title: Neurokinin B/NK3 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(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.
authors.affiliation: Section of Translational Neuropharmacology, Department of Physiology and Pharmacology, Karolinska Institute, 17177 Stockholm, Sweden.
authors.forename: Xiaoqun
authors.initials: X
authors.lastname: Zhang
authors.forename: Per E
authors.initials: PE
authors.lastname: Andren
authors.forename: Karima
authors.initials: K
authors.lastname: Chergui
authors.forename: Per
authors.initials: P
authors.lastname: Svenningsson
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use; D001345:Autoradiography / Q000379:methods; D001522:Behavior, Animal; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D003042:Cocaine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D005246:Feedback / Q000502:physiology*; D007839:Functional Laterality; D005786:Gene Expression Regulation / Q000187:drug effects; D007980:Levodopa / Q000627:therapeutic use; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D010446:Peptide Fragments / Q000493:pharmacokinetics; D011804:Quinolines / Q000494:pharmacology; D011868:Radioisotopes / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D018042:Receptors, Neurokinin-3 / Q000502:physiology*; D012694:Serine / Q000378:metabolism; D013373:Substance P / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D013565:Sympatholytics / Q000633:toxicity; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D000978:Antiparkinson Agents; D010446:Peptide Fragments; D011804:Quinolines; D011868:Radioisotopes; D018042:Receptors, Neurokinin-3; C109112:SB 222200; D013565:Sympatholytics; C054724:senktide; D013373:Substance P; D012694:Serine; D007980:Levodopa; C069723:2beta-carbomethoxy-3beta-(4-iodophenyl)tropane; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D003042:Cocaine; D004298:Dopamine