PROJECT SUMMARY Chronic, heavy alcohol consumption leads to a disruption of stress homeostasis and a feed-forward cycle of alcohol-stress interactions that further exacerbate alcohol drinking. The rhesus monkey model of alcohol self- administration has documented allostatic changes within key brain areas associated with chronic heavy alcohol drinking. These include hypothalamic control of the stress axis and the dorsal striatum (caudate and putamen) implicated in control of action selection. Specifically, the striatal and HPA axis neuroadaptations were associated with an increase in alcohol drinking during relapse, deficits in flexibility in action selection and shift in the excitatory-to-inhibitory balance favoring the sensorimotor neurocircuitry. The proposed studies will exploit individual differences in stress regulation and behavioral flexibility to identify mechanisms underlying excessive drinking and susceptibility to relapse. The integrative designs encompass: self-administration with repeated abstinence/relapse cycles in rhesus monkeys; longitudinal measures of flexibility in action selection, stress response and integrity of brain neurocircuitry using rs-fMRI; manipulating cortico-dorsostriatal circuits in primate brain using designer receptors exclusively activated by designer drug (DREADDs) to alter ethanol drinking, behavioral flexibility and stress response. Ultimately, this project aims to define the role of cortico-striatal circuitry in protecting or facilitating excessive alcohol drinking. The research will also contribute to emerging sex differences in the stress response to chronic drinking through a balanced sex design.