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BEHAVIORAL PHARMACOLOGY

Effects of Combined Dopamine and Serotonin Transporter Inhibitors on Cocaine Self-Administration in Rhesus Monkeys

Yerkes National Primate Research Center (L.L.H., H.L.K.), Departments of Psychiatry and Behavioral Sciences (L.L.H.), Pharmacology (L.L.H., H.L.K.), and Radiology (J.R.V., M.M.G.), Emory University, Atlanta, Georgia; and Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, North Carolina (F.I.C.)

Dopamine transporter (DAT) inhibitors may represent a promising class of drugs in the development of cocaine pharmacotherapies. In the present study, the effects of pretreatments with the selective DAT inhibitor 3-(4-chlorophenyl)tropane-2-[3-(4'-methylphenyl)isoxazol-5-yl] hydrochloride (RTI-336) (0.3–1.7 mg/kg) were characterized in rhesus monkeys trained to self-administer cocaine (0.1 and 0.3 mg/kg/injection) under a multiple second-order schedule of i.v. drug or food delivery. In addition, RTI-336 (0.01–1.0 mg/kg/injection) was substituted for cocaine to characterize its reinforcing effects. Last, the dose of RTI-336 that reduced cocaine-maintained behavior by 50% (ED₅₀) was coadministered with the selective serotonin transporter (SERT) inhibitors fluoxetine (3.0 mg/kg) and citalopram (3.0 mg/kg) to characterize their combined effects on cocaine self-administration. PET neuroimaging with the selective DAT ligand [¹⁸F]8-(2-[¹⁸F]fluoroethyl)-2-carbomethoxy-3-(4-chlorophenyl)nortropane quantified DAT occupancy at behaviorally relevant doses of RTI-336. Pretreatments of RTI-336 produced dose-related reductions in cocaine self-administration, and the ED₅₀ dose resulted in approximately 90% DAT occupancy. RTI-336 was reliably self-administered, but responding maintained by RTI-336 was lower than responding maintained by cocaine. Doses of RTI-336 that maintained peak rates of responding resulted in approximately 62% DAT occupancy. Co-administration of the ED₅₀ dose of RTI-336 in combination with either SERT inhibitor completely suppressed cocaine self-administration without affecting DAT occupancy. Hence, at comparable levels of DAT occupancy, coadministration of SERT inhibitors with RTI-336 produced more robust reductions in cocaine self-administration compared with RTI-336 alone. Collectively, the results indicate that combined inhibition of DAT and SERT warrants consideration as a viable approach in the development of cocaine medications.

Address correspondence to: Dr. Leonard L. Howell, Yerkes National Primate Research Center, 954 Gatewood Rd. NE, Emory University, Atlanta, GA 30329. E-mail: leonard{at}rmy.emory.edu

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