Drug and alcohol abuse pose an enormous public health burden on society, with high rates of mortality, great human suffering and incalculable economic costs. Yet, substance abuse is preventable, especially with a deeper understanding of the etiology and sources of individual risk. People vary in their susceptibility to use and abuse drugs, for reasons that are not fully understood. Translational studies in animal models and humans offer several promising leads for identifying high-risk individuals, including those who experience greater reward from drugs. In this project we examine two predictors of drug reward in humans, the personality trait of extraversion, and the sensitivity of the brain reward circuit t monetary gains. The brain reward circuit, known as the Fronto-Limbic Accumbens REward Seeking (FLARES) circuit, has been well characterized in human imaging studies and in studies with laboratory animals. It is comprised of the ventral striatum including the nucleus accumbens, with dynamic interactions with the frontal cortex, limbic and ventral tegmental areas. Using healthy volunteers as subjects, we will extend previous findings that extraversion is related to both brain responses to monetary reward and behavioral responses to drug reward. Then, addressing an as-yet unstudied relationship, we will determine whether the activity of the FLARES circuit predicts behavioral preference and subjective reward (euphoria) with two drugs of abuse, amphetamine and alcohol. Finally, we will test the novel hypothesis that the relationship between extraversion and drug euphoria is mediated by the brain reward circuit. Our long-term goal is to identify the neurobiological and psychological processes that underlie risk for drug abuse. We hypothesize that the trait measure of risk (extraversion), the measure of brain reward and the measure of drug-induced euphoria are closely inter-related, and together represent a bio- behavioral risk factor for drug use. The project involves a unique collaboration combining the behavioral expertise of Dr. de Wit with the brain imaging expertise of Dr. Phan. Our central hypothesis is that sensitivity of the brain reward circuit mediates the relationship between personality and the rewarding effects of drugs. We will use an innovative design that links brain to behavior by coupling functional magnetic resonance imaging with psychopharmacology.