The impact that drug addictions have on health disparities impacting at-risk African Americans who reside in the rural South are grossly understudied. While there is strong evidence linking drug use and abuse to violent behaviors, injuries, mental health, and physical health problems, it is unclear how African Americans are disproportionately at risk given their relatively low incidence rates of drug use and abuse. There is a growing body of literature linking stress and the subsequent activation of the hypothalamic-pituitary-adrenal (HPA) axis to addictions. Given the considerable heterogeneity within drug-related phenotypes and limited evidence of large-magnitude single gene influences, stress dysregulation will be investigated as an endophenotype for clarifying the more subtle relationship between specific genes and drug use vulnerability. This study will pursue two specific aims using innovative experimental methodologies from drug abuse, molecular genetics, endocrinology, social psychology, and cross-cultural research: (1) Investigate whether genotype interacts with environmental variables (GxE) to affect physiological responses to acute stress;and (2) Investigate whether stress dysregulation predicts drug related attitudes, craving, and history of drug use. Acute stress will be elicited via the Trier Social Stress Test. Subjects (N = 100) will be randomly assigned into one of two speech tasks: (a) shoplifting or (b) experience of discrimination. Measured variables will include genotype (CRH and CRHR1), hormones (cortisol and DHEA), autonomic measures (galvanic skin conductance and heart rate variability), chronic environmental stressors, implicit drug-related cognitions, drug craving, and drug use history. It is envisioned that this proposed study can initiate a multidisciplinary program of research aimed at investigating gene by environment (GxE) influences on drug use vulnerability. Empirical research in this area is needed in order to gain insight into the biopsychosocial risk factors that have the capacity to inform theory, research, prevention, and treatment in the area of drug addictions. PUBLIC HEALTH RELEVANCE: African American drug use and abuse behaviors are often characterized by oversimplified models that are rooted in research studies that rarely include them. This proposal seeks to take a multidimensional approach (e.g., genetics, endocrinology, psychology, culture, social environment) towards investigating mechanisms that may increase drug use vulnerability in at-risk African American adults who reside in the rural South. Such research is needed in order to inform theory, research, prevention, and intervention efforts aimed at elimination health disparities that disproportionately impact this community.