P 7/7: Glucocorticoid antagonists in heavy drinkers:effects on fMRI connectivity, withdrawal and drinking

Gary Wand
Betsy McCaul

PROJECT SUMMARY
Cortisol (CORT) is a glucocorticoid hormone, often associated with response to stress and playing a key role in alcohol use and problems. First, acute alcohol administration increases CORT, which in turn amplifies the mesolimbic dopamine reward signal. Second, alcohol withdrawal elevates CORT levels in AUD compared with healthy control subjects, and CORT levels in early abstinence predict subsequent relapse to drinking. Finally, the magnitude of CORT response to external stressors predicts motivation to work for and consumption of alcohol in the human laboratory and in the natural environment. Importantly, recent studies in rodents and humans have demonstrated that blocking CORT activity using a glucocorticoid receptor (GR) antagonist reduces these effects of CORT on alcohol behaviors, indicating a causal role for glucocorticoids in these relationships. The proposed research will test the effectiveness of two glucocorticoid receptor antagonists with different receptor binding and side-effect profiles. In alcohol use disorder (AUD) and matched healthy control (HC) men and women, the proposed research examines MIFE, with demonstrated preclinical effects on drinking-related behaviors, and CORT125134, a newer medication with improved safety profile but as yet unexamined efficacy for AUD, on a breadth of alcohol-related measures. All subjects will be randomized to daily MIFE, CORT125134 or placebo. Before and during medication, AUD and HC subjects undergo fMRI scanning measuring resting-state functional connectivity and alcohol cue-induced brain activation focused on brain reward and stress pathways. All subjects are admitted to the Clinical Research Unit; AUD subjects undergo supervised alcohol withdrawal with daily measurements of alcohol craving and symptom severity. Using validated human laboratory procedures in AUD subjects, we examine the effects of stress on motivation to drink and alcohol sensitivity/reward as a function of GR antagonism. This work will help pave the way for improved pharmacotherapies that target stress and reward pathways in the brain involved in initiating and maintaining drinking.