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The Journal of Neuroscience, August 15, 2001, 21(16):6338-6347

Preferential Increases in Nucleus Accumbens Dopamine after Systemic Cocaine Administration Are Caused by Unique Characteristics of Dopamine Neurotransmission

Qun Wu¹, Maarten E. A. Reith², Michael J. Kuhar³, F. Ivy Carroll⁴, and Paul A. Garris^{1, 2}

¹ Cellular and Integrative Physiology Section, Department of Biological Sciences, Illinois State University, Normal, Illinois 61790-4120, ² Department of Biomedical and Therapeutic Sciences, University of Illinois College of Medicine at Peoria, Peoria, Illinois 61656-1649, ³ Neuroscience Division, Yerkes Regional Primate Research Center, Emory University, Atlanta, Georgia 30322, and ⁴ Chemistry and Life Sciences, Research Triangle Institute, Research Triangle Park, North Carolina 27709-9981

In vivo voltammetry was used to investigate the preferential increase of extracellular dopamine in the nucleus accumbens relative to the caudate-putamen after systemic cocaine administration. In the first part of this study, cocaine (40 mg/kg, i.p.) was compared with two other blockers of dopamine uptake, nomifensine (10 mg/kg, i.p.) and 3-(p-chlorophenyl)tropan-2-carboxylic acid p-isothiocyanatophenylmethyl ester hydrochloride (RTI-76; 100 nmol, i.c.v.), to assess whether the inhibitory mechanism of cocaine differed in the two regions. All three drugs robustly increased electrically evoked levels of dopamine, and cocaine elevated dopamine signals to a greater extent in the nucleus accumbens. However, kinetic analysis of the evoked dopamine signals indicated that cocaine and nomifensine increased the K_m for dopamine uptake whereas the dominant effect of RTI-76 was a decrease in V_max. Under the present in vivo conditions, therefore, cocaine is a competitive inhibitor of dopamine uptake in both the nucleus accumbens and caudate-putamen. Whether the preferential effect of cocaine was mediated by regional differences in the presynaptic control of extracellular DA that are described by rates for DA uptake and release was examined next by a correlation analysis. The lower rates for dopamine release and uptake measured in the nucleus accumbens were found to underlie the preferential increase in extracellular dopamine after cocaine. This relationship explains the paradox that cocaine more effectively increases accumbal dopamine despite identical effects on the dopamine transporter in the two regions. The mechanism proposed for the preferential actions of cocaine may also mediate the differential effects of psychostimulant in extrastriatal regions and other uptake inhibitors in the striatum.

Key words: cocaine; dopamine; caudate-putamen; nucleus accumbens; voltammetry; uptake

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21166338-10$05.00/0

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