Alcohol Responses - Genetics, Sex Differences, Treatment

Rukstalis, Margaret

Abstract

This proposal for a Mentored Clinical Scientist Development Award (MCSDA) is aimed at developing the career of Margaret R. Rukstalis, M.D. at the University of Pennsylvania as an independent scientist with research, teaching and patient care opportunities in the field of substance abuse treatment. The MCSDA will build on Dr. Rukstalis's prior training in Psychiatry, Clinical Pharmacology and Substance Abuse and on her background in clinical research and methodology. The training has five components. (1) Supervision and mentoring by a senior scientist who will serve as a primary preceptor, Joseph R. Volpicelli, M.D., Ph.D., as well as secondary preceptors: Helen Pettinati, Ph.D., Ellen W. Freeman, Ph.D., Irwin Lucki, Ph.D. and Charles P. O Brien, M.D., Ph.D. (2) Formal coursework and tutorials in a) research design and statistical analysis, b) basic neuroendocrinology. (3) Participation in three ongoing clinical research projects under the mentorship of Drs. Volpicelli and Pettinati. (4) Design and execution of two original research projects: a) An acute alcohol administration study comparing the dose-response to alcohol in social drinkers stratified by sex and family history of alcohol dependence; b) An acute alcohol administration study comparing the response to alcohol with naltrexone pretreatment in social drinkers stratified by sex and family history of alcohol dependence. (5) Preparation of an R01 grant application based on the research performed during the award period. The two proposed experiments will test whether men are similar or different from women in acute alcohol administration studies with or without pretreatment with naltrexone, which was recently developed at the University of Pennsylvania as the first new FDA approved medication for alcohol dependence in the past fifty years by Joseph Volpicelli, M.D., Ph.D., the senior preceptor. In order to study a population of individuals at high risk for developing alcohol dependence, male and female subjects who are heavy social drinkers in both studies will be stratified between a paternal family history of alcohol dependence in two successive generation or no family history of alcohol dependence. In study number 1, 60 social drinking subjects, 30 men (15 FH+, 15 FH-) and 30 women (15 FH+, 15 FH-) will receive .4g/kg,.8g/kg or placebo ethanol adjusted for percent body fat. Women will be tested at two phases of their menstrual cycle: follicular and midluteal to determine whether their responses to alcohol vary as a function of fluctuating ovarian hormones. In study number 2, 60 social drinking subjects, 30 men (15 FH+, 15FH-) and 30 women (15 FH+, 15 FH-) will receive naltrexone 25mg, 100 mg or placebo prior to a single dose of alcohol. Dependent measures for both studies will include: blood alcohol, naltrexone and 6-naltrexol concentrations (study number 2) endorphins, sex steroids and subjective and behavioral responses will be measured for the subsequent 120 minutes. This training program will assist Dr. Rukstalis in making the transition from her current role as clinician and participant in research, to that of independent investigator at the University of Pennsylvania.