Previous work demonstrated that stimulation of D(2) dopamine receptors (D(2)DRs) in the unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rat enhanced striatal extracellular signal-regulated kinase (ERK) activity ipsilateral to the lesion. The present work was designed to explore the mechanism underlying the activation of ERK in the denervated striatum. Stimulation of D(2)DR induced a 60% inhibition in protein tyrosine phosphatase (PTP) activity but not in PSP activity in lesioned striata. The D(2)DR antagonist spiperone blocked quinpirole-elicited PTP inhibition, and the D(1) receptor agonist 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine (SKF38393) did not inhibit PTP activity, indicating that PTP inhibition is a specific effect mediated by stimulation of D(2)DR. We further discovered that striatal mitogen-activated protein kinase phosphatase (MKP), a protein phosphatase that is responsible for ERK dephosphorylation, is inhibited in response to D(2)DR stimulation in 6-OHDA-lesioned rats. More specifically, MKP1 was identified to be the isozyme affected by D(2)DR stimulation. In PC12 cells that express D(2)DR, quinpirole elicited no change in PTP or MKP activity, whereas ERK was activated by D(2) dopamine receptor stimulation. The results indicate that 6-OHDA-induced striatal denervation leads to abnormal coupling between D(2)DR and PTP/MKP pathway. Moreover, unilateral inhibition of striatal PTP by an intrastriatal injection of vanadate induced contralateral rotation in control rats in response to D(2)DR stimulation, thus mimicking the response observed in the unilateral 6-OHDA-lesioned rat. The results indicate that attenuation of the PTP/MKP pathway may be responsible for the development of D(2)DR supersensitivity.