Synergistic effect of D1 and D2 dopamine receptors on AP-1 DNA-binding activity in the striatum and globus pallidus of the rat with a unilateral 6-OHDA lesion of the medical forebrain bundle.

Abstract

The synergistic effect of D1 and D2 dopamine receptors on transcription factor AP-1 was studied in the striatum and globus pallidus of rats with unilateral 6-OHDA lesions of the medial forebrain bundle. Contralateral rotational behavior in response to a challenge dose of D1 agonist with and without D2 agonist was determined by behavioral observation, and AP-1 induction was studied by a gel mobility-shift assay. Single administration of vehicle and of a low dose of the D1 agonist (SKF38393, 0.5 mg/kg, i.p.) failed to induce rotational behavior, while the D2 agonists bromocriptine (2.5 mg/kg, i.p.) and quinpirole (1 mg/kg. i.p.) induced low rate rotations. High dose of SKF38393, 10 mg/kg, i.p., and low dose D1 and D2 agonists administered together induced a higher rate of rotation. The gel mobility-shift assay also suggested a synergistic interaction between D1 and D2 receptors on AP-1 induction in both the striatum and globus pallidus ipsilateral to the 6-OHDA lesioned nigrostriatal pathway. However, the mode of AP-1 induction via each dopamine receptor subtype appeared to differ between these brain structures. Thus, in the striatum of the lesioned side, single administration of a high dose of D1 agonist, and combined administration of D1 agonist with either of the D2 agonists resulted in AP-1 induction, while in the globus pallidus, AP-1 binding was induced by the D2 agonist bromocriptine and combined administration of a low dose D1 agonist with D2 agonists, but not by D1 agonist alone, even at a high dose. These results demonstrate that a D1/D2 dopamine receptor synergism is involved is the induction of AP-1 both in the striatum and globus pallidus of the rat with ipsilateral dopamine depletion. The induction of AP-1 via each receptor subtype appears, however, to be differently regulated in these two structures.