title: Permissive role of neurokinin NK(3) receptors in NK(1) receptor-mediated activation of the locus coeruleus revealed by SR 142801.
abstract: The present experiments investigated the role of neurokinin-1 (NK(1)) and neurokinin-3 (NK(3)) receptors on the activity of the locus coeruleus (LC)-noradrenergic system by using a dual probe microdialysis technique in anesthetized guinea pigs. The local application in the LC of the selective NK(1) receptor agonists [SAR(9),Met(O(2))(11)]-SP (10 microM) and septide (1 microM) as well as the selective NK(3) receptor agonist senktide (1 microM), enhanced the extracellular norepinephrine (NE) levels in the prefrontal cortex. The enhancing effect of [SAR(9),Met(O(2))(11)]-SP was completely blocked by the peripheral administration of the selective non peptide NK(1) and NK(3) receptor antagonists, GR 205171 (1 mg/kg, i.p.) and SR 142801 (0.1 mg/kg, i.p.), respectively, whereas SR 142806 (0.1 mg/kg, i.p.) the inactive enantiomer of SR 142801 had no effect. Moreover, the [SAR(9),Met(O(2))(11)]-SP-induced increase in LC DOPAC concentrations, is only antagonized by GR 205171. In contrast, only SR 142801 (0.3 mg/kg, i.p.) could block stereoselectively the senktide-evoked increase in NE levels. Both [SAR(9),Met(O(2))(11)]-SP and senktide effects were blocked by local infusion into the LC of SR 142801 (10(-9) M). These results demonstrate that stimulation of NK(1) and NK(3) receptors located in the LC area modulates the activity of the LC-NE system, and that the excitatory effects of NK(1) receptor agonists require NKB/NK(3) receptor activation in the LC.
authors.affiliation: Sanofi-Synthélabo, Central Nervous System Department, Montpellier, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Bert
authors.forename: Daniel
authors.initials: D
authors.lastname: Rodier
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bougault
authors.forename: Nathalie
authors.initials: N
authors.lastname: Allouard
authors.forename: Gérard
authors.initials: G
authors.lastname: Le-Fur
authors.forename: Philippe
authors.initials: P
authors.lastname: Soubrié
authors.forename: Régis
authors.initials: R
authors.lastname: Steinberg
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D000932:Antiemetics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D008125:Locus Coeruleus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009434:Neural Pathways / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D064729:Neurokinin-1 Receptor Antagonists; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives; D018040:Receptors, Neurokinin-1 / Q000819:agonists / Q000378:metabolism*; D018042:Receptors, Neurokinin-3 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013373:Substance P / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology
chemical_list: D000932:Antiemetics; D064729:Neurokinin-1 Receptor Antagonists; D010446:Peptide Fragments; D010880:Piperidines; D018040:Receptors, Neurokinin-1; D018042:Receptors, Neurokinin-3; D013777:Tetrazoles; D015102:3,4-Dihydroxyphenylacetic Acid; C054724:senktide; C062618:substance P, Sar(9)-Met(O2)(11)-; D013373:Substance P; C054725:septide; C103207:vofopitant; C091554:SR 142801; D011761:Pyrrolidonecarboxylic Acid; D009638:Norepinephrine