Project Summary Cocaine addiction is a chronic, relapsing brain disease that is intimately associated with dysregulations of the dopamine and dynorphin systems, which contributes to the dysphoric syndrome seen during withdrawal from cocaine. Furthermore, during abstinence, a negative affect persists, in addition to a reward deficiency, heightened stress response, and an inability to feel pleasure—all contributing to a high risk of relapse. The cycle from abstinence to withdrawal to subsequent escalation of drug use is far too common, and even though ample therapeutics targeted at the dopamine and dynorphin systems have been created, none have yet been proven effective and approved by the FDA to treat cocaine addiction. Due to the profound dysfunction of the dopamine and dynorphin systems, we propose to use the dopamine transporter and kappa opioid receptor as possible cellular targets in the development of therapeutics for cocaine addiction. Our overarching hypothesis is to combine a dopamine releaser to enhance dopaminergic tone and a kappa opioid receptor antagonist to produce anxiolytic and antidepressant effects, ultimately to reduce motivation to take cocaine and normalize the dopamine and kappa opioid receptor systems after chronic cocaine use in rats. Guided by our preliminary data showing promising results for combining two drugs that target the dopamine and dynorphin systems, we propose to pursue the following specific aims: (1) To assess whether phenmetrazine and LY2444296, both individually and in combination, will reduce the motivation to take cocaine; and (2) To assess whether phenmetrazine and LY2444296, both individually and in combination, will reverse long-term dysregulations in the dopamine and kappa opioid receptor systems. Collectively, our proposed studies use a combination therapy approach, in which the dopamine releaser phenmetrazine and the kappa opioid receptor antagonist LY2444296 may accentuate the beneficial effects of each individual drug, with the advantage of targeting two dysregulated neurotransmitter systems post-chronic cocaine exposure, in a cocaine self-administration rat model. These studies have the potential to uncover potential cellular interactions that can be targeted for treatment of cocaine use disorder.