The role of the phosphatidyinositol-linked D1 dopamine receptor in the pharmacology of SKF83959

SKF83959, previously described as an antagonist of the D-1 dopamine receptor, has been shown to be a potent anti-parkinsonian agent. However, its mechanism of action is unknown. The present communication was designed to study the mechanism by which SKF83959 exerts its pharmacological effects. SKF83959 induced contralateral rotations in the unilateral 6-OHDA-lesioned rat model of Parkinson's disease (PD). The rotations were completely blocked by the D-1 dopamine receptor antagonist, SCH23390. The response was not affected by the serotonin receptor antagonist, mesulergine and was transiently allenuated by alpha(1) adrenergic or D2 dopamine receptor antagonists, prazosin or spiperone, respectively. Injection of 0.5 and 1 mg/kg SKF83959 elicited significant elevations in IP3 accumulation in lesioned as compared to intact striata. This effect was blocked by SCH23390 at a dose that completely obviated the rotational response to SKF83959, suggesting that activation of the PI-linked D-1 dopamine receptor and the PLC/IP3 pathway may be the underlying mechanism for the rotational activity induced by SKF83959. The present data provide the first evidence that the PI-linked D-1 dopamine receptor plays a role in regulating motor activity in striatum and that modulation of the D-1 dopamine receptor/PLC/IP3 pathway may be a novel target in the discovery of drugs for the treatment of Parkinson's disease. (c) 2005 Elsevier Inc. All rights reserved.