Differential modulation of striatonigral dynorphin and enkephalin by dopamine receptor subtypes

Abstract

Previous studies indicate that dopaminergic transmission inhibits the biosynthesis of enkephalin and stimulates that of dynorphin in the striatonigral pathway of intact rat. The purpose of this study was to determine which dopamine (DA) receptor subtype(s) mediate the modulatory actions of DA. We measured striatal and nigral levels of enkephalin and dynorphin in: (1) intact rats repeatedly injected with D 1 (SKF-38393, 5 mg/kg, i.p.) or D 2 (LY-171555, 1 mg/kg, i.p.) agonists, alone or in combination, (2) 6-hydroxydopamine (6-OHDA)-lesioned rats repeatedly injected with the same D 1 or D 2 agonists, and (3) intact rats repeatedly injected with D 1 (SCH-23390, 0.05 mg/kg, s.c.) or D 2 (sulpiride, 100 mg/kg, s.c.) antagonists, given alone or in combination with the mixed D1/D2 agonist apomorphine (5 mg/kg, i.p.). Repeated injections of the D 1 agonist to intact rats (twice daily for 7 days) produced a small but not statistically significant increase in striatal levels of dynorphin; similar treatment with the D 2 agonist did not affect dynorphin levels at all. Combined treatments with D 1 and D 2 agonists did not potentiate the effect of the D 1 agonist. 6-OHDA lesions of the nigrostriatal DA pathway alone decreased the level of dynorphin in both the striatum and substantia nigra. However, repeated D 1 agonist, but not D 2, injections not only reversed the decrease in dynorphin levels, but caused a significant increase above control levels. In intact rats, repeated injections of the D 1 or D 2 antagonist alone failed to alter the levels of dynorphin, but the D 1 antagonist, not the D 2 antagonist, attenuated the apomorphine-induced increase in striatal dynorphin. Regulation of striatal [Met 5]enkephalin (ME) was found to be different from that of dynorphin. While repeated D 1 agonist injections in intact rats had no effect on striatal ME, D 2 agonist treatment caused a modest increase in ME. The effect of the D 2 agonist in intact rats was blocked by co-administration with the D 1 agonist. In addition, 6-OHDA lesions alone increased striatal levels of ME, and this increase was blocked by the D 1 agonist, but not the D 2 agonist. Finally, the D 1 antagonist increased the striatal level of ME in intact rats, whereas the D 2 antagonist had no effect. These data indicate that D 1 receptors mediate excitatory control over the biosynthesis of striatonigral dynorphin and also exert a tonic inhibitory influence on the enkephalin system. Furthermore, stimulation of the D 2 subtype imposes an excitatory stimulus on enkephalin biosynthesis but has no effect on dynorphin.