PROJECT SUMMARY/ABSTRACT The recent resurgence in cocaine use in the U.S. is a significant public health concern and there is an urgent need to address the long-standing absence of effective treatments for cocaine-use disorder (CUD). Highly innovative research into unexplored brain mechanisms of addiction may provide insights into alternative therapeutic solutions. The proposed research program will investigate one such brain system, the type-1 muscarinic acetylcholine receptor (M1), in individuals with CUD following a phased research approach consistent with the scope of the NIDA Phased Innovation Award (PAR-19-282). The M1 receptor is the most abundant receptor in the brain for acetylcholine, a principal modulatory neurotransmitter system, and is linked to neural plasticity. M1 receptors are highly expressed throughout the brain and are particularly concentrated in the striatum and hippocampus, key hubs of addiction-related functioning. Preclinical evidence is consistent in demonstrating that activation of M1 receptors reduces, and M1 inhibition enhances, the rewarding effects of cocaine. Similarly, research is consistent in demonstrating that the number of M1 receptors is lower in preclinical models of regular cocaine use. Given these implications of M1 receptor functioning in CUD, and close neurobiological links to regulating dopamine, another critical neurotransmitter in addictions, the potential for M1-targeting pharmacotherapies to benefit individuals with CUD motivates exploration into this novel area of addiction neurobiology. The recent development of the M1-selective agonist radiotracer [11C]-LSN3172176 allows, for the first time, in vivo assessment of M1 receptor availability in humans. Non-treatment-seeking individuals with a current CUD, and matched healthy comparison participants will complete [11C]-LSN3172176 PET imaging and exploratory MRI and neurocognitive testing using a phased research design. This approach provides an opportunity for an interim assessment of the preliminary data to determine the merits of further data collection and possible refinement of procedures to optimize the benefit of this highly exploratory research. Greater knowledge of the M1 receptor holds potential to inform the development of effective interventions for CUD, particularly in the developing area of cognitive enhancement and pharmacologically augmented behavioral therapy.