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.

Jul 10, 1998The Journal of pharmacology and experimental therapeutics

Effects of full D1 dopamine receptor activators on activity in movement control areas compared to a partial activator

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Abstract

SKF 82958 strongly inhibited dopamine cell firing at an ED50 of 0.70 mg/kg.

Dihydrexidine, SKF 81297, and A-77636 did not affect the firing rates of midbrain dopamine neurons at doses up to 10.2 mg/kg.
SKF 82958 increased firing rates in globus pallidus neurons when administered at 5.0 mg/kg, but not at 1.0 mg/kg.
All four full D1 agonists enhanced the pallidal response to quinpirole, indicating a potential interaction between D1 and D2 receptors.
SKF 82958 may be better classified as a mixed D1/D2 agonist due to its unique effects on dopamine cells.
The findings support the involvement of D1 receptors in midbrain and globus pallidus neuronal activities.

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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.

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.

Abstract

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