously identified by the NIAAA Neurogenetics Laboratory. By using large SNP array we gain flexibility to relate our results to large-scale genetic analyses being performed worldwide and avoid biasing our results by being too focused on a narrow set of genetic polymorphisms. Similarly, by using a genotyping array that is a standard product in genetic epidemiology we will also be in a position to contribute to meta-analytic efforts that combine data across studies.
Since we are primarily a behavioral laboratory, preparing and preserving our DNA from saliva samples, we required a reliable kit that could be used by non-specialists. Our laboratory assistants have found Oragene to be ideal for our needs.
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