Journal
SYNAPSE
Volume 43, Issue 1, Pages 78-85Publisher
WILEY
DOI: 10.1002/syn.10018
Keywords
positron emission tomography; dopamine transporter; cocaine; RTI-113; nonhuman primate
Categories
Funding
- NATIONAL CENTER FOR RESEARCH RESOURCES [P51RR000165] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON DRUG ABUSE [R01DA010344, R37DA005477, F32DA006051, R37DA010344, R01DA005477] Funding Source: NIH RePORTER
- NCRR NIH HHS [RR-00165] Funding Source: Medline
- NIDA NIH HHS [DA-06051, DA-05477, DA-10344] Funding Source: Medline
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Dopaminergic mechanisms are thought to play a central role in the reinforcing effects of cocaine. The present study examined the reinforcing effects of 3 beta-(4-chlorophenyl)tropane-2 beta -carboxylic acid phenyl ester (RTI-113), a long-acting, selective, high-affinity dopamine uptake inhibitor. Additionally, the effects of RTI-113 pretreatment on cocaine self-administration were determined. Monkeys were trained to respond under a second-order schedule for intravenous cocaine administration (0.10 or 0.17 mg/kg/infusion). When responding was stable, cocaine (0.0030-1.0 mg/kg/infusion) and RTI-113 (0.010-0.30 mg/kg/infusion) were substituted for the cocaine training dose. Cocaine and RTI-113 were equipotent for their reinforcing effects. However, cocaine maintained higher response rates in two of the three monkeys tested. When administered as a pretreatment, RTI-113 (0.10-0.30 mg/kg) dose-dependently reduced responding maintained by two doses of cocaine. Drug effects on behavior were related to dopamine transporter (DAT) occupancy in monkey striatum during neuroimaging with positron emission tomography. DAT occupancy was determined by displacement of 8-(2-[F-18]fluroethyl)2 beta -carbomethoxy-3 beta-(4-chlorophenyl)nortropane (FECNT). DAT occupancy was between 65-76% and 94-99% for doses of cocaine and RTI-113 that maintained maximum response rates, respectively. DAT occupancy did not differ markedly across RTI-113 pretreatment doses and ranged between 72-84%. The results suggest that the pharmacokinetic profile of RTI-113 (i.e., long-acting) may influence its ability to maintain self-administration, and therefore its abuse liability. Additionally, high DAT occupancy is required for RTI-113 to reduce cocaine-maintained responding. (C) 2001 Wiley-Liss. Inc.
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