title: Pharmacological characterisation of the orexin receptor subtype mediating postsynaptic excitation in the rat dorsal raphe nucleus.
abstract: Electrophysiological recordings from dorsal raphe nucleus (DRN) neurones in rat brain slices have revealed that the orexins can cause direct and reversible depolarisation of the postsynaptic membrane. Whilst it is known that the membrane depolarisation produced by orexin-A can dramatically increase the firing rate of DRN neurones, quantitative pharmacological analysis that determines the receptor subtype mediating the orexinergic response has not yet been performed. Here, we demonstrate that the rank order of potencies of orexin receptor agonists to excite serotonergic DRN neurones is orexin-A = orexin-B > SB-668875-DM. In contrast, the rank order of potency of these agonists to excite noradrenergic locus coreleus (LC) neurones is orexin-A > orexin-B > SB-668875-DM. We show further that the orexin receptor antagonist, SB-334867-A, inhibits the effects of orexin-A in the LC and DRN with pKB values of 6.93 and 5.84, respectively, values similar to those calculated for human OX1 (7.27) and OX2 (5.60) receptors expressed in CHO cells. These data suggest a differential role for OX1 and OX2 receptors in stimulating distinct populations of monoaminergic neurones in the rat CNS with OX2 receptors exhibiting a more pronounced functional significance in serotonergic neurones and OX1 in noradrenergic neurones.
authors.affiliation: Department of Psychiatry, Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. ellen_m_soffin@gsk.com
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Soffin
authors.forename: Catherine H
authors.initials: CH
authors.lastname: Gill
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Brough
authors.forename: Jeff C
authors.initials: JC
authors.lastname: Jerman
authors.forename: Ceri H
authors.initials: CH
authors.lastname: Davies
mesh_terms: D000818:Animals; D001583:Benzoxazoles / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009287:Naphthyridines; D064446:Orexin Receptors; D011903:Raphe Nuclei / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; D001583:Benzoxazoles; D009287:Naphthyridines; D064446:Orexin Receptors; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D014508:Urea