Abstract
The plasmalemmal dopamine (DA) transporter (DAT) is a principal site of action for cocaine. This report presents the novel finding that in addition to inhibiting DAT function, cocaine administration rapidly alters vesicular DA transport. Specifically, cocaine treatment abruptly and reversibly increased both the Vmax of DA uptake and the Bmax of vesicular monoamine transporter-2 (VMAT-2) ligand (dihydrotetrabenazine) binding, as assessed ex vivo in purified rat striatal synaptic vesicles. Selective inhibitors of the DAT (amfonelic acid and GBR12935), but not the plasmalemmal serotonin transporter (fluoxetine), also increased vesicular DA uptake. Moreover, DA depletion resulting from administration of the tyrosine hydroxylase inhibitor α-methyl-p-tyrosine had cocaine-like effects. Conversely, administration of the DA-releasing agent methamphetamine rapidly decreased vesicular uptake. Taken together, these data demonstrate for the first time ex vivo that cocaine treatment rapidly alters vesicular monoamine transport, and suggest that alterations in cytoplasmic DA concentrations contribute to stimulant-induced changes in vesicular DA uptake. Hence, the VMAT-2 may be an important target for developing strategies to treat not only cocaine addiction but also other disorders involving alterations in neuronal DA disposition, including Parkinson's disease.
Footnotes
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Send reprint requests to: Annette E. Fleckenstein, Ph.D., University of Utah, Department of Pharmacology and Toxicology, 30 South 2000 East Rm. 201, Salt Lake City, UT 84112. E-mail:fleckenstein{at}hsc.utah.edu
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This work was supported by U.S. Public Health Service Grants DA00869, DA04222, DA00378, and DA11389.
- Abbreviations:
- DA
- dopamine
- DAT
- dopamine transporter
- VMAT-2
- vesicular monoamine transporter-2
- DHTBZ
- dihydrotetrabenazine
- METH
- methamphetamine
- αMPT
- α-methyl-p-tyrosine
- AADC
- aromatic amino acid decarboxylase
- Received August 15, 2000.
- Accepted November 3, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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