Dopamine receptor-modulated [S-35]GTP gamma S binding in striatum of 6-hydroxydopamine-lesioned rats

The role of dopamine receptor-G protein coupling in the development of stri atal dopamine receptor supersensitivity was studied in rats with a 6-hydrox ydopamine (6-OHDA)-induced unilateral lesion of the nigrostriatal pathway. This coupling was assessed by the measurement of dopamine agonist-induced g uanosine 5'-O-(gamma[S-35]thio)triphosphate ([S-35]GTP gamma S) binding in striatal membranes, at different periods of time (1-5 weeks) following the microinjection of the neurotoxin. From the first to the fifth week followin g the lesion, basal and dopamine-stimulated [S-35]GTP gamma S-specific bind ing were found to be enhanced in the denervated striata as compared to thei r control counterpart. D-2 dopamine receptors were clearly demonstrated to be involved in this supersensitivity, as assessed by measuring N-propylnora pomorphine (NPA)-, quinpirole- and bromocriptine-induced [S-35]GTP gamma S- specific binding. The involvement of D-1 dopamine receptors was indirectly studied by the combination of dopamine with a saturating concentration of t he selective and potent D-2 antagonist domperidone. In these conditions, th e remaining response to dopamine was also found to be significantly increas ed following the lesion. These results are consistent with the hypothesis t hat, in addition to D-2 dopamine receptor upregulation, modulation of dopam ine receptor-G protein interaction is involved in the hypersensitivity acco mpanying striatal dopamine depletion. (C) 1999 Elsevier Science B.V. All ri ghts reserved.