PROJECT SUMMARY Cocaine addiction remains a serious problem in the US and worldwide. In 2018, an estimated 5.5 million people aged 12 or older were past year users of cocaine (2% of population), including about 757,000 users of crack. Repeated cocaine use is documented to be associated with adverse psychological and behavioral effects, supported by neuroadaptive changes shown by imaging in cocaine addicts. Unfortunately, cocaine has potent euphorigenic and reinforcing effects, and terminating its use leads to adverse psychological consequences, strong feelings of craving and withdrawal-associated anxiety, eventually leading to relapse. Although numerous (mainly repurposed) medications have been tested in clinical trials, there are no currently accepted FDA-approved pharmacotherapies for cocaine use disorders. New targets based on a strong premise of fundamental research may ultimately lead to new approaches for cocaine treatment. This project proposes to validate such a new approach, for treating craving and withdrawal-associated negative symptoms, based on basic research findings from the pharmacology of the nociceptin opioid receptor. The nociceptin receptor NOP and its endogenous neuropeptide agonist nociceptin/orphaninFQ (N/OFQ) are widely distributed throughout the CNS (in preclinical species as well as humans), particularly in neurons and circuits involved in motivated behaviors, reward, learning and memory, anxiety and stress response, that play a major role in the development and maintenance of addictive behaviors. A growing body of evidence, from studies in rodents and from human PET imaging suggests that the NOP-N/OFQ system undergoes significant neuroadaptive changes in several key brain regions, involved in aspects of addiction and therefore, could be a potential target for novel medications to treat cocaine addiction. Consistent with this, N/OFQ and small-molecule NOP agonists, including several drug-like NOP agonists from our research, have been shown to block cocaine place preference, cocaine self-administration and reinstatement of drug-seeking in preclinical models. NOP agonists also have anxiolytic activity, and recent data from our work suggests that NOP agonists may have efficacy in blocking or reversing behavioral sensitization, a preclinical correlate of craving. The objective of this Target Validation project is to demonstrate the efficacy of drug-like small-molecule NOP agonists to reduce behavioral sensitization and anxiety in preclinical models of cocaine craving and withdrawal. With our existing data demonstrating that NOP agonists reduce the rewarding effects of cocaine and block relapse, the outcome of the project will provide critical validation of a new approach for medication-assisted treatment of anxiety symptoms and craving during early abstinence and support abstinence for those seeking treatment for cocaine addiction.