Potentiation of the D2 mutant motor phenotype in mice lacking dopamine D2 and D3 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 extent to which these two receptor subtypes have similar or different functional properties is unclear. The present study used gene targeting to generate mice deficient for D-2, D-3, and D-2/D-3 receptors. A comparative analysis 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 immunoprecipitation experiments revealed that D-2 single mutants express higher levels of D-3 receptor proteins during later stages of their postnatal development. 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 receptors, detected in mice with a D-2 mutant genetic background, remain masked when the abundant D-2 receptor is expressed. (C) 1999 IBRO. Published by Elsevier Science Ltd.