This application is in response to RFA: DA-04-001 "Stress and Drug Abuse: Epidemiology, Etiology, Prevention, and Treatment". The interaction between stress and the development of substance use disorders (SUD) often begins with the early experience of trauma. Individuals who experienced childhood maltreatment consistently report higher rates of substance use than those without childhood maltreatment. Because persons with childhood maltreatment are impaired in multiple social domains in addition to substance abuse, targeting this group of individuals for treatment and prevention programs will have significant socioeconomic impact. However, in order to develop more effective interventions, it is critical to understand the underlying mechanisms of association between childhood abuse and vulnerability to SUD. Evidence suggests that stress endured early in life, during a time of high neuronal plasticity, may result in a persistent sensitization of the neurobiological systems to even mild stress, contributing to the development of SUD. Studies in animals suggest that the hypothalamic-pituitary-adrenal (HPA) axis might be involved, at least partially, in mediating the effects of early-life stress on the risk for SUD. In support of this hypothesis, in two preliminary studies, we showed that elevated HPA activity serves as a vulnerability marker for SUD in adolescents. We propose to replicate and extend these findings by examining the interactions between childhood maltreatment and HPA regulation in relation to the susceptibility to SUD in adolescents. Evidence suggests that adolescent substance use may induce stronger effects on the stressor-sensitive brain regions than in adults, consequently leading to more severe dependence-related behaviors and problems. Hence, a better understanding of the factors associated with vulnerability to substance use and dependence during adolescence will be beneficial not only for the youngsters, but also for adult patients with SUD. Using a controlled longitudinal design, this study will examine the relationships among early-life stress, HPA responsivity and vulnerability to SUD in adolescents with and without a history of childhood maltreatment by recruiting them prior to the onset of SUD. We hypothesize that a higher proportion of adolescents with childhood maltreatment will develop SUD during prospective follow-up compared with adolescents without childhood maltreatment, and that this increase in vulnerability to SUD will be mediated, at least in part, by HPA dysregulation measured at baseline. In addition to examining the association between premorbid stress and HPA dysregulation as related to susceptibility for the development of SUD, other factors that are known to influence these processes will be assessed from a multi-dimensional perspective. The identification of specific vulnerabilities and associated biological alterations will aid in the development of more focused and effective pharmacological and psychosocial interventions to reduce the risk of SUD in such youth.