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 OX1R antagonist, JNJ-10397049 (N-(2,4-dibromophenyl)-N′-[(4S,5S)-2,2-dimethyl-4-phenyl-1,3-dioxan-5-yl]urea), a selective OX2R 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 OX1/OX2R 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 OX1R mechanisms in BE, suggesting that selective antagonism at OX1R could represent a novel pharmacological treatment for BE and possibly other eating disorders with a compulsive component.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
American Psychiatric Association (2000). Diagnostic and Statistic Manual of Mental Disorders, IV-TR. American Psychiatric Association: Washington, DC.
Appolinario JC, Godoy-Matos A, Fontenelle LF, Carraro L, Cabral M, Vieira A et al (2000). An open-label trial of sibutramine in obese patients with binge-eating disorder. J Clin Psychiatry 63: 8–30.
Arunlakshana O, Schild HO (1959). Some quantitative uses of drug antagonists. Br J Pharmacol Chemother 14: 48–58.
Avena NM, Bocarsly ME (2011). Dysregulation of brain reward systems in eating disorders: neurochemical information from animal models of binge eating, bulimia nervosa, and anorexia nervosa. Neuropharmacology; e-pub ahead of print 27 November 2011.
Avena NM, Rada P, Hoebel BG (2008). Evidence for sugar addiction: behavioral and neurochemical effects of intermittent, excessive sugar intake. Neurosci Biobehav Rev 32: 20–39.
Bello NT, Hajnal A (2010). Dopamine and binge eating behaviors. Pharmacol Bioichem Behav 97: 25–33.
Bonci A, Borgland S (2009). Role of orexin/hypocretin and CRF in the formation of drug-dependent synaptic plasticity in the mesolimbic system. Neuropharmacology 56: 107–111.
Borgland SL, Taha SA, Sarti F, Fields HL, Bonci A (2006). Orexin A in the VTA is critical for the induction of synaptic plasticity and behavioral sensitization to cocaine. Neuron 49: 589–601.
Boutrel B, Kenny PJ, Specio SE, Martin-Fardon R, Markou A, Koob GF et al (2005). Role for hypocretin in mediating stress-induced reinstatement of cocaine-seeking behavior. Proc Natl Acad Sci USA 102: 19168–19173.
Brandish PE, Hill LA, Zheng W, Scolnick EM (2003). Scintillation proximity assay of inositol phosphates in cells extracts: high-throughput measurement of G-protein-coupled receptor activation. Anal Biochem 313: 311–318.
Brisbare-Roch C, Dingemanse J, Koberstein R, Hoever P, Aissaoui H, Flores S et al (2007). Promotion of sleep by targeting the orexin system in rats, dogs and humans. Nat Med 13: 50–155.
Broft AI, Berner LA, Martinez D, Walsh BT (2011). Bulimia nervosa and evidence for striatal dopamine dysregulation: a conceptual review. Physiol Behav 104: 122–127.
Carter WP, Hudson JI, Lalonde JK, Pindyck L, Mcelroy SL, Pope Jr HG (2003). Pharmacologic treatment of binge eating disorder. Int J Eat Disord 34 (Suppl): S74–S88.
Cason AM, Smith RJ, Tahsili-Fahadan P, Moorman DE, Sartor GC, Aston-Jones G (2010). Role of orexin/hypocretin in reward seeking and addiction: implications for obesity. Physiol Behav 100: 419–428.
Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, Lee C et al (1999). Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98: 437–451.
Cifani C, Polidori C, Melotto S, Ciccocioppo R, Massi MA (2009). Preclinical model of binge-eating elicited by yo–yo dieting and stressful exposure to food: effect of sibutramine, fluoxetine, topiramate and midazolam. Psychopharmacology 204: 113–125.
Corwin R, Avena NM, Boggiano MM (2011). Feeling and reward: perspective from three rat models of binge eating. Physiol Behav 104: 87–97.
Crowther JH, Sanftner J, Bonifazi DZ, Shepherd KL (2001). The role of daily hassles in binge eating. Int J Eat Disord 29: 449–454.
de Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE et al (1998). The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci USA 95: 322–327.
Devlin MJ, Yanovski SZ, Wilson GT (2000). Obesity: what mental health professionals need to know. Am J Psychiatry 157: 854–866.
Di Fabio R, Pellacani A, Faedo S, Roth A, Piccoli L, Gerrard P et al (2011). Discovery process and pharmacological characterization of a novel dual orexin 1 and orexin 2 receptor antagonist useful for treatment of sleep disorders. Biorg Med Chem Lett 21: 5562–5567.
Dugovic C, Shelton JE, Aluisio LE, Fraser IC, Jiang X, Sutton SW et al (2009). Blockade of orexin-1 receptors attenuates orexin-2 receptor antagonism-induced sleep promotion in the rat. J Pharmacol Exp Ther 330: 142–151.
Fassino S, Leombruni P, Pierò A, Abbate-Daga G, Giacomo Rovera G (2003). Mood, eating attitudes, and anger in obese women with and without binge eating disorder. J Psychosom Res 54: 559–566.
Foulds Mathes W, Brownley KA, Mo X, Bulik CM (2009). The biology of binge eating. Appetite 52: 545–553.
Freeman LM, Gil KM (2004). Daily stress, coping, and dietary restraint in binge eating. Int J Eat Disord 36: 204–212.
Gearhardt AN, Corbin WR, Brownell KD (2011a). Food addiction: an examination of the diagnostic criteria for dependence. J Addict Med 3: 1–7.
Gearhardt AN, Yokum S, Orr PT, Stice E, Corbin WR, Brownell KD (2011b). Neural correlates of food addiction. Arch Gen Psychiatry 68: 808–816.
Gold MS, Frost-Pineda K, Jacobs WS (2003). Overeating, binge eating, and eating disorders as addictions. Psychiatr Ann 33: 112–116.
Gozzi A, Turrini G, Piccoli L, Massagrande M, Amantini D, Antolini M et al (2011). Functional magnetic resonance imaging reveals different neural substrates for the effects of orexin-1 and orexin-2 receptor antagonists. PLoS One 6: e16406.
Grucza RA, Przybeck TR, Cloninger CR (2007). Prevalence and correlates of binge eating disorder in a community sample. Compr Psychiatry 48: 124–131.
Harris GC, Aston-Jones G (2006). Arousal and reward: a dichotomy in orexin function. Trends Neurosci 29: 571–577.
Harris GC, Wimmer M, Aston-Jones G (2005). A role for lateral hypothalamic orexin neurons in reward seeking. Nature 437: 556–559.
Haynes AC, Jackson B, Chapman H, Tadayyon M, Johns A, Porter RA et al (2000). A selective orexin-1 receptor antagonist reduces food consumption in male and female rats. Regul Pept 96: 45–51.
Heath AC (1998). Binge-eating and bulimia: potential insights into etiology and pathophysiology through genetic epidemiologic studies. Biol Psychiatry 44: 1208–1209.
Hoebel BG (1985). Brain neurotransmitters in food and drug reward. Am J Clin Nutr 42 (Suppl): 1133–1150.
Hollander JA, Lu Q, Cameron MD, Kamenecka TM, Kenny PJ (2008). Insular hypocretin transmission regulates nicotine reward. Proc Natl Acad Sci USA 105: 19480–19485.
Hudson JI, Hiripi E, Pope Jr HG, Kessler RC (2007). The prevalence and correlates of eating disorders in the national comorbidity survey replication. Biol Psychiatry 61: 348–358.
Ifland JR, Preuss HG, Marcus MT, Rourke KM, Taylor WC, Burau K et al (2009). Refined food addiction: a classic substance use disorder. Med Hypotheses 72: 518–526.
Kenakin T, Jenkinson S, Watson C (2006). Determining the potency and molecular mechanism of action of unsurmountable antagonists. J Pharmacol Exp Ther 319: 710–723.
Kenny PJ (2011). Common cellular and molecular mechanisms in obesity and drug addiction. Nat Rev Neurosci 12: 638–651.
Koob GF (2008). A role for brain stress system in addiction. Neuron 59: 11–34.
Kuwaki T (2011). Orexin links emotional stress to autonomic functions. Auton Neurosci 161: 20–27.
Javaras KN, Pope HG, Lalonde JK, Roberts JL, Nillni YI, Laird NM et al (2008). Co-occurrence of binge eating disorder with psychiatric and medical disorders. J Clin Psychiatry 269: 266–273.
Johnson PL, Truitt W, Fitz SD, Minick PE, Dietrich A, Sanghani S et al (2010). A key role for orexin in panic anxiety. Nat Med 16: 111–115.
Johnson PM, Kenny PJ (2010). Dopamine D2 receptors in addiction-like reward dysfunction and compulsive eating in obese rats. Nat Neurosci 13: 635–641.
Jupp B, Krivdic B, Krstew E, Lawrence AJ (2011). The orexin1 receptor antagonist SB-334867 dissociates the motivational properties of alcohol and sucrose in rats. Brain Res 1391: 54–59.
Lawrence AJ, Cowen MS, Yang HJ, Chen F, Oldfield B (2006). The orexin system regulates alcohol-seeking in rats. Br J Pharmacol 148: 752–759.
Lu XY, Bagnol D, Burke S, Akil H, Watson SJ (2000). Differential distribution and regulation of OX1 and OX2 orexin/hypocretin receptor messenger RNA in the brain upon fasting. Horm Behav 37: 335–344.
Malherbe P, Borroni E, Pinard E, Wettstein JG, Knoflach F (2009). Biochemical and electrophysiological characterization of almorexant, a dual orexin 1 receptor (OX1)/orexin 2 receptor (OX2) antagonist: comparison with selective OX1 and OX2 antagonists. Mol Pharmacol 76: 618–631.
Marcus JN, Aschkenasi CJ, Lee CE, Chemelli RM, Saper CB, Yanagisawa M et al (2001). Differential expression of orexin receptors 1 and 2 in the rat brain. J Comp Neurol 435: 6–25.
Martin-Fardon R, Zorrilla EP, Ciccocioppo R, Weiss F (2010). Role of innate and drug-induced dysregulation of brain stress and arousal systems in addiction: focus on corticotropin-releasing factor, nociceptin/orphanin FQ, and orexin/hypocretin. Brain Res 1314: 145–161.
McAtee LC, Sutton SW, Rudolph DA, Li X, Aluisio LE, Phuong VK et al (2004). Novel substituted 4-phenyl-[1,3]dioxanes: potent and selective orexin receptor 2 (OX2R) antagonists. Bioorg Med Chem Lett 14: 4225–4229.
McElroy SL, Guerdjikova AI, Martens B, Keck Jr PE, Pope HG, Hudson JI (2009). Role of antiepileptic drugs in the management of eating disorders. CNS Drugs 23: 139–156.
McElroy SL, Hudson JI, Capece JA, Beyers K, Fisher AC, Rosenthal NR (2007). Topiramate for the treatment of binge eating disorder associated with obesity: a placebo controlled study. Biol Psychiatry 61: 1039–1048.
Nair SG, Golden SA, Shaham Y (2008). Differential effects of the hypocretin 1 receptor antagonist SB 334867 on high-fat food self-administration and reinstatement of food seeking in rats. Br J Pharmacol 154: 406–416.
Pelchat ML, Johnson A, Chan R, Valdez J, Ragland JD (2004). Images of desire: food-craving activation during fMRI. NeuroImage 23: 1486–1493.
Perello M, Sakata I, Birnbaum S, Chuang JC, Osborne-Lawrence S, Rovinsky SA et al (2010). Ghrelin increases the rewarding value of high fat diet in an orexin-dependent manner. Biol Psych 67: 880–886.
Polivy J, Zeitlin SB, Herman CP, Beal AL (1994). Food restriction and binge eating: a study of former prisoner of war. J Abnorm Psychol 103: 409–411.
Read KD, Braggio S (2010). Assessing brain free fraction in early drug discovery. Expert Opin Drug Metab Toxicol 6: 337–344.
Richards JK, Simms JA, Steensland P, Taha SA, Borgland SL, Bonci A et al (2008). Inhibition of orexin-1/hypocretin-1 receptors inhibits yohimbine-induced reinstatement of ethanol and sucrose seeking in Long–Evans rats. Psychopharmacology 199: 109–117.
Rodgers RJ, Halford JC, Nunes de Souza RL, Canto de Souza AL, Piper DC, Arch JR et al (2001). SB-334867, a selective orexin-1 receptor antagonist, enhances behavioural satiety and blocks the hyperphagic effect of orexin-A in rats. Eur J Neurosci 13: 1444–1452.
Sakamoto F, Yamada S, Ueta Y (2004). Centrally administered orexin-A activates corticotropin-releasing factor containing neurons in the hypothalamic paraventricular nucleus and central amygdaloid nucleus of rats: possible involvement of central orexins on stress-activated central CRF neurons. Reg Pept 118: 183–191.
Sakurai T (2007). The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness. Nat Rev Neurosci 8: 171–181.
Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H et al (1998). Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92: 573–585.
Sharf R, Sarhan M, Brayton CE, Guarnieri DJ, Taylor JR, DiLeone RJ (2010). Orexin signaling via OX1R mediates operant responding for food reinforcement. Biol Psychiatry 67: 753–760.
Shoblock JR, Welty N, Aluisio L, Fraser I, Motley ST, Morton K et al (2011). Selective blockade of the orexin-2 receptor attenuates ethanol self-administration, place preference, and reinstatement. Psychopharmacology 215: 191–203.
Smith RJ, Tahsili-Fahadan P, Aston-Jones G (2010). Orexin/hypocretin is necessary for context-driven cocaine-seeking. Neuropharmacology 58: 179–184.
Stice E, Agras WS, Telch FC, Halmi KA, Mitchell JE, Wilson T (2001). Subtyping binge eating-disordered women along dieting and negative affect dimensions. Int J Eat Disord 30: 11–27.
Trivedi P, Yu H, MacNeil DJ, Van der Ploeg LH, Guan XM (1998). Distribution of orexin receptor mRNA in the rat brain. FEBS Lett 438: 71–75.
Uramura K, Funahashi H, Muroya S, Shioda S, Takigawa M, Yada T (2001). Orexin-a activates phospholipase C and protein kinase C mediated Ca2+ signaling in dopamine neurons of the ventral tegmental area. NeuroReport 12: 1885–1889.
Volkow ND, Wise RA (2005). How can drug addiction help us understand obesity? Nat Neurosci 8: 555–560.
Yager J (2008). Binge eating disorder: the search for better treatments. Am J Psychiatry 165: 4–6.
Yanovski SZ (2003). Binge eating disorder and obesity in 2003: could treating an eating disorder have a positive effect on the obesity epidemic? Int J Eat Disord 34 (Suppl): S117–S120.
Walsh BT, Devlin MJ (1998). Eating disorders: progress and problems. Science 280: 1387–1390.
Wang GJ, Geliebter A, Volkow ND, Telang FW, Logan J, Jayne MC et al (2011). Enhanced striatal dopamine release during food stimulation during binge eating disorder. Obesity 19: 1601–1608.
Wardle J, Steptoe A, Oliver G, Lipsey Z (2000). Stress, dietary restraint and food intake. J Psychosom Res 48: 195–202.
Waters A, Hill A, Waller G (2001). Internal and external antecedents of binge eating episodes in a group of women with bulimia nervosa. Int J Eat Disord 29: 17–22.
Wilfley DE, Crow SJ, Hudson JI, Mitchell JE, Berkowitz RI, Blakesley V et al (2008). Sibutramine eating disorder research group. Efficacy of sibutramine for the treatment of binge eating disorder: a randomized multicenter placebo-controlled double-blind study. Am J Psychiatry 165: 51–58.
Willie JT, Chemelli RM, Sinton CM, Yanagisawa M (2001). To eat or to sleep? Orexin in the regulation of feeding and wakefulness. Annu Rev Neurosci 24: 429–458.
Wolff GE, Crosby RD, Roberts JA, Wittrock DA (2000). Differences in daily stress, mood, coping, and eating behavior in binge eating and nonbinge eating college women. Addict Behav 25: 205–216.
Zheng H, Patterson LM, Berthoud HR (2007). Orexin signaling in the ventral tegmental area is required for high-fat appetite induced by opioid stimulation of the nucleus accumbens. J Neurosci 27: 11075–11082.
Acknowledgements
We thank Dr Charles Pickens for stylistic correction of the manuscript.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
EM-P is full-time employee of GSK.
Rights and permissions
About this article
Cite this article
Piccoli, L., Micioni Di Bonaventura, M., Cifani, C. et al. Role of Orexin-1 Receptor Mechanisms on Compulsive Food Consumption in a Model of Binge Eating in Female Rats. Neuropsychopharmacol 37, 1999–2011 (2012). https://doi.org/10.1038/npp.2012.48
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/npp.2012.48
Keywords
This article is cited by
-
Insomnia and the Orexinergic Pathway in the Link with Psychopathology: Effects of DORAs in Insomnia Comorbid with Mental Disturbances
Current Sleep Medicine Reports (2024)
-
Estradiol-dependent hypocretinergic/orexinergic behaviors throughout the estrous cycle
Psychopharmacology (2023)
-
Orexin 2 receptor (OX2R) protein distribution measured by autoradiography using radiolabeled OX2R-selective antagonist EMPA in rodent brain and peripheral tissues
Scientific Reports (2022)
-
Sleep dysregulation in binge eating disorder and “food addiction”: the orexin (hypocretin) system as a potential neurobiological link
Neuropsychopharmacology (2021)
-
Differential importance of nucleus accumbens Ox1Rs and AMPARs for female and male mouse binge alcohol drinking
Scientific Reports (2021)
