Potentiation of the D-2 mutant motor phenotype in mice lacking dopamine D-2 and D-3 receptors

Within the D-2-class of dopamine receptors, the D-2 and D-3 subtypes share the highest degree of similarity in their primary structure. However, the e xtent to which these two receptor subtypes have similar or different functi onal properties is unclear. The present study used gene targeting to genera te mice deficient for D-2, D-3, and D-2/D-3 receptors. A comparative analys is of D-2 and D-3 single mutants and D-2/D-3 double mutants revealed that D -2/D-3 double mutants develop motor phenotypes that, although qualitatively similar to those seen in D-2 single mutants, are significantly more severe . Furthermore, increased levels of the dopamine metabolites dihydroxyphenyl acetic acid and homovanillic acid are found in the dorsal striatum of D-2 single mutants. The levels of these metabolites, however, are significantly higher in mice lacking D-2 and D-3 receptors. In addition, results of immu noprecipitation experiments revealed that D-2 single mutants express higher levels of D-3 receptor proteins during later stages of their postnatal dev elopment. These results suggest that D-3 receptors compensate for some of the lacking D-2 receptor functions and that these functional properties of D-3 recepto rs, detected in mice with a D-2 mutant genetic background, remain masked wh en the abundant D-2 receptor is expressed. (C) 1999 IBRO. Published by Else vier Science Ltd.