Abstract
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 3β-(4-chlorophenyl)tropane-2β-[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)-2β-carbomethoxy-3β-(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.
Footnotes
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This work was supported in part by U.S. Public Health Service Grants DA10344 (to L.L.H.), DA00517 (to L.L.H.), DA13326 (to F.I.C.), DA15092 (to H.L.K.), and RR00165 (Division of Research Resources, National Institutes of Health, Bethesda, MD). The Yerkes National Primate Research Center is fully accredited by the Association for the Advancement and Accreditation of Laboratory Animal Care International.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.108324.
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ABBREVIATIONS: DAT, dopamine transporter; GBR12909, 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-[3-phenylpropyl]piperazine; SERT, serotonin transporter; RTI-336, 3β-(4-chlorophenyl)tropane-2β-[3-(4′-methylphenyl)isoxazol-5-yl] hydrochloride; FR, fixed ratio; PET, positron emission tomography; FECNT, 8-(2-[18F]fluoroethyl)-2β-carbomethoxy-3β-(4-chlorophenyl)nortropane; RTI-112, 3β-(3-methyl-4-chlorophenyl)-2β-carboxylic acid methyl ester hydrochloride; RTI-113, 3β-(4-chlorophenyl)tropan-2β carboxylic acid phenyl ester hydrochloride; RTI-177, 3β-(4-chlorophenyl)tropane-2β-(3-phenylisoxazol-5-yl) hydrochloride.
- Received May 23, 2006.
- Accepted November 10, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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