Neurokinin B/NK 3 receptors exert feedback inhibition on l-DOPA actions in the 6-OHDA lesion rat model of Parkinson's disease

Abstract

Neurokinin B (NKB) and substance P (SP) act via NK 3 and NK 1 receptors. Using the unilateral 6-hydroxydopamine (6-OHDA) lesion rat model of Parkinson's disease (PD), it was found that chronic, but not acute, administration of l-DOPA increases striatal NKB expression in the dopamine-depleted hemisphere. In contrast, both acute and chronic administrations of l-DOPA restore reduced levels of SP mRNA. Co-treatment with the NK 3 receptor antagonist, SB222200, and l-DOPA increased contralateral rotations compared to l-DOPA alone in l-DOPA primed rats. The NK 3R agonist, senktide, increased the phosphorylation of tyrosine hydroxylase (TH) at Ser 19-TH, a CaMKII site, and of Thr 286-CaMKII in striatal slices. Senktide had no effect on P-Ser 31-TH, a MAPK site, but reduced P-Ser 217/221-MEK. Amperometry demonstrated that senktide increased evoked dopamine release. SB222200 blocked the effects of senktide. In striatal slices prepared from 6-OHDA-lesioned rats repeatedly treated with l-DOPA, senktide no longer increased P-Thr 286-CaMKII, suggesting a role of NK 3R on dopamine terminals under normal conditions. SB222200 increased P-Ser 217/221-MEK only in dopamine-depleted slices, indicating an increased NK 3R tone under Parkinsonism conditions. Altogether, these data demonstrate a differential regulation of NKB and SP by l-DOPA in an animal model of PD and indicate a unique role of NKB in long-term effects of l-DOPA. Behavioural, biochemical and amperometric data indicate that NKB/NK 3R signalling stimulates dopamine transmission at the presynaptic site, but inhibits it at the postsynaptic site. The inhibitory influence of NKB/NK 3R on dopamine transmission dominates in an animal model of PD and provides a feedback inhibition on actions mediated via l-DOPA.