||In rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal dopaminergic pathway, I-dihydroxyphenyl-alanine (L-DOPA) induces contralateral turning through activation of denervated D1 and D2 receptors. Blockade of N-methyl-D-aspartate (NMDA) receptors by the noncompetitive antagonist (+)MK-801 (0.1 mg/kg, i.p.), potentiated L-DOPA-induced contralateral turning. In 6-OHDA lesioned rats, selective agonists of D1 (SKF 38393, CY 208-243) or D2 (LY 171555) receptors also induce contralateral turning; however, (+)MK-801 pretreatment, although markedly potentiating D1, almost completely inhibited D2-mediated turning. The potentiation of SKF 38393-induced contralateral turning by MK-801 was stereospecific and was observed also with the noncompetitive NMDA antagonist phencyclidine, and with the competitive antagonist CPP. Administration of the D1 antagonist SCH 23390 (0.1 mg/kg s.c.) blocked (+)MK-801-induced potentiation of L-DOPA contralateral turning, confirming the D1 nature of the effects observed. Expression of the early gene c-fos in the caudate-putamen (CPu) is known to be activated by stimulation of supersensitive D1 receptors. Immunohistochemical studies on c-fos revealed sparse c-fos positive nuclei in the lesioned CPu after 1.5 mg/kg of SKF 38393, whereas after combined administration of (+)MK-801 and SKF 38393, dense labeling of nuclei was obtained in the dorso-lateral aspect of the CPu. Therefore, blockade of NMDA receptors acts synergistically with D1 and antagonistically with D2 receptor stimulation in the 6-OHDA model of turning, suggesting that different neuronal pathways are involved in the mediation of D1 and D2 responses.