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Research ArticlePERSPECTIVES IN PHARMACOLOGY

The Dopamine Transporter and Cocaine Medication Development: Drug Self-Administration in Nonhuman Primates

Leonard L. Howell and Kristin M. Wilcox
Journal of Pharmacology and Experimental Therapeutics July 2001, 298 (1) 1-6;
Leonard L. Howell
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Kristin M. Wilcox
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Abstract

Despite intensive medication development efforts, no effective pharmacotherapy for cocaine abuse has demonstrated efficacy for long-term use. Given the obvious importance of the dopamine transporter in the addictive properties of cocaine, the development and use of compounds that target the dopamine transporter represents a reasonable approach for the pharmacological treatment of cocaine abuse. The therapeutic approach of replacement or substitute agonist medication has been successful, as shown with methadone maintenance for heroin dependence and nicotine replacement for tobacco use. A number of preclinical studies with dopamine transporter inhibitors provide evidence that substitute agonists may be used effectively to reduce cocaine use. Nonhuman primate models of drug self-administration provide a rigorous, systematic approach to characterize medication effectiveness in subjects with a documented history of drug use. Several cocaine analogs and other dopamine transporter inhibitors, including analogs of GBR 12909 and WIN 35,065-2, have been shown to reduce cocaine self-administration in nonhuman primates. A possible limitation to the use of selective dopamine transporter inhibitors as medications is their potential for abuse liability given their demonstrated reinforcing effects in nonhuman primates. However, limited reinforcing properties in the context of treatment programs may be advantageous, contributing to improved patient compliance and enhanced medication effectiveness. Moreover, pharmacokinetic properties that result in slow onset and long duration of action may enhance their effectiveness to reduce cocaine use while limiting their abuse liability.

Footnotes

  • This research was supported in part by United States Public Health Service Grants DA10344, DA12514, and RR00165 (Division of Research Resources, National Institutes of Health). The Yerkes Regional Primate Research Center is fully accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC International).

  • Abbreviations:
    RTI-113
    3β-(4-chlorophenyl)tropane-2β-carboxylic acid phenyl ester
    PTT
    2β-propanoyl-3β-(4-tolyl)-tropane
    GBR 12909
    1-{2-[bis(4-fluorophenyl-)methoxy]ethyl}-4-(3-phenylpropyl)piperazine
    PET
    positron emission tomography
    • Received November 14, 2000.
    • Accepted February 19, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 298 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 298, Issue 1
1 Jul 2001
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Research ArticlePERSPECTIVES IN PHARMACOLOGY

The Dopamine Transporter and Cocaine Medication Development: Drug Self-Administration in Nonhuman Primates

Leonard L. Howell and Kristin M. Wilcox
Journal of Pharmacology and Experimental Therapeutics July 1, 2001, 298 (1) 1-6;

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Research ArticlePERSPECTIVES IN PHARMACOLOGY

The Dopamine Transporter and Cocaine Medication Development: Drug Self-Administration in Nonhuman Primates

Leonard L. Howell and Kristin M. Wilcox
Journal of Pharmacology and Experimental Therapeutics July 1, 2001, 298 (1) 1-6;
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  • Article
    • Abstract
    • Pharmacotherapy for Cocaine Addiction
    • Rationale for Targeting the Dopamine Transporter
    • Nonhuman Primate Models of Drug Self-Administration
    • Dopamine Transporter Inhibitors and Cocaine Self-Administration
    • Abuse Liability of Dopamine Transporter Inhibitors
    • Serotonin and Norepinephrine Transporter Inhibitors
    • Clinical Relevance for Medications Development
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