PROJECT SUMMARY Despite the prevalence of cocaine use disorder, there is currently no medicine available to treat this disease. National rates of cocaine use have steadily climbed over recent years with approximately 2.2 million regular users and 1 million addicted individuals reported in 2019. A core feature of addiction is the propensity for relapse during abstinence. Natural mechanisms occurring over abstinence may combat relapse, by reversing normal function in reward-related brain areas. As the syndrome of addition can only be identified in afflicted patients, the identification of this type of mechanism has important therapeutic implications. We recently discovered that activation of orphan nuclear receptor, Nr4a1, during abstinence suppresses cocaine reward behavior in mice. This proposal is designed to validate Nr4a1 as a novel target for cocaine addiction using small molecule activators of Nr4a1, Csn-B and C-DIM. We hypothesize that Nr4a1 agonists cross the blood brain barrier to induce Nr4a1 expression and suppress cocaine behavior. In all studies we will apply cocaine self-administration, the most well-established mouse paradigm for modeling core features of human addiction such as drug motivation and reward saliency. Our work will go beyond all published data to validate novel Nr4a1 agonists in reducing volitional cocaine behavior following abstinence, in both male and female mice. The first aim of this proposal will determine the therapeutic potential of Csn-B in addiction. Aim 1 tests the hypothesis that Csn-B activates Nr4a1 expression and suppresses cocaine behavior. We will first determine the optimal dose of Csn- B for maximal Nr4a1 activation. We will measure Csn-B and metabolite concentration in brain and plasma, and Nr4a1 protein levels. Next, we will validate Csn-B in suppressing cocaine seeking and conditioned place preference (CPP) following abstinence. The second aim of this proposal will determine the therapeutic potential of novel C-DIM compounds. C-DIMs are well tolerated in vivo, penetrate the blood brain barrier, modulate neuronal activity and regulate neuronal homoeostasis. There is, however, no study of these compounds in cocaine addiction. To address this gap in knowledge, we will quantify the concentration of C-DIM metabolites in plasma and brain and Nr4a1 activity. Finally, we will determine the efficacy of of C-DIM in suppressing cued cocaine seeking and CPP following cocaine abstinence. At the conclusion of these fundamental neuroscience studies we will have advanced knowledge on the therapeutic potential of Nr4a1 as a novel target in cocaine addiction. This confirmatory research will define activation of Nr4a1 as a mechanism to suppress volitional cocaine seeking behavior in mice. We will elucidate the optimal doses of two distinct compounds, Csn-B and Br-OCF3, in activating Nr4a1 activity in mouse NAc and determine their efficacy in model cocaine addiction behavior. The confirmatory experiments proposed will produce conclusive data on the promise of Nr4a1 agonists as medicines to treat substance use disorders.

PROJECT NARRATIVE Despite the prevalence of cocaine use disorder, there is currently no medicine available to treat this disease. Using fundamental approaches, we recently discovered that activation of orphan nuclear receptor, Nr4a1, suppresses cocaine reward behavior in mice. The confirmatory experiments proposed will produce conclusive data on the promise of Nr4a1 agonists as medicines to treat substance use disorders.