REPEATED QUINPIROLE TREATMENT - LOCOMOTOR-ACTIVITY, DOPAMINE SYNTHESIS, AND EFFECTS OF SELECTIVE DOPAMINE ANTAGONISTS

Repeated treatment with the non-selective dopamine agonist apomorphine results in behavioral sensitization and enhanced dopamine synthesis in dopamine projection fields. To examine the role of D-2-type dopamine receptors in modulating these effects, the present experiment assessed the effects of repeated treatment with the D-2-type agonist quinpirole on locomotor activity and dopamine synthesis. In the first experiment, rats were treated with vehicle or one of two doses (0.3 or 3.0 mg/kg) of quinpirole for 8 days. Daily measures of locomotor activity revealed an initial suppression of activity produced by quinpirole which dissipated over the 8 days of treatment. A trend for an increase in activity for 3.0 mg/kg quinpirole compared to vehicle was obtained on day 8. Twenty-four hours after cessation of treatment, dopamine synthesis, measured as accumulation of 3,4-dihydroxyphenylalanine (DOPA) after treatment with the DOPA decarboxylase inhibitor NSD-1015, was enhanced in the striatum, but not nucleus accumbens-olfactory tubercle (NAOT) or ventral mesencephalon (VM). In Experiment 2, rats were treated for 8 days with vehicle, 3.0 mg/kg quinpirole or the D-1 antagonist SCH 23390 (0.5 mg/kg) in a two (vehicle or quinpirole) x two (vehicle or SCH 23390) design. Quinpirole-alone treatment resulted in a reduction of the locomotor suppressant effects of the drug. SCH 23390-alone and quinpirole-SCH 23390 combined treatment resulted in decreased activity compared to the vehicle control group that did not change across days. DOPA accumulation was enhanced in the striatum and NAOT after quinpirole treatment; however, SCH 23390 had no effect. In Experiment 3, rats were treated for 10 days with vehicle, 3.0 mg/kg quinpirole or the D-2 antagonist eticlopride (1.0 mg/kg) in a two (vehicle or quinpirole) x two (vehicle or eticlopride) design. As in the first two experiments, repeated quinpirole-alone treatment resulted in a reduction of the locomotor suppressant effects of the drug; however, locomotor activity in this group was enhanced compared to vehicle controls on day 10. Eticlopride-alone and eticlopride-quinpirole treated rats had suppressed locomotor activity across the 10 days. DOPA accumulation was enhanced by both repeated quinpirole and repeated eticlopride treatment in the striatum and NAOT. DOPA accumulation in eticlopride-quinpirole treated rats was not different from vehicle control levels in the NAOT, while no significant difference was obtained between the eticlopride-alone and eticlopride-quinpirole groups in the striatum. The locomotor activity data suggest that repeated quinpirole treatment results in tolerance to the locomotor suppressant effect of the drug. Evidence for sensitization was obtained in two out of three of the experiments. These results suggest that enhanced dopamine synthesis after repeated non-selective dopamine agonist treatment is modulated by D-2-type dopamine receptors. (C) 1995 Wiley-Liss, Inc.