The Reinforcing Efficacy of the Dopamine Reuptake Inhibitor 2β-Propanoyl-3β-(4-tolyl)-tropane (PTT) as Measured by a Progressive-Ratio Schedule and a Choice Procedure in Rhesus Monkeys
- Joshua A. Lile1,
- Drake Morgan1,
- Anne M. Birmingham1,
- Zhixia Wang3,
- William L. Woolverton3,
- Huw M. L. Davies4 and
- Michael A. Nader1,2
- 1Center for the Neurobiological Investigation of Drug Abuse, Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina (J.A.L., D.M., A.M.B., M.A.N.); 2Department of Radiology, Wake Forest University School of Medicine, Winston-Salem, North Carolina (M.A.N.); 3Department of Psychiatry, University of Mississippi Medical Center, Jackson, Mississippi (Z.W., W.L.W.); and 4Department of Chemistry, State University of New York, Buffalo, New York (H.M.L.D.)
- Dr. Michael A. Nader, Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157-1083. E-mail:mnader{at}wfubmc.edu
Abstract
The present series of experiments was undertaken to investigate the variables that influence the reinforcing efficacy of psychostimulants. The time of onset for dopamine transporter (DAT) occupancy of the long-acting, high-affinity DAT blocker 2β-propanoyl-3β-(4-tolyl)-tropane (PTT) was measured using an ex vivo binding assay in rodents and was determined to be significantly longer than for cocaine (30 min versus 2 min). To assess the reinforcing efficacy of PTT relative to cocaine, a discrete-trials drug-drug choice procedure (n = 3) and a progressive-ratio (PR) schedule (n = 4) were used in rhesus monkeys. Cocaine (0.003–0.56 mg/kg/injection) and PTT (0.003–0.03 mg/kg/injection) maintained responding greater than saline under the PR schedule. Maximal breaking points were significantly higher for cocaine compared with PTT. A separate group of monkeys prepared with double-lumen catheters was allowed to choose between cocaine (saline and 0.03–0.3 mg/kg/injection) and PTT (saline, and 0.01 and 0.03 mg/kg/injection). Under these conditions, PTT was not preferred over saline. When saline or 0.01 mg/kg/injection PTT was available as alternatives to cocaine, the highest dose of cocaine maintained greater than 80% choice. When 0.03 mg/kg/injection PTT was the alternative to cocaine, cocaine choice declined to approximately 50%, and total cocaine intake was decreased by ∼70% at the highest cocaine dose. These results suggest that the reinforcing efficacy of PTT is less than cocaine in nonhuman primates. Data from studies with PTT indicate that slow-onset, long-acting DAT inhibitors can decrease cocaine self-administration while not functioning robustly as reinforcers, and support the further investigation of these drugs as treatment for cocaine addiction.
Footnotes
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This research was supported by National Institute on Drug Abuse research Grants P50 DA-06634 (to M.A.N. and H.M.L.D.), DA-10352 (to W.L.W.), DA-00161 (to W.L.W.), T32 DA-07246 (to J.A.L.), and F31 DA-05934 (to J.A.L.). Animal maintenance and research were conducted in accordance with guidelines provided by National Institutes of Health Office of Protection from Research Risks. The protocol for experiment 1 was reviewed and approved by the Institutional Animal Care and Use Committee of the University of Mississippi Medical Center. The protocol for experiments 2 and 3 were reviewed and approved by the Wake Forest University Animal Care and Use Committee. Wake Forest University is fully accredited by the Association for the Assessment and Accreditation of Laboratory Animal Care International.
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DOI: 10.1124/jpet.102.039180
- Abbreviations:
- DA
- dopamine
- DAT
- dopamine transporter
- PTT
- 2β-propanoyl-3β-(4-tolyl)-tropane
- CFT
- 2β-carbomethoxy-3β-(4-flourophenyl)-tropane
- PR
- progressive-ratio
- BP
- breaking point
- 5-HTT
- serotonin transporter
- S/C
- striatal/cerebellar ratio
- FR
- fixed-ratio
- TO
- time-out
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- Received May 21, 2002.
- Accepted July 12, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
