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

The role of dopamine receptor-G protein coupling in the development of striatal dopamine receptor supersensitivity was studied in rats with a 6-hydroxydopamine (6-OHDA)-induced unilateral lesion of the nigrostriatal pathway. This coupling was assessed by the measurement of dopamine agonist-induced guanosine 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 following the lesion, basal and dopamine-stimulated [S-35]GTP gamma S-specific binding were found to be enhanced in the denervated striata as compared to their control counterpart. D-2 dopamine receptors were clearly demonstrated to be involved in this supersensitivity, as assessed by measuring N-propylnorapomorphine (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 the selective and potent D-2 antagonist domperidone. In these conditions, the remaining response to dopamine was also found to be significantly increased following the lesion. These results are consistent with the hypothesis that, in addition to D-2 dopamine receptor upregulation, modulation of dopamine receptor-G protein interaction is involved in the hypersensitivity accompanying striatal dopamine depletion. (C) 1999 Elsevier Science B.V. All rights reserved.