title: Role of orexin-1 receptor mechanisms on compulsive food consumption in a model of binge eating in female rats.
abstract: Orexins (OX) and their receptors (OXR) modulate feeding, arousal, stress, and drug abuse. Neural systems that motivate and reinforce drug abuse may also underlie compulsive food seeking and intake. Therefore, the effects of GSK1059865 (5-bromo-N-[(2S,5S)-1-(3-fluoro-2-methoxybenzoyl)-5-methylpiperidin-2-yl]methyl-pyridin-2-amine), a selective OX(1)R antagonist, JNJ-10397049 (N-(2,4-dibromophenyl)-N'-[(4S,5S)-2,2-dimethyl-4-phenyl-1,3-dioxan-5-yl]urea), a selective OX(2)R antagonist, and SB-649868 (N-[((2S)-1-{[5-(4-fluorophenyl)-2-methyl-1,3-thiazol-4-yl]carbonyl}-2-piperidinyl)methyl]-1-benzofuran-4-carboxamide), a dual OX(1)/OX(2)R antagonist were evaluated in a binge eating (BE) model in female rats. BE of highly palatable food (HPF) was evoked by three cycles of food restriction followed by stress, elicited by exposing rats to HPF, but preventing them from having access to it for 15 min. Pharmacokinetic assessments of all compounds were obtained under the same experimental conditions used for the behavioral experiments. Topiramate was used as the reference compound as it selectively blocks BE in rats and humans. Dose-related thresholds for sleep-inducing effects of the OXR antagonists were measured using polysomnography in parallel experiments. SB-649868 and GSK1059865, but not JNJ-10397049, selectively reduced BE for HPF without affecting standard food pellet intake, at doses that did not induce sleep. These results indicate, for the first time, a major role of OX(1)R mechanisms in BE, suggesting that selective antagonism at OX(1)R could represent a novel pharmacological treatment for BE and possibly other eating disorders with a compulsive component.
authors.affiliation: GlaxoSmithKline, Medicines Research Centre, Verona, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Piccoli
authors.forename: Maria Vittoria
authors.initials: MV
authors.lastname: Micioni Di Bonaventura
authors.forename: Carlo
authors.initials: C
authors.lastname: Cifani
authors.forename: Vivian J A
authors.initials: VJ
authors.lastname: Costantini
authors.forename: Mario
authors.initials: M
authors.lastname: Massagrande
authors.forename: Dino
authors.initials: D
authors.lastname: Montanari
authors.forename: Prisca
authors.initials: P
authors.lastname: Martinelli
authors.forename: Marinella
authors.initials: M
authors.lastname: Antolini
authors.forename: Roberto
authors.initials: R
authors.lastname: Ciccocioppo
authors.forename: Maurizio
authors.initials: M
authors.lastname: Massi
authors.forename: Emilio
authors.initials: E
authors.lastname: Merlo-Pich
authors.forename: Romano
authors.initials: R
authors.lastname: Di Fabio
authors.forename: Mauro
authors.initials: M
authors.lastname: Corsi
mesh_terms: D000818:Animals; D002032:Bulimia / Q000188:drug therapy / Q000378:metabolism* / Q000523:psychology; D003192:Compulsive Behavior / Q000188:drug therapy / Q000523:psychology; D004435:Eating / Q000187:drug effects / Q000502:physiology* / Q000523:psychology; D005260:Female; D005632:Fructose / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D047908:Intracellular Signaling Peptides and Proteins / Q000494:pharmacology; D008297:Male; D009479:Neuropeptides / Q000494:pharmacology; D064446:Orexin Receptors; D000068797:Orexins; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D018013:Receptors, Neuropeptide / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D012055:Reinforcement Schedule; D012737:Sex Factors; D000077236:Topiramate; D014407:Tumor Cells, Cultured
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D064446:Orexin Receptors; D000068797:Orexins; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D000077236:Topiramate; D005632:Fructose