Differences between A 68930 and SKF 82958 could suggest synergistic roles of D 1 and D 5 receptors

Abstract

The isochroman A 68930 and the benzazepine SKF 82958 are two full dopamine D 1 receptor 1 1 In this paper we have used the D 1 through D 5 nomenclature in accordance with IUPHAR recommendations (Schwartz J-C, Carlsson A, Caron M, Scatton B, Civelli O, Kebabian JW et al (2000). Dopamine Receptors. The IUPHAR Compendium of Receptor Characterization and Classification. Anonymous. IUPHAR Media: London. pp 171-181.) despite the fact that for rodent receptors D 1 receptors are often referred to as D 1a and D 5 receptors as D 1b. agonists. Responses to these compounds are different in several important aspects. When given to rats in a novel environment, A 68930 caused a dose-dependent (0.019–4.9 mg/kg) suppression of locomotion. SKF 82958 had no such effect at any dose studied (0.051–3.3 mg/kg). In animals habituated to the environment, A 68930 had no effect but SKF 82958 increased locomotor activity. Both A 68930 and SKF 82958 caused a decrease in core temperature at early time points. Both agonists increased c- fos and NGFI-A expression in caudate putamen but only SKF 82958 did so in the accumbens nucleus (at 1.6 mg/kg). Quantitative receptor autoradiography showed that A 68930 is 9–13 times more potent than SKF 82958 at displacing the selective dopamine D 1 antagonist [ 3H]SCH 23390. This difference agrees with the difference observed when the agonists were used to stimulate cAMP formation in cells transfected with the D 1 receptor. In contrast, SKF 82958 was 5 times more potent than A 68930 in cells transfected with the D 5 receptor. We suggest that the balance between signaling via dopamine D 1 and D 5 receptors determines the functional effects of agonists at D 1/D 5 receptors.