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The Journal of Neuroscience, July 15, 2002, 22(14):6218-6227

Concurrent Activation of Dopamine D₁ and D₂ Receptors Is Required to Evoke Neural and Behavioral Phenotypes of Cocaine Sensitization

Christine Capper-Loup¹, Juan J. Canales², Neena Kadaba³, and Ann M. Graybiel³

¹ Department of Neurology, University Hospital, 3010 Bern, Switzerland, ² Area of Psychobiology, University Jaume I, E-12080 Castellón, Spain, and ³ Department of Brain and Cognitive Sciences and the McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139

Repeated exposure to psychomotor stimulants produces a striking behavioral syndrome involving repetitive, stereotypic behaviors that occur if an additional exposure to the stimulant is experienced. The same stimulant exposure produces specific alterations in gene expression patterns in the striatum. To identify the dopamine receptor subtypes required for the parallel expression of these acquired neural and behavioral responses, we treated rats with different D₁-class and D₂-class dopamine receptor agonists and compared the responses of drug-naive rats with those of rats given previous intermittent treatment with cocaine. In rats exposed to repeated cocaine treatment, the effects of a subsequent challenge treatment with either a D₁-class agonist (SKF 81297) or a D₂-class agonist (quinpirole) were not significantly different from those observed in drug-naive animals: the drugs administered singly did not induce robust stereotyped motor behaviors nor produce significantly striosome-predominant expression of early genes in the striatum. In contrast, challenge treatment with the D₁-class and D₂-class agonists in combination led to marked and correlated increases in stereotypy and striosome-predominant gene expression in the striatum. Thus, immediately after repeated psychomotor stimulant exposure, only the concurrent activation of D₁ and D₂ receptor subclasses evoked expression of the neural and behavioral phenotypes acquired through repeated cocaine exposure. These findings suggest that D₁-D₂ dopamine receptor synergisms underlie the coordinate expression of both network-level changes in basal ganglia activation patterns and the repetitive and stereotypic motor response patterns characteristic of psychomotor stimulant sensitization.

Key words: stereotypy; gene expression; dopamine receptors; basal ganglia; striosomes; striatum

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Copyright © 2002 Society for Neuroscience  0270-6474/02/22146218-10$05.00/0

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