Differential D1 and D2 receptor-mediated effects on immediate early gene induction in a transgenic mouse model of Huntington's disease.

Abstract The diminished expression of D 1 and D 2 dopamine receptors is a well-documented hallmark of Huntington’s disease (HD), but relatively little is known about how these changes in receptor populations affect the dopaminergic responses of striatal neurons. Using transgenic mice expressing an N-terminal portion of mutant huntingtin (R6/2 mice), we have examined immediate early gene (IEG) expression as an index of dopaminergic signal transduction. c-fos, jun B, zif268, and N10 mRNA levels and expression patterns were analyzed using quantitative in situ hybridization histochemistry following intraperitoneal administration of selective D 1 and D 2 family pharmacological agents (SKF-82958 and eticlopride). Basal IEG levels were generally lower in the dorsal subregion of R6/2 striata relative to wild-type control striata at 10–11 weeks of age, a finding in accord with previously reported decreases in D 1 and adenosine A 2A receptors. D 2 -antagonist-stimulated IEG expression was significantly reduced in the striata of transgenic animals. In contrast, D 1 -agonist-induced striatal R6/2 IEG mRNA levels were either equivalent or significantly enhanced relative to control levels, an unexpected result given the reduced level of D 1 receptors in R6/2 animals. Understanding the functional bases for these effects may further elucidate the complex pathophysiology of Huntington’s disease.