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Neurokinin B/NK3 receptors exert feedback inhibition on L-DOPA actions in the 6-OHDA lesion rat model of Parkinson's disease
Karolinska Institutet, Institutionen för fysiologi och farmakologi. (Translationell neurofarmakologi)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, MMS, Medical Mass Spectrometry.
Karolinska Institutet, Institutionen för fysiologi och farmakologi.
Karolinska Institutet, Institutionen för fysiologi och farmakologi. (Translationell neurofarmakologi)
2008 (English)In: Neuropharmacology, ISSN 0028-3908, E-ISSN 1873-7064, Vol. 54, no 7, 1143-1152 p.Article in journal (Refereed) Published
Abstract [en]

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(3)R 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(3)R on dopamine terminals under normal conditions. SB222200 increased P-Ser(217/221)-MEK only in dopamine-depleted slices, indicating an increased NK(3)R 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(3)R signalling stimulates dopamine transmission at the presynaptic site, but inhibits it at the postsynaptic site. The inhibitory influence of NKB/NK(3)R on dopamine transmission dominates in an animal model of PD and provides a feedback inhibition on actions mediated via L-DOPA.

Place, publisher, year, edition, pages
2008. Vol. 54, no 7, 1143-1152 p.
Keyword [en]
Parkinsonism, tachykinins, striatum, basal ganglia, dopamine
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-109766DOI: 10.1016/j.neuropharm.2008.03.005ISI: 000256652100015PubMedID: 18423776OAI: oai:DiVA.org:uu-109766DiVA: diva2:273927
Available from: 2009-10-26 Created: 2009-10-26 Last updated: 2017-12-12Bibliographically approved

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