Enhanced expression of dopamine D-1 and glutamate NMDA receptors in dopamine D-4 receptor knockout mice

Expression of dopamine ([DA] D-1 and D-2) and glutamate ([Glu], (N-methyl-D-aspartic acid [NMDA] alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA], and kanaic acid [KA]) receptor types were analyzed autoradiographically in forebrain regions of D-4 receptor knockout mice and their wild-type controls. Selective radioligand binding to D-4 receptors was virtually absent in D-4 receptor knockout mouse brain in contrast to significant specific D-4 binding in forebrain tissue of wild-type controls. Labeling of D-1 receptors was significantly increased in nucleus accumbens (NAc; 39%) and caudate putamen (CPu; 42%) of D-4-knockout mice vs wild-type controls. In addition, NMDA receptor labeling was significantly increased in NAc (31%), CPu (40%), and hippocampal CA(1) (21%) and CA(3) (25%) regions of D-4 knockouts vs wild-type controls. No changes in D-2, AMPA or KA receptors were found. The findings suggest that D-1, D-4, and NMDA receptors might interact functionally and that developmental absence of D-4 receptors might trigger compensatory mechanisms that enhance expression of D-1 receptors in NAc and CPu, and NMDA receptors in NAc, CPu, and hippocampus. The findings also encourage cautious interpretation of results in knockout mice with targeted absence of specific genes, as complex adaptive changes not directly related to the missing gene might contribute to physiological and behavioral responses.