Project Summary and Abstract Binge and high-intensity drinking (BHID) represent a significant threat to health and increase the risk for developing an alcohol use disorder (AUD). There is a critical need to understand the mechanisms and neurobiology of BHID to improve prevention and treatment. Most research has focused on amount consumed or alcohol concentration obtained; the rate (speed) of drinking is nevertheless understudied. Our central hypothesis is that people maximize and maintain perceived reward by controlling both the rate and magnitude of consumption. This behavior is modified by genetics, experience and tolerance. This component’s objectives are to determine the relationship between how quickly a participant self-administers to the binge threshold (80 mg/dL), a model of preclinical “front loading” sensitive to BHID, and 1) acute tolerance to rewarding subjective effects at 80 mg/dL, 2) the neurocircuitry of salience, and 3) associated risks such as biological family history of AUD, sex, lifetime drinking history, and impulsivity. Our objectives leverage two domains of Indiana Alcohol Research Center (IARC) expertise: intravenous alcohol administration and neuroimaging. The alcohol clamp provides each participant an identical, steady- state alcohol concentration during which initial response and acute tolerance can be measured, including that evident in electrophysiologically measured neurocircuitry. The clamp has been shown to be sensitive to genetic influence, recent drinking, and impulsivity. In the alcohol self-administration Rate-Control paradigm, participants precisely and reproducibly adjust rate of change in alcohol concentration every 3 minutes. Preliminary data reveal that time-to-80 mg/dL (T80) varies with BHID outside the lab, which is in turn associated with family history of alcoholism (FHA). Our preliminary neuroimaging data further show that an intensely sweet taste: 1) induces regional SN activation that correlates with the subjective effects of a rapid alcohol prime and real-life drinking and 2) enhances functional connectivity between salience and ventral striatal reward areas. Finally, 3) our data show that during mental state transitions brain-wide network connectivity reconfiguration (including in the SN) is lower in those with FHA. Our specific aims are to: 1. Characterize relationships between alcohol self-administration rate, acute tolerance, and FHA; 2. Determine how SN function relates to alcohol’s rate-dependent subjective effects and acute tolerance; 3. Identify brain network transitions affected by FHA. Success will demonstrate how acute tolerance to alcohol, neural circuitry and FHA contribute to BHID. The results will provide directions for intervention (e.g., neuromodulation of reward circuitry to alter the relationship between rate and subjective response) and inform translational study of this high-risk drinking pattern.