期刊
NEUROPHARMACOLOGY
卷 54, 期 7, 页码 1143-1152出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuropharm.2008.03.005
关键词
Parkinsonism; tachykinins; striatum; basal ganglia; dopamine
Neurokinin B (NKB) and substance P (SP) act via NK3 and NK1 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 NK3 receptor antagonist, SB222200, and L-DOPA increased contralateral rotations compared to L-DOPA alone in L-DOPA primed rats. The NK3R 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 NK3R on dopamine terminals under normal conditions. SB222200 increased P-Set(217/221)-MEK only in dopamine-depleted slices, indicating an increased NK3R 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/NK3R signalling stimulates dopamine transmission at the presynaptic site, but inhibits it at the postsynaptic site. The inhibitory influence of NKB/NK3R on dopamine transmission dominates in an animal model of PD and provides a feedback inhibition on actions mediated Via L-DOPA. (C) 2008 Elsevier Ltd. All rights reserved.
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