PT - JOURNAL ARTICLE AU - Omeed Rahimi AU - Jianjing Cao AU - Jenny Lam AU - Steven R. Childers AU - Rana Rais AU - Linda J. Porrino, PhD AU - Amy Newman AU - Michael A. Nader TI - <strong>THE EFFECTS OF THE DOPAMINE TRANSPORTER LIGANDS JJC8-088 AND JJC8-091 ON COCAINE VS. FOOD CHOICE IN RHESUS MONKEYS</strong> AID - 10.1124/jpet.122.001363 DP - 2022 Jan 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - JPET-AR-2022-001363 4099 - http://jpet.aspetjournals.org/content/early/2022/12/06/jpet.122.001363.short 4100 - http://jpet.aspetjournals.org/content/early/2022/12/06/jpet.122.001363.full AB - While there are no FDA-approved treatments for cocaine use disorder (CUD), several modafinil analogs have demonstrated promise in reducing cocaine self-administration and reinstatement in rats. Furthermore, the range of dopamine transporter (DAT) compounds provides an opportunity to develop pharmacotherapeutics without abuse liability. This study extended the comparison of JJC8-088 and JJC8-091, the former compound having higher DAT affinity and predicted abuse liability, to rhesus monkeys using a concurrent cocaine-food schedule of reinforcement. First, binding to striatal DAT was examined in cocaine-naïve monkey tissue. Next, i.v. pharmacokinetics of both JJC compounds were evaluated in cocaine-experienced male monkeys (n=3/drug). In behavioral studies, acute and chronic administration of both compounds were evaluated in these same monkeys responding under a concurrent food vs. cocaine (0, 0.003-0.1 mg/kg/injection) schedule of reinforcement. In nonhuman primate striatum, JJC8-088 had higher DAT affinity compared to JJC8-091 (14.4 {plus minus} 9 vs. 2,730 {plus minus} 1,270 nM, respectively). Both JJC compounds had favorable plasma pharmacokinetics for behavioral assessments, with half-lives (t1/2) of 1.1 h and 3.5 h for JJC8-088 (0.7 mg/kg, i.v.) and JJC8-091 (1.9 mg/kg, i.v.), respectively. Acute treatment with both compounds shifted the cocaine dose-response curve to the left. Chronic treatment with JJC8-088 decreased cocaine choice in two of the three monkeys, while JJC8-091 only modestly reduced cocaine allocation in one monkey. Differences in affinities of JJC8-091 DAT binding in monkeys compared to rat, may account for the poor rodent-to-monkey translation. Future studies should evaluate atypical DAT blockers in combination with behavioral interventions that may further decrease cocaine choice. Significance Statement Cocaine use disorder (CUD) remains a significant public health problem with no FDA-approved treatments. The ability of drugs that act in the brain in a similar manner to cocaine, but with lower abuse liability, has clinical implications for a treatment of CUD.