Document Detail

Role of orexin-1 receptor mechanisms on compulsive food consumption in a model of binge eating in female rats.
MedLine Citation:
PMID:  22569505     Owner:  NLM     Status:  MEDLINE    
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.
Laura Piccoli; Maria Vittoria Micioni Di Bonaventura; Carlo Cifani; Vivian J A Costantini; Mario Massagrande; Dino Montanari; Prisca Martinelli; Marinella Antolini; Roberto Ciccocioppo; Maurizio Massi; Emilio Merlo-Pich; Romano Di Fabio; Mauro Corsi
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Publication Detail:
Type:  Journal Article     Date:  2012-05-09
Journal Detail:
Title:  Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology     Volume:  37     ISSN:  1740-634X     ISO Abbreviation:  Neuropsychopharmacology     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-07-18     Completed Date:  2013-03-17     Revised Date:  2013-08-21    
Medline Journal Info:
Nlm Unique ID:  8904907     Medline TA:  Neuropsychopharmacology     Country:  England    
Other Details:
Languages:  eng     Pagination:  1999-2011     Citation Subset:  IM    
GlaxoSmithKline, Medicines Research Centre, Verona, Italy.
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MeSH Terms
Bulimia / drug therapy,  metabolism*,  psychology
Compulsive Behavior* / drug therapy,  psychology
Eating / drug effects,  physiology*,  psychology
Fructose / analogs & derivatives,  pharmacology,  therapeutic use
Intracellular Signaling Peptides and Proteins / pharmacology
Neuropeptides / pharmacology
Rats, Sprague-Dawley
Receptors, G-Protein-Coupled / agonists,  antagonists & inhibitors,  physiology*
Receptors, Neuropeptide / agonists,  antagonists & inhibitors,  physiology*
Reinforcement Schedule
Sex Factors
Tumor Cells, Cultured
Reg. No./Substance:
0/Intracellular Signaling Peptides and Proteins; 0/Neuropeptides; 0/Receptors, G-Protein-Coupled; 0/Receptors, Neuropeptide; 0/orexin receptors; 0/orexins; 0H73WJJ391/topiramate; 30237-26-4/Fructose

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