Effects of full D1 dopamine receptor agonists on firing rates in the globus pallidus and substantia nigra pars compacta in vivo: tests for D1 receptor selectivity and comparisons to the partial agonist SKF 38393.

Many studies have used the D1 agonist SKF 38393 to characterize D1 receptor influences on firing rates in basal ganglia nuclei in vivo. However, SKF 38393 is a partial agonist and so may not be ideal for delineating D1 receptor effects. This study characterizes the effects of four full D1 agonists, SKF 82958 (chloro-APB), SKF 81297 (6-chloro-PB), dihydrexidine and A-77636, on the firing rates of midbrain dopamine and globus pallidus neurons. Recordings were done in fully anesthetized or paralyzed, locally anesthetized rats, and drugs were given systemically intravenously. Dihydrexidine, SKF 81297 and A-77636 were free of rate effects on midbrain dopamine neurons (up to 10.2 mg/kg) and also did not antagonize the inhibitory effects of quinpirole. In contrast, SKF 82958 strongly inhibited dopamine cells through activation of D2 autoreceptors (ED50 = 0.70 mg/kg). Of these drugs, SKF 82958 also was the only one to increase pallidal unit firing rates when given alone (at 5.0 but not 1.0 mg/kg); the other compounds appeared to be selective for postsynaptic D1 receptors. The results suggest that SKF 82958 may be more properly classified as a mixed D1/D2 agonist. In addition, all four agonists strongly potentiated the pallidal response to quinpirole, demonstrating a D1 receptor potentiation of D2 receptor effects. The results support the role of D1 receptors in the midbrain and globus pallidus as previously characterized with SKF 38393. The similar actions of partial and full D1 agonists in these systems support evidence for a D1 receptor reserve and possibly an effector system other than adenylate cyclase.

The response of subthalamic nucleus neurons to dopamine receptor stimulation in a rodent model of Parkinson's disease.

Overactivity in the subthalamic nucleus (STN) is believed to contribute to the pathophysiology of Parkinson's disease. It is hypothesized that dopamine receptor agonists reduce neuronal output from the STN. The present study tests this hypothesis by using in vivo extracellular single unit recording techniques to measure neuronal activity in the STN of rats with 6-hydroxydopamine-induced lesions of the nigrostriatal pathway (a model of Parkinson's disease). As predicted, firing rates of STN neurons in lesioned rats were tonically elevated under basal conditions and were decreased by the nonselective dopamine receptor agonists apomorphine and L-3, 4-dihydroxyphenylalanine (L-DOPA). STN firing rates were also decreased by the D2 receptor agonist quinpirole when administered after the D1 receptor agonist (+/-)- 1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol (SKF 38393). Results of the present study challenge the prediction that dopaminergic agonists reduce STN activity predominantly through actions at striatal dopamine D2 receptors. Firing rates of STN neurons were not altered by selective stimulation of D2 receptors and were increased by selective stimulation of D1 receptors. Moreover, there was a striking difference between the responses of the STN to D1/D2 receptor stimulation in the lesioned and intact rat; apomorphine inhibited STN firing in the lesioned rat and increased STN firing in the intact rat. These findings support the premise that therapeutic efficacy in the treatment of Parkinson's disease is associated with a decrease in the activity of the STN, but challenge assumptions about the roles of D1 and D2 receptors in the regulation of neuronal activity of the STN in both the intact and dopamine-depleted states.