PROJECT SUMMARY Sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) are the most effective weight (wt) loss procedures for severe obesity. Our lab recently showed decreased brain reward activation to high energy dense (HED) vs low energy dense (LED) food cues following both SG and RYGB. The reward activation changes, however, have not been correlated with changes in actual intake of HED or LED foods. There is also recent concerning evidence of increased alcohol intake and new onset alcohol use disorder (AUD) by 2 y postsurgery. Although there are overlapping neural reward pathways underlying food intake and alcohol use, the mechanisms behind increased alcohol intake postsurgery remain unknown. There is, however, evidence of more rapid alcohol absorption in both SG and RYGB, which could be a factor in increased alcohol intake. Alcohol absorption, however, has not been studied over time postsurgery to link it to increased alcohol intake or AUD. To investigate the neurobiological mechanisms, we will conduct a study of three groups of 70 each: SG, RYGB, and a nontreatment (NT) group, matched for baseline BMI, sex, age, and alcohol intake, at presurgery, 1 y (when body weight tends to stabilize), and 2 y postsurgery (when alcohol intake increases). Although weight loss is similar for SG and RYGB, the surgeries differ anatomically, yet lead to similar increased drinking, making them both worthwhile to study. Primary Aim 1: a) Determine neural responses to visual cues of alcohol (ALC) and non-alcohol (NA) drinks as well as HED and LED foods. From pre to post surgery, cue reactivity in 9 common reward ROIs to alcohol and food is expected to increase in response to cues of ALC vs NA and decrease to HED vs LED. The changes are expected to manifest at 1 y and strengthen at 2 y postsurgery. b) Relate changes in neural responses to ALC vs NA cues with changes in alcohol intake, # AUD symptoms, and AUD status at 1 and 2 y. c) Test whether baseline reward activation to ALC vs NA cues predicts increased postsurgical alcohol intake at 1 and 2 y. d) Compare for the above, the effects of (SG + RYGB) vs NT (primary) and RYGB vs SG (secondary), expecting greater effects for RYGB than SG. Primary Aim 2: a) Determine pharmacokinetics (PK) after 1 alcohol drink equivalent from blood alcohol concentrations (BAC) at pre-drink, 2, 5, 15, 25, 35, 50, 65, 80 min post-drink. We expect that the surgical groups will exhibit higher and sooner BAC peaks than NT, and that RYGB will result in higher and earlier peak BAC than SG. b) Correlate changes in brain activation to ALC vs. NA cues in the common reward areas with changes in BAC peak and time to peakpredict alcohol intake and AUD based on changes in BAC peak and time to peak. The study results should enhance knowledge of neural mechanisms underlying the postsurgical changes in alcohol and food intake, in association with changes in alcohol PK. This knowledge could lead to development of new surgery procedures which do ...