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Lindsey KP, Wilcox KM, Votaw JR, Goodman MM, Plisson C, Carroll FI, Rice KC, Howell LL: Effects of dopamine transporter inhibitors on cocaine self-administration in rhesus monkeys: relationship to transporter occupancy determined by positron emission tomography neuroimaging. J Pharmacol Exp Ther. 2004 Jun;309(3):959-69. Epub 2004 Feb 24.
The dopamine transporter (DAT) is a critical recognition site for cocaine and contributes to its significant abuse liability. Accordingly, the development of compounds that target the DAT represents a logical approach in the pharmacological treatment of cocaine abuse. The present study characterized the effects of DAT inhibitors as pretreatments in rhesus monkeys trained to self-administer cocaine under a second-order schedule of i.v. drug delivery. The drugs also were substituted for cocaine to characterize their effectiveness in maintaining drug self-administration. Positron emission tomography neuroimaging with [(18) F] 8-(2-[(18) F] fluoroethyl)-2beta-carbomethoxy-3beta-(4-chlorophenyl) nortropane established the DAT occupancy associated with behaviorally relevant doses of each drug. The drugs studied included a selective DAT inhibitor, [1-(2 [bis (4-fluorophenyl-) methoxy] ethyl)-4-(3-phenylpropyl) piperazine] bimesylate hydrate (GBR 12909); an inhibitor with equal potency at dopamine and norepinephrine transporters, [3beta-(4-chlorophenyl) tropane-2beta-(3-phenylisoxazol-5-yl)] HCl (RTI-177); and a nonselective inhibitor of dopamine, norepinephrinem and serotonin transporters, [(-)-3beta-(3'-methyl-4-chlorophenyl) tropane-2beta-carboxylic acid methyl ester] tartrate (RTI-112). All drugs produced dose-related reductions in cocaine self-administration. Doses of GBR 12909 and RTI-177 that reduced responding by 50% (ED (50)) resulted in DAT occupancies of 67 +/- 5 and 73 +/- 5%, respectively. In contrast, DAT occupancy was below the limit of detection for the ED (50) dose of RTI-112. Both GBR 12909 and RTI-177 reliably maintained drug self-administration, and DAT occupancies at doses that maintained peak rates of responding were 57 +/- 1 and 92 +/- 7%, respectively. In contrast, RTI-112 failed to maintain robust drug self-administration in any subject. The results indicate that selective DAT inhibitors may require high DAT occupancy to reduce cocaine self-administration and maintain drug self-administration. Moreover, the behavioral profile of DAT inhibitors may be influenced by actions at other monoamine transporters. |
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