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Centrally administered orexin A increases motivation for sweet pellets in rats

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Abstract

Rationale

Centrally administered orexin A induces both feeding and locomotion in rats. Thus, the feeding response following orexin A administration may be secondary to general increases in activity rather than a specific motivation to eat.

Objective

The aim of the study is to determine whether orexin A increases the motivation to eat.

Methods

The effect of orexin A (0, 31.25, 62.5, 125, 250, and 500 pmol) on breakpoint was determined in male Sprague–Dawley rats with rostro-lateral hypothalamic cannulae under a progressive ratio of five schedule (PR5). The effect of orexin A (0, 31.25, 125, and 500 pmol) on pressing rate under a fixed ratio (20) schedule was obtained to analyze the time course of orexin-A-induced pressing. The effect of 24-h food deprivation on breakpoint under PR5 and the effect of orexin A (125 pmol) on free feeding (sweet pellets) and on open-field locomotor activity (0, 100, 500, and 1,000 pmol) were also tested.

Results

Orexin A significantly augmented free feeding of sweet pellets, open-field locomotor activity, rate of pressing (FR20 schedule), and breakpoint (PR5 schedule), although compared to 24-h deprivation, the effect of orexin A on breakpoint was mild. However, there was a differential dose response relationship and time course of stimulation between orexin A's effects on locomotion and lever pressing.

Conclusion

These data indicate that infusion of orexin A enhances free feeding by enhancing and possibly prolonging motivation to eat.

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References

  • Arnold JM, Roberts DC (1997) A critique of fixed and progressive ratio schedules used to examine the neural substrates of drug reinforcement. Pharmacol Biochem Behav 57:441–447

    Article  PubMed  CAS  Google Scholar 

  • Backberg M, Hervieu G, Wilson S, Meister B (2002) Orexin receptor-1 (OX-R1) immunoreactivity in chemically identified neurons of the hypothalamus: focus on orexin targets involved in control of food and water intake. Eur J Neurosci 15:315–328

    Article  PubMed  Google Scholar 

  • Bernardis LL, Bellinger LL (1996) The lateral hypothalamic area revisited: ingestive behavior. Neurosci Biobehav Rev 20:189–287

    Article  PubMed  CAS  Google Scholar 

  • Broberger C (1999) Hypothalamic cocaine- and amphetamine-regulated transcript (CART) neurons: histochemical relationship to thyrotropin-releasing hormone, melanin-concentrating hormone, orexin/hypocretin and neuropeptide Y. Brain Res 848:101–113

    Article  PubMed  CAS  Google Scholar 

  • Broberger C, De Lecea L, Sutcliffe JG, Hokfelt T (1998) Hypocretin/orexin- and melanin-concentrating hormone-expressing cells form distinct populations in the rodent lateral hypothalamus: relationship to the neuropeptide Y and agouti gene-related protein systems. J Comp Neurol 402:460–474

    Article  PubMed  CAS  Google Scholar 

  • Brown CM, Fletcher PJ, Coscina DV (1998) Neuropeptide Y-induced operant responding for sucrose is not mediated by dopamine. Peptides 19:1667–1673

    Article  PubMed  CAS  Google Scholar 

  • Cai XJ, Widdowson PS, Harrold J, Wilson S, Buckingham RE, Arch JR, Tadayyon M, Clapham JC, Wilding J, Williams G (1999) Hypothalamic orexin expression: modulation by blood glucose and feeding. Diabetes 48:2132–2137

    Article  PubMed  CAS  Google Scholar 

  • Clegg DJ, Air EL, Woods SC, Seeley RJ (2002) Eating elicited by orexin-a, but not melanin-concentrating hormone, is opioid mediated. Endocrinology 143:2995–3000

    Article  PubMed  CAS  Google Scholar 

  • Cluderay JE, Harrison DC, Hervieu GJ (2002) Protein distribution of the orexin-2 receptor in the rat central nervous system. Regul Pept 104:131–144

    Article  PubMed  CAS  Google Scholar 

  • Date Y, Ueta Y, Yamashita H, Yamaguchi H, Matsukura S, Kangawa K, Sakurai T, Yanagisawa M, Nakazato M (1999) Orexins, orexigenic hypothalamic peptides, interact with autonomic, neuroendocrine and neuroregulatory systems. Proc Natl Acad Sci U S A 96:748–753

    Article  PubMed  CAS  Google Scholar 

  • de Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE, Fukuhara C, Battenberg EL, Gautvik VT, Bartlett FS II, Frankel WN, van den Pol AN, Bloom FE, Gautvik KM, Sutcliffe JG (1998) The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci U S A 95:322–327

    Article  PubMed  Google Scholar 

  • Edwards CM, Abusnana S, Sunter D, Murphy KG, Ghatei MA, Bloom SR (1999) The effect of the orexins on food intake: comparison with neuropeptide Y, melanin-concentrating hormone and galanin. J Endocrinol 160:R7–R12

    Article  PubMed  CAS  Google Scholar 

  • Espana RA, Plahn S, Berridge CW (2002) Circadian-dependent and circadian-independent behavioral actions of hypocretin/orexin. Brain Res 943:224–236

    Article  PubMed  CAS  Google Scholar 

  • Fujiki N, Yoshida Y, Ripley B, Honda K, Mignot E, Nishino S (2001) Changes in CSF hypocretin-1 (orexin A) levels in rats across 24 hours and in response to food deprivation. NeuroReport 12:993–997

    Article  PubMed  CAS  Google Scholar 

  • Guan JL, Saotome T, Wang QP, Funahashi H, Hori T, Tanaka S, Shioda S (2001) Orexinergic innervation of POMC-containing neurons in the rat arcuate nucleus. NeuroReport 12:547–551

    Article  PubMed  CAS  Google Scholar 

  • Hagan JJ, Leslie RA, Patel S, Evans ML, Wattam TA, Holmes S, Benham CD, Taylor SG, Routledge C, Hemmati P, Munton RP, Ashmeade TE, Shah AS, Hatcher JP, Hatcher PD, Jones DN, Smith MI, Piper DC, Hunter AJ, Porter RA, Upton N (1999) Orexin A activates locus coeruleus cell firing and increases arousal in the rat. Proc Natl Acad Sci U S A 96:10911–10916

    Article  PubMed  CAS  Google Scholar 

  • Haynes AC, Jackson B, Overend P, Buckingham RE, Wilson S, Tadayyon M, Arch JR (1999) Effects of single and chronic intracerebroventricular administration of the orexins on feeding in the rat. Peptides 20:1099–1105

    Article  PubMed  CAS  Google Scholar 

  • Haynes AC, Jackson B, Chapman H, Tadayyon M, Johns A, Porter RA, Arch JR (2000) A selective orexin-1 receptor antagonist reduces food consumption in male and female rats. Regul Pept 96:45–51

    Article  PubMed  CAS  Google Scholar 

  • Hodos W (1961) Progressive ratio as a measure of reward strength. Science 134:943–944

    Article  PubMed  CAS  Google Scholar 

  • Hodos W, Kalman G (1963) Effects of increment size and reinforcer volume on progressive ratio performance. J Exp Anal Behav 6:387–392

    Article  PubMed  CAS  Google Scholar 

  • Horvath TL, Diano S, van den Pol AN (1999) Synaptic interaction between hypocretin (orexin) and neuropeptide Y cells in the rodent and primate hypothalamus: a novel circuit implicated in metabolic and endocrine regulations. J Neurosci 19:1072–1087

    PubMed  CAS  Google Scholar 

  • Ida T, Nakahara K, Katayama T, Murakami N, Nakazato M (1999) Effect of lateral cerebroventricular injection of the appetite-stimulating neuropeptide, orexin and neuropeptide Y, on the various behavioral activities of rats. Brain Res 821:526–529

    Article  PubMed  CAS  Google Scholar 

  • Ida T, Nakahara K, Kuroiwa T, Fukui K, Nakazato M, Murakami T, Murakami N (2000) Both corticotropin releasing factor and neuropeptide Y are involved in the effect of orexin (hypocretin) on the food intake in rats. Neurosci Lett 293:119–122

    Article  PubMed  CAS  Google Scholar 

  • Jain MR, Horvath TL, Kalra PS, Kalra SP (2000) Evidence that NPY Y1 receptors are involved in stimulation of feeding by orexins (hypocretins) in sated rats. Regul Pept 87:19–24

    Article  PubMed  CAS  Google Scholar 

  • Jewett DC, Cleary J, Levine AS, Schaal DW, Thompson T (1995) Effects of neuropeptide Y, insulin, 2-deoxyglucose, and food deprivation on food-motivated behavior. Psychopharmacology (Berl) 120:267–271

    Article  CAS  Google Scholar 

  • Kotz CM, Teske JA, Levine JA, Wang C (2002) Feeding and activity induced by orexin A in the lateral hypothalamus in rats. Regul Pept 104:27–32

    Article  PubMed  CAS  Google Scholar 

  • Lin L, Faraco J, Li R, Kadotani H, Rogers W, Lin X, Qiu X, de Jong PJ, Nishino S, Mignot E (1999) The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 98:365–376

    Article  PubMed  CAS  Google Scholar 

  • Marsh DJ, Hollopeter G, Huszar D, Laufer R, Yagaloff KA, Fisher SL, Burn P, Palmiter RD (1999) Response of melanocortin-4 receptor-deficient mice to anorectic and orexigenic peptides. Nat Genet 21:119–122

    Article  PubMed  CAS  Google Scholar 

  • Mignot E (2001) A commentary on the neurobiology of the hypocretin/orexin system. Neuropsychopharmacology 25:S5–S13

    Article  PubMed  CAS  Google Scholar 

  • Mullett MA, Billington CJ, Levine AS, Kotz CM (2000) Hypocretin I in the lateral hypothalamus activates key feeding-regulatory brain sites. NeuroReport 11:103–108

    Article  PubMed  CAS  Google Scholar 

  • Muroya S, Funahashi H, Yamanaka A, Kohno D, Uramura K, Nambu T, Shibahara M, Kuramochi M, Takigawa M, Yanagisawa M, Sakurai T, Shioda S, Yada T (2004) Orexins (hypocretins) directly interact with neuropeptide Y, POMC and glucose-responsive neurons to regulate Ca 2+ signaling in a reciprocal manner to leptin: orexigenic neuronal pathways in the mediobasal hypothalamus. Eur J Neurosci 19:1524–1534

    Article  PubMed  Google Scholar 

  • Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E (2000) Hypocretin (orexin) deficiency in human narcolepsy. Lancet 355:39–40

    Article  PubMed  CAS  Google Scholar 

  • Paxinos GW (1998) The Rat Brain In Stereotaxic Coordinates, Fourth Edition edn. Academic Press, Academic Press

  • Peyron C, Faraco J, Rogers W, Ripley B, Overeem S, Charnay Y, Nevsimalova S, Aldrich M, Reynolds D, Albin R, Li R, Hungs M, Pedrazzoli M, Padigaru M, Kucherlapati M, Fan J, Maki R, Lammers GJ, Bouras C, Kucherlapati R, Nishino S, Mignot E (2000) A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med 6:991–997

    Article  PubMed  CAS  Google Scholar 

  • Richardson NR, Roberts DC (1996) Progressive ratio schedules in drug self-administration studies in rats: a method to evaluate reinforcing efficacy. J Neurosci Methods 66:1–11

    Article  PubMed  CAS  Google Scholar 

  • Rodgers RJ, Halford JC, Nunes de Souza RL, Canto de Souza AL, Piper DC, Arch JR, Blundell JE (2000) Dose-response effects of orexin-A on food intake and the behavioural satiety sequence in rats. Regul Pept 96:71–84

    Article  PubMed  CAS  Google Scholar 

  • Rodgers RJ, Ishii Y, Halford JC, Blundell JE (2002) Orexins and appetite regulation. Neuropeptides 36:303–325

    Article  PubMed  CAS  Google Scholar 

  • Sahu A (2002) Interactions of neuropeptide Y, hypocretin-I (orexin A) and melanin-concentrating hormone on feeding in rats. Brain Res 944:232–238

    Article  PubMed  CAS  Google Scholar 

  • Sakurai T (2003) Orexin: a link between energy homeostasis and adaptive behaviour. Curr Opin Clin Nutr Metab Care 6:353–360

    Article  PubMed  CAS  Google Scholar 

  • Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richarson JA, Kozlowski GP, Wilson S, Arch JR, Buckingham RE, Haynes AC, Carr SA, Annan RS, McNulty DE, Liu WS, Terrett JA, Elshourbagy NA, Bergsma DJ, Yanagisawa M (1998) Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92:1 page following 696

    Google Scholar 

  • Sunter D, Morgan I, Edwards CM, Dakin CL, Murphy KG, Gardiner J, Taheri S, Rayes E, Bloom SR (2001) Orexins: effects on behavior and localisation of orexin receptor 2 messenger ribonucleic acid in the rat brainstem. Brain Res 907:27–34

    Article  PubMed  CAS  Google Scholar 

  • Sutcliffe JG, De Lecea L (2002) The hypocretins: setting the arousal threshold. Nat Rev Neurosci 3:339–349

    Article  PubMed  CAS  Google Scholar 

  • Sweet DC, Levine AS, Billington CJ, Kotz CM (1999) Feeding response to central orexins. Brain Res 821:535–538

    Article  PubMed  CAS  Google Scholar 

  • Szekely M, Petervari E, Balasko M, Hernadi I, Uzsoki B (2002) Effects of orexins on energy balance and thermoregulation. Regul Pept 104:47–53

    Article  PubMed  CAS  Google Scholar 

  • Thannickal TC, Moore RY, Nienhuis R, Ramanathan L, Gulyani S, Aldrich M, Cornford M, Siegel JM (2000) Reduced number of hypocretin neurons in human narcolepsy. Neuron 27:469–474

    Article  PubMed  CAS  Google Scholar 

  • Thorpe A.J. MMA, Wang C, Kotz M (2003) Regional, metabolic and circadian specificity of LH orexin A. Am J Physiol Regul Integr Comp Physiol 284:R1409–R1417

    PubMed  CAS  Google Scholar 

  • Yamanaka A, Sakurai T, Katsumoto T, Yanagisawa M, Goto K (1999) Chronic intracerebroventricular administration of orexin-A to rats increases food intake in daytime, but has no effect on body weight. Brain Res 849:248–252

    Article  PubMed  CAS  Google Scholar 

  • Yamanaka A, Kunii K, Nambu T, Tsujino N, Sakai A, Matsuzaki I, Miwa Y, Goto K, Sakurai T (2000) Orexin-induced food intake involves neuropeptide Y pathway. Brain Res 859:404–409

    Article  PubMed  CAS  Google Scholar 

  • Yoshida Y, Fujiki N, Nakajima T, Ripley B, Matsumura H, Yoneda H, Mignot E, Nishino S (2001) Fluctuation of extracellular hypocretin-1 (orexin A) levels in the rat in relation to the light–dark cycle and sleep–wake activities. Eur J Neurosci 14:1075–1081

    Article  PubMed  CAS  Google Scholar 

  • Zhang M, Balmadrid C, Kelley AE (2003) Nucleus accumbens opioid, GABaergic, and dopaminergic modulation of palatable food motivation: contrasting effects revealed by a progressive ratio study in the rat. Behav Neurosci 117:202–211

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

We would like to thank Ms. Jennifer Lockie and Ms. Jennifer Teske for their expert technical assistance with training of animals.

This article is supported by the Department of Veterans Affairs, the National Institute of Diabetes and Digestive and Kidney Diseases Grant DK 57573, and the Minnesota Craniofacial Training Program NIDCR T32 DE07288-8.

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Correspondence to C. M. Kotz.

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Thorpe, A.J., Cleary, J.P., Levine, A.S. et al. Centrally administered orexin A increases motivation for sweet pellets in rats. Psychopharmacology 182, 75–83 (2005). https://doi.org/10.1007/s00213-005-0040-5

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  • DOI: https://doi.org/10.1007/s00213-005-0040-5

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