D-2 RECEPTOR ANTAGONISTS DO NOT MODIFY GUANINE-NUCLEOTIDE-SENSITIVE INTERACTIONS BETWEEN DOPAMINE AND D-1 DOPAMINE-RECEPTORS UNDER IN-VITROCONDITIONS

This study investigated possible D-1/D-2 interactions in rat and bovin e striatal tissue by examining the effects of D-2 antagonists on the a ction of dopamine at D-1 dopamine receptors. In addition, the extent t o which D-2 antagonists may induce an agonist low-affinity state of th e D-1 receptor was evaluated in comparison with the effects of the gua nine nucleotide analogue 5'-guanylylimidodiphosphate [Gpp(NH)p]. In sa turation experiments dopamine caused a dose-dependent decrease in rat striatal and bovine caudate D-1 receptor density. This effect of dopam ine, which has been shown to be sensitive to Gpp(NH)p, was not altered by pretreatment with either of the selective D-2 antagonists eticlopr ide (200 nM) or domperidone (200 nM). Results from displacement experi ments show that the affinity of dopamine for D-1 receptors, and the pr oportion of receptors in an agonist high-affinity state, are reduced b y Gpp(NH)p (100 mu M) but not by eticlopride. A molar excess of dopami ne (100 mu M) promotes the dissociation of (+/-) -8-chloro-2,3,4,5-tet rahydro-3-methyl-5-phenyl-1 H-3-benzazepine-7-ol ([H-3]SCH 23390) from rat striatal D-1 receptors at a rate that is significantly slower tha n when dissociation is initiated using 1 mu M piflutixol. After pretre atment with Gpp(NH)p, [H-3]SCH 23390 dissociation induced by dopamine occurred at an even slower rate, Pretreatment with eticlopride had no effect on the dopamine-induced rate of [H-3]SCH 23390 dissociation. Th ese results-indicate that all experimental approaches detected dopamin e effects at D-1 receptors that are Gpp(NH)p sensitive and D-2 antagon ist insensitive and provide no evidence to support a D-1/D-2 link oper ating at the receptor level.