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
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
Bernardis LL, Bellinger LL (1996) The lateral hypothalamic area revisited: ingestive behavior. Neurosci Biobehav Rev 20:189–287
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
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
Brown CM, Fletcher PJ, Coscina DV (1998) Neuropeptide Y-induced operant responding for sucrose is not mediated by dopamine. Peptides 19:1667–1673
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
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
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
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
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
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
Espana RA, Plahn S, Berridge CW (2002) Circadian-dependent and circadian-independent behavioral actions of hypocretin/orexin. Brain Res 943:224–236
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
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
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
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
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
Hodos W (1961) Progressive ratio as a measure of reward strength. Science 134:943–944
Hodos W, Kalman G (1963) Effects of increment size and reinforcer volume on progressive ratio performance. J Exp Anal Behav 6:387–392
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
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
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
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
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
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
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
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
Mignot E (2001) A commentary on the neurobiology of the hypocretin/orexin system. Neuropsychopharmacology 25:S5–S13
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
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
Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E (2000) Hypocretin (orexin) deficiency in human narcolepsy. Lancet 355:39–40
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
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
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
Rodgers RJ, Ishii Y, Halford JC, Blundell JE (2002) Orexins and appetite regulation. Neuropeptides 36:303–325
Sahu A (2002) Interactions of neuropeptide Y, hypocretin-I (orexin A) and melanin-concentrating hormone on feeding in rats. Brain Res 944:232–238
Sakurai T (2003) Orexin: a link between energy homeostasis and adaptive behaviour. Curr Opin Clin Nutr Metab Care 6:353–360
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
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
Sutcliffe JG, De Lecea L (2002) The hypocretins: setting the arousal threshold. Nat Rev Neurosci 3:339–349
Sweet DC, Levine AS, Billington CJ, Kotz CM (1999) Feeding response to central orexins. Brain Res 821:535–538
Szekely M, Petervari E, Balasko M, Hernadi I, Uzsoki B (2002) Effects of orexins on energy balance and thermoregulation. Regul Pept 104:47–53
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
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
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
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
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
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
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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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