Cocaine Use Disorder (CUD) is a major public health problem. CUD affects 3% of the general population over a lifetime and is associated with a high mortality rate. Cocaine is the most rapidly addictive substance. Its use, including crack cocaine, has been on the rise in Europe over the last ten years. This led to an increase in admissions for cocaine detoxification in specialized clinics. Unfortunately, neither biomarkers nor validated specific medication are available for CUD. A recent model proposes that CUD can be due to compulsive drug use caused by an imbalance between goal-directed behaviors (GDB) and habits (HB). The GDB/HB balance is finely tuned by dopaminergic and acetylcholine nicotinic transmissions in the caudate nucleus and in the putamen. However, human brain imaging of the striatum in CUD produced inconsistent results because of difficulties to finely analyze these striatal areas. Furthermore, several clinical trials conducted with cholinergic drugs yielded provided inconsistent results. The interpretation of these clinical studies is limited because of their short durations, very small sample sizes, and the paucity of analyzed clinical data. Our recent findings in transgenic rodents (self-administration, brain imaging, pharmacology) as well as in patients (clinical genetics, case/control brain imaging) confirms the pivotal involvement of the nicotinic cholinergic regulation of dopamine signaling in CUD. We recently identified a genetic variant of the alpha5 subunit of the nicotinic receptor (alpaha5SNP) in a population of patients with substance use disorders. We obtained a rat line expressing the alpha5SNP. The central objective of our proposal is to better characterize the impact of the a5SNP variant on compulsive cocaine-self administration, focusing on the striatal function. We will determine the morphology (structure and connectivity) of striatal subregions and on acetylcholine/dopamine balance in the caudate and the putamen of our unique humanized rat model. Based on recent results from the consortium we will assess a novel treatment of CUD in rat model with the cholinesterase inhibitor donepezil. We will also expand our investigations to patients hospitalized for severe CUD. To parallel rodent experiments, we will characterize the structure and resting-state functional connectivity of different regions of the striatum as a function of alpha5SNP genotypes and CUD severity in 68 patients. Finally, we will also test the effect of a donepezil in a long-term (6-month) randomized controlled trial in 120 CUD patients. The phenotypic characterization of the two cohorts will also parallel rodent experiments. It includes extensive clinical data about compulsive cocaine use, the trajectory of acquisition of CUD, and diagnostic criteria for CUD corresponding to addiction-like behavior. The feasibility of this ambitious translational research program is excellent, thanks to the complementary expertise and long-standing collaboration of the consortium. We already obtained solid preliminary preclinical and partly acquired clinical human data supporting the project. This project could open the way to increased understanding of CUD and consequently lead to the development of novel therapeutical avenues. The expected results are far-reaching, numerous possibilities for valorization in neuroscience and patient care.