Abstract
Several dopamine (DA) indirect agonists have been proposed as potential medications for treating cocaine abuse. The objective of the present study was to quantify the interactions among cocaine and DA uptake inhibitors or DA releasers to better understand how these drugs may be working when administered in combination. The DA uptake inhibitors GBR 12909 [1-{2-[bis-(4-fluorophenyl)methoxy]-ethyl}-4-(3-phenylpropyl)piperazine], WIN 35,428 [2β-carbomethoxy-3β-(4-fluorophenyl)tropane], methylphenidate, indatraline, nomifensine, and mazindol and DA releasers methamphetamine, d-amphetamine, methcathinone, cathinone, fencamfamine, and phentermine were examined alone and in combination with cocaine in rats trained to discriminate cocaine (10 mg/kg i.p.) from saline injections. All of the DA indirect agonists dose-dependently substituted for cocaine and shifted the cocaine dose-effect curve leftward. Isobolographic analysis indicated the interactions were generally additive, although both methamphetamine and d-amphetamine were quantitatively determined to be more potent than DA uptake inhibitors in shifting the cocaine dose-effect function to the left. The potential of d-amphetamine as an effective treatment for cocaine abuse and negative clinical results with dopamine uptake inhibitors suggest that differences in shifts in dose-effect curves should be further examined with emerging clinical data as a predictive index of potential treatments for cocaine abuse.
Footnotes
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This work was supported by the Intramural Research Program of the National Institute on Drug Abuse.
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Some of the data were reported at the Annual Meeting of the Society for Neuroscience, San Diego, CA (Oct 25, 2004) and Washington, DC (Nov 13, 2005).
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doi:10.1124/jpet.105.100594.
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ABBREVIATIONS: DA, dopamine; GBR 12909, 1-{2-[bis-(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazine; LED, light-emitting diode; FR, fixed ratio; CL, confidence limit; WIN 35,428, 2β-carbomethoxy-3β-(4-fluorophenyl)tropane.
- Received December 23, 2005.
- Accepted February 13, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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