This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This protocol represents the aims of an NIH K23 Mentored Patient-Oriented Research Career Development Award. Under this protocol, subjects will participate in a comprehensive characterization of acute subjective, physiological and neuroendocrine responses to acute alcohol administration. This protocol will accomplish the following specific aims: 1. To examine if genetic variation in GABAA -receptor subunit genes mediate, in part, the observed variance in sensitivity to alcohol in a healthy social-drinking population. 2. To examine the physiological, subjective and neuroendocrine responses to acute alcohol administration in a healthy social-drinking population. RATIONALE Alcohol dependence is a highly prevalent disorder that is associated with serious morbidity and mortality. It is estimated that approximately 14% of men and 5% of women in the United States will experience the symptoms of alcohol abuse or dependence sometime in their lives. There is clear evidence that alcohol use disorders have complex genetic and environmental determinants. Studies of the pharmacogenetics of alcohol seek to identify variation in specific genes that interact with alcohol exposure to modify both the short-term and long-term effects of alcohol, including alcohol dependence. Given the difficulty in detecting differences related to genetic variation in complex genetic disorders such as alcohol dependence, it emphasizes the need to evaluate less complex phenotypes in association with alcoholism risk. There is evidence suggesting that genetically determined differences in alcohol sensitivity may represent one pathway by which an increase in alcohol dependence risk occurs. Alcohol exerts many of its effects via interactions with receptors for the major inhibitory amino acid gamma-aminobutyric acid (GABA). The actions of GABA are mediated by receptors belonging to two major classes, termed GABAA and GABAB. GABAA receptors are the most widely expressed in the central nervous system, and are involved in the reinforcing effects of alcohol. Because differences in sensitivity to alcohol are a risk factor for the development of alcohol use disorders, in the proposed protocol we conduct a genetic association study to investigate the effects of GABAA receptor subunit gene variation on the subjective, physiologic and neuroendocrine response to acute alcohol consumption in a healthy social-drinking population. Growth hormone (GH) secretion is among the neuroendocrine responses to acute alcohol administration to be examined during our study. It is well known that GH is synthesized and secreted from the anterior pituitary gland in a pulsatile manner throughout the day;between the peaks, basal GH levels are low, often undetectable by our current assay methods. Therefore, we plan to evaluate GH secretion following the administration of GH secretagogues. We propose to administer arginine, which is widely used in humans for stimulation of GH secretion upon its administration. These stimulation tests will also be used to study the underlying mechanisms involved in alcohol?s effects on growth-hormone release. In addition, given that the largest and most predictable of GH peaks occur about an hour after onset of sleep, we plan to examine neuroendocrine responses to acute alcohol administration during the night. Interestingly, one possible mechanism involved in alcohol effects on GH could be mediated by its effects on ghrelin. However, although a few studies have examined the effects of acute alcohol administration on ghrelin release, none of these studies examined the relationship between ghrelin and GH secretion following acute alcohol administration. Given that it is possible that the energy provided with alcohol administration rather than alcohol per se could account for the effects observed on ghrelin and GH secretion, we plan to examine neuroendocrine responses following administration of isocaloric, isovolemc beverages. SIGNIFICANCE My proposed studies will expand our understanding of one possible mechanism by which risk of alcoholism may be transmitted. The present study will include a detailed examination of gene variations in relationship to both changes in validated subjective measures of alcohol?s effects and quantitative behaviorally relevant measures of alcohol?s effects on neural processing. In addition, the present protocol will examine the underlying mechanisms involved in alcohol?s effects on neuroendocrine measures. Furthermore, this proposal will extend these findings by examining if genetic variations that are found to predict differences in response to alcohol will also predict genetic risk for alcohol dependence. The current proposal is innovative, because although it employs many of the same assessments (subjective alcohol effects rating scales, physiological measures) and alcohol dosing methods that have been refined in human laboratory studies of alcohol, it focuses on the role of genetic variation in receptors involved in alcohol?s action and the mechanisms involved in alcohol?s effects on neuroendocrine measures. Ultimately, greater understanding of the role of genetic variation and the mechanisms mediating alcohol effects in humans may contribute to the development of pharmacogenetic and other interventional approaches in the screening and management of alcohol dependence. SUBJECT POPULATION Healthy male and female subjects 21 to 30 years old will be recruited via newspaper, flyers and other advertisements from the local Los Angeles area and on surrounding college/university campuses. Subjects will be recruited to yield a broadly representative sample of community-dwelling young adult drinkers. All interested persons will be screened by telephone using a questionnaire addressing demography, personal and familial alcohol and drug use patterns and associated problems, and medical and mental health history. This telephone screening will address major study inclusion and exclusion criteria, and identify at the outset the majority of those who do not qualify. Following the initial telephone screening, eligible individuals will be interviewed in person by an interviewer with experience in administering structured diagnostic interviews. Prior to any research participation, subjects will be required to provide written informed consent using a form approved by the Cedars-Sinai Institutional Review Board.
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