Targeting Anhedonia in Cocaine Use Disorder



 DESCRIPTION (provided by applicant): Development of effective addiction treatments has been difficult, likely in part because addiction treatment re- search has generally targeted the end symptom of drug use, and there are many possible etiological pathways to drug use. The goal of this award is to support the training and career development of Dr. Margaret Wardle, in the context of a research program that will instead target underlying neurobehavioral dysfunctions to improve addiction treatment outcomes. Dr. Wardle's long-term career goal is to become an independent scientist using a neuroscience-based approach to treatment development for addiction. The proposed training builds on Dr. Wardle's prior experience with drug effects in healthy adults by increasing her expertise in: 1. Clinical re- search, including behavioral and medication treatments for addiction; 2. Functional Magnetic Resonance Imaging to directly measure underlying neural processes; 3. Advanced Bayesian statistical methods to increase in- formation gained from smaller trials. This training will position Dr. Wardle as an independent scientist at the cutting edge of addiction treatment development. The complementary research program uses a proof-of- concept design, targeting one specific neurobehavioral dysfunction, anhedonia, i.e. lack of interest or pleasure in non-drug rewards, in Cocaine Use Disorder (CUD), and specifically in contingency management (CM), a validated CUD treatment in which individuals receive non-drug rewards for abstaining. Several lines of evidence suggest that anhedonia negatively affects CM, that dopaminergic (DAergic) drugs improve CM outcomes, and that this improvement may be mediated by reduced anhedonia. Dr. Wardle's own preliminary data has established that anhedonia predicts worse outcomes in CM for CUD, and that DAergic drugs can enhance responsiveness to rewards. The current grant will integrate and expand on these findings by fully testing the hypothesis that anhedonia is a key neurobehavioral dysfunction in CUD that affects CM outcomes, and that DAergic drugs enhance CM by reducing anhedonia. This will be accomplished by: 1. Testing the relationship of anhedonia to CUD severity at baseline, 2. Testing whether baseline anhedonia predicts outcomes in an intensive 4 week CM treatment. 3. Testing the role of anhedonia in DAergic enhancement of CM, by examining the effects of CM combined with a DAergic stimulant against CM alone and a DAergic stimulant alone, and measuring effects on anhedonia and clinical outcomes. This study will use a neuroscience-based approach to anhedonia that measures multiple possible underlying deficits in reward functioning across subjective, behavioral, psychophysiological and neural levels. This work will: 1. Contribute to personalized medicine for CUD by establishing a key moderator of a validated treatment 2. Demonstrate the value of targeting neurobehavioral processes in addiction treatment 3. Provide Dr. Wardle with training in clinical research, imaging, and Bayesian statistics needed to apply this approach to accelerate the development of addiction treatments.