The use of genetically engineered mice has provided substantial new insights into the functional organization of the striatum. Increasing evidence suggests that specific genes expressed within the striatum contribute to its functional activity. We studied the dopamine (DA) D1 receptor gene and one of its downstream targets, the transcription factor c-Fos. We have evaluated the functional interaction between the D1 and D2 DA receptor subtypes at the cellular and behavioral levels. Our results show that haloperidol, a DA D2-class receptor antagonist, activates c-Fos predominantly in enkephalin-positive striatal neurons, which project to the globus pallidus and are thought to mediate motor inhibition. Deletion of the DA D1 receptor increased the responsiveness of enkephalin neurons to haloperidol, in that haloperidol-induced increases in c-Fos and catalepsy were enhanced in D1 receptor knockout mice. These results suggest a functionally opposing role of the D1 receptor against the D2 DA-class receptors in the striatum.