Striatal and nigral D-1 mechanisms involved in the antiparkinsonian effects of SKF 82958 (APB): studies of tremulous jaw movements in rats

Rationale: Previous work has demonstrated that cholinomimetic-induced tremu lous jaw movements in rats have temporal and pharmacological characteristic s similar to parkinsonian tremor. Objective: This rodent model was used to characterize the putative antiparkinsonian effects of the full D-1 dopamine receptor agonist. SKF 82958. Methods: Jaw movement activity was induced by the muscarine agonist pilocarpine (4.0 mg/kg IP), and a series of experime nts studied the pharmacological characteristics of the reversal of pilocarp ine-induced jaw movements by SKF 82958. Results: SKF 82958 (0.5-2.0 mg/kg I P) reduced the tremulous jaw movements induced by pilocarpine. The suppress ive effects of SKF 82958 on jaw movements were dose-dependently reversed by systemic pretreatment with the selective D-1 dopamine receptor antagonist SCH 23390 (0.025-0.2 mg/kg IP); SCH 23390 was about 16 times more potent th an the D-2 antagonist raclopride at reversing the effects of SKF 82958. Int racranial injection of SCH 23390 (0.5-2.0 mu g/side) into the ventrolateral striatum, the rodent homologue of the human ventral putamen, dose-dependen tly reversed the reduction of pilocarpine-induced jaw movements produced by SKF 82958. Intracranial injection of SCH 23390 (0.5-2.0 mu g/side) into th e substantia nigra pars reticulata also dose-dependently reversed the reduc tion by SKF 82958 of pilocarpine-induced jaw movements. Injections of SCH 2 3390 (2.0 mu g/side) into control sites dorsal to the striatum or substanti a nigra had no effects on the action of SKF 82958, Intranigral (SNr) inject ions of the GABA-A antagonist bicuculline blocked the suppressive effect of systemically administered SKF 82958 on jaw movement activity. Conclusions: These data suggest that the antiparkinsonian actions of SKF 82958 may be d ue to stimulation of D-1 receptors in the ventrolateral striatum and substa ntia nigra pars reticulata. In addition, these results indicate that GABA m echanisms in the substantia nigra pars reticulata may be important for the antiparkinsonian effects of D-1 agonists.