Nonhuman Primate Neuroimaging and Cocaine Medication Development

• Type of Material: Article
• Authors: Leonard Howell, Emory University
• Language: English
• Date: 2008-12
• Publisher: American Psychological Association
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2008, American Psychological Association
• Final Published Version (URL): http://www.apa.org/pubs/journals/pha/
• Title of Journal or Parent Work: Experimental and Clinical Psychopharmacology
• ISSN: 1064-1297
• Volume: 16
• Issue: 6
• Start Page: 446
• End Page: 457
• Grant/Funding Information: Research from the laboratory of the author and preparation of the manuscript were supported in part by U.S. Public Health Service Grants DA010344, DA012514, DA016589, DA000517, DA013326 and RR000165 (Division of Research Resources, National Institutes of Health).
• Keywords: cocaine; PET imaging; dopamine transporter; serotonin transporter; nonhuman primates
• Research Categories: Health Sciences, Pharmacology; Biology, Neuroscience

Abstract

Given the important role of the dopamine transporter (DAT) in the addictive properties of cocaine, the development and use of compounds that target the DAT represents a reasonable approach for the pharmacological treatment of cocaine abuse. The present report describes a series of studies conducted in nonhuman primates that evaluated the effectiveness of DAT inhibitors in reducing cocaine self-administration. In addition, drug substitution studies evaluated the abuse liability of the DAT inhibitors. PET neuroimaging studies quantified DAT occupancy at behaviorally relevant doses, characterized the time-course of drug uptake in brain, and documented drug-induced changes in cerebral blood flow as a model of brain activation. Selective DAT inhibitors were effective in reducing cocaine use but high (>70%) levels of DAT occupancy were associated with significant reductions in cocaine self-administration. The selective DAT inhibitors were reliably self-administered but rates of responding were lower than those maintained by cocaine even at higher levels of DAT occupancy. A profile of slow rate of drug uptake in brain accompanied by a gradual increase in extracellular dopamine may account for the more limited reinforcing effectiveness of the DAT inhibitors. Selective serotonin transporter (SERT) inhibitors were also effective in reducing cocaine use and blocked cocaine-induced brain activation and increases in extracellular dopamine. Co-administration of SERT inhibitors with a selective DAT inhibitor was more effective than the DAT inhibitor administered alone, even at comparable levels of DAT occupancy. The results indicate that combined inhibition of DAT and SERT may be a viable approach to treat cocaine addiction.