Contrasting the Reinforcing Effects of the Novel Dopamine Transport Inhibitors JJC8-088 and JJC8-091 in Monkeys: Potential Translation to Medication Assisted Treatment .

Autor:	Allen MI; Translational Neurosciene, Wake Forest University School of Medicine, United States., Rahimi O; EncepHeal Therapeutics, United States., Johnson BN; Translational Neuroscince, Wake Forest University School of Medicine, United States., Cao J; NIH-NIDA-IRP, United States., Newman AH; Medicinal Chemistry Section, NIDA-IRP, United States., Nader MA; Translational Neuroscience, Wake Forest University School of Medicine, United States mnader@wakehealth.edu.
Jazyk:	angličtina
Zdroj:	The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2024 Sep 20. Date of Electronic Publication: 2024 Sep 20.
DOI:	10.1124/jpet.124.002356
Abstrakt:	Despite considerable efforts, there remains no FDA-approved medications for cocaine use disorder (CUD). One strategy to mitigate cocaine craving and relapse is to elevate dopamine (DA). The DA transport inhibitor and releaser d -amphetamine has been shown to decrease cocaine self-administration (SA), although it has abuse liability. Recently, several modafinil analogues reduced cocaine SA in rats and monkeys, including JJC8-088, characterized as "cocaine like" in rats, and JJC8-091, characterized as "atypical" and not SA by rats. The present studies evaluated the reinforcing effects of both compounds in monkeys under several conditions. For Experiment 1, four male cocaine-experienced rhesus monkeys self-administered cocaine (0.001-0.3 mg/kg/injection), JJC8-088 (0.001-0.3 mg/kg/injection), and JJC8-091 (0.1-3.0 mg/kg/injection) under a progressive-ratio (PR) schedule of reinforcement. Both JJC compounds functioned as reinforcers with equal reinforcing strength to cocaine. Although JJC8-091 was less potent than cocaine, JJC8-088 and cocaine had similar potencies. For Experiment 2, one male and two females drug-naïve cynomolgus monkeys responded on a fixed-ratio schedule of food reinforcement. JJC8-091 was self-administered at rates higher than saline in all three monkeys. In Experiment 3, monkeys from Experiment 2 responded under a concurrent drug vs. food choice paradigm and given access to cocaine or JJC8-091 under these conditions. At doses equal to or one-half log-units higher than doses used in Experiment 2, cocaine, but not JJC8-091, was chosen over food. Together, these results demonstrate that while JJC8-091 may be reinforcing under some conditions, its reinforcing strength, in the presence of an alternative reinforcer, is substantially less than cocaine. Significance Statement JJC8-088 and JJC8-091 have shown efficacy is reducing cocaine self-administration in rats and in nonhuman primates. This study found that both compounds maintained self-administration in monkeys responding under several conditions. However, when given access to an alternative reinforcer during the self-administration session, JJC8-091 was not reinforcing, suggesting that JJC8-091 may be a viable candidate for CUD since, in the human population, alternatives to drug use are often available. (U.S. Government Work not Protected by U.S. Copyright.)
Databáze:	MEDLINE
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