DIFFERENTIAL MODULATION OF STRIATONIGRAL DYNORPHIN AND ENKEPHALIN BY DOPAMINE RECEPTOR SUBTYPES

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 D1 (SKF-38393, 5 mg/kg, i.p.) or D2 (LY-171555, 1 mg/kg, i.p.) agonists, alone or in combination, (2) 6-hydroxydopamine (6-OHDA)-lesioned rats repeatedly injected with the same D1 or D2 agonists, and (3) intact rats repeatedly injected with D1 (SCH-23390, 0.05 mg/kg, s.c.) or D2 (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 D1 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 D2 agonist did not affect dynorphin levels at all. Combined treatments with D1 and D2 agonists did not potentiate the effect of the D1 agonist. 6-OHDA lesions of the nigrostriatal DA pathway alone decreased the level of dynorphin in both the striatum and substantia nigra. However, repeated D1 agonist, but not D2, injections not only reversed the decrease in dynorphin levels, but caused a significant increase above control levels. In intact rats, repeated injections of the D1 or D2 antagonist alone failed to alter the levels of dynorphin, but the D1 antagonist, not the D2 antagonist, attenuated the apomorphine-induced increase in striatal dynorphin. Regulation of striatal [Met5]enkephalin (ME) was found to be different from that of dynorphin. While repeated D1 agonist injections in intact rats had no effect on striatal ME, D2 agonist treatment caused a modest increase in ME. The effect of the D2 agonist in intact rats was blocked by co-administration with the D1 agonist. In addition, 6-OHDA lesions alone increased striatal levels of ME, and this increase was blocked by the D1 agonist, but not the D2 agonist. Finally, the D1 antagonist increased the striatal level of ME in intact rats, whereas the D2 antagonist had no effect. These data indicate that D1 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 D2 subtype imposes an excitatory stimulus on enkephalin biosynthesis but has no effect on dynorphin. © 1990.