Abstract
The hypocretins (also know as orexins) are two neuropeptides now commonly described as critical components for maintaining and regulating the stability of arousal. Several lines of evidence have raised the hypothesis that hypocretin-producing neurons are part of the circuitries that mediate the hypothalamic response to acute stress. New data indicate that the corticotrophin-releasing factor (CRF) peptidergic system directly innervates hypocretin-expressing neurons. CRF depolarizes hypocretin neurons, and this effect is blocked by a CRF-R1 antagonist. Furthermore, activation of hypocretinergic neurons by stress is impaired in CRF-R1 knockout mice. These data suggest that CRF-R1 receptor mediates the stress-induced activation of the hypocretinergic system. A significant amount of evidence also indicates that hypocretin cells connect reciprocally to the CRF system. We propose that upon stressor stimuli, CRF activates the hypocretin system, which relays these signals to brain stem nuclei involved in the modulation of arousal as well as to the extended amygdala, a structure involved in the negative motivational state that drives addiction.
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de Lecea L., Kilduff T. S., Peyron C., et al. (1998) The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc. Natl. Acad. Sci. USA 95, 322–327.
Sakurai T., Amemiya A., Ishii M., 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.
Marcus J. N., Aschkenasi C. J., Lee C. E., et al. (2001) Differential expression of orexin receptors 1 and 2 in the rat brain. J. Comp. Neurol. 435, 6–25.
Peyron C., Tighe D. K., van den Pol A. N., et al. (1998) Neurons Containing Hypocretin (Orexin) Project to Multiple Neuronal Systems. J. Neurosci. 18, 9996–10,015.
Mignot E., Taheri S., and Nishino S. (2002) Sleeping with the hypothalamus: emerging therapeutic targets for sleep disorders. Nat. Neurosci. 5(Suppl), 1071–1075.
Willie J. T., Chemelli R. M., Sinton C. M., and Yanagisawa M. (2001) To eat or to sleep? orexin in the regulation of feeding and wakefulness. Annu. Rev. Neurosci. 24, 429–458.
Sutcliffe J. G. and de Lecea L. (2002) The hypocretins: setting the arousal threshold. Nat. Rev. Neurosci. 3, 339–349.
Scammell T. E. (2003) The neurobiology, diagnosis, and treatment of narcolepsy. Ann. Neurol. 53, 154–166.
Lin L., Faraco J., Li R., et al. (1999) The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 98, 365–376.
Chemelli R. M., Willie J. T., Sinton C. M., et al. (1999) Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98, 437–451.
Willie J. T., Chemelli R. M., Sinton C. M., et al. (2003) Distinct narcolepsy syndromes in Orexin receptor-2 and Orexin null mice: molecular genetic dissection of Non-REM and REM sleep regulatory processes. Neuron 38, 715–730.
Hara J., Beuckmann C. T., Nambu T., et al. (2001) Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron 30, 345–354.
Beuckmann C. T., Sinton C. M., Williams S. C., et al. (2004) Expression of a poly-glutamine-ataxin-3 transgene in orexin neurons induces narcolepsy-cataplexy in the rat. J. Neurosci. 24, 4469–4477.
Mieda M., Willie J. T., Hara J., Sinton C. M., Sakurai T., and Yanagisawa M. (2004) Orexin peptides prevent cataplexy and improve wakefulness in an orexin neuron-ablated model of narcolepsy in mice. Proc. Natl. Acad. Sci. USA 101, 4649–4654.
Yamanaka A., Beuckmann C. T., Willie J. T., et al. (2003) Hypothalamic orexin neurons regulate arousal according to energy balance in mice. Neuron 38, 701–713.
Owens M. J. and Nemeroff C. B. (1991) Physiology and pharmacology of corticotropin-releasing factor. Pharmacol. Rev. 43, 425–473.
Lubkin M. and Stricker-Krongrad A. (1998) Independent Feeding and Metabolic Actions of Orexins in Mice. Biochem. Biophys. Res. Commun. 253, 241–245.
Dube M. G., Kalra S. P., and Kalra P. S. (1999) Food intake elicited by central administration of orexins/hypocretins: identification of hypothalamic sites of action. Brain Res. 842, 473–477.
Haynes A. C., Jackson B., Overend P., et al. (1999) Effects of single and chronic intracere-broventricular administration of the orexins on feeding in the rat [In Process Citation]. Peptides 20, 1099–1105.
Sweet D. C., Levine A. S., Billington C. J., and Kotz C. M. (1999) Feeding response to central orexins. Brain Res. 821, 535–538.
Espana R. A., Plahn S., and Berridge C. W. (2002) Circadian-dependent and circadian-independent behavioral actions of hypocretin/orexin. Brain Res. 943, 224–236.
Estabrooke I. V., McCarthy M. T., Ko E., et al. (2001) Fos expression in orexin neurons varies with behavioral state. J. Neurosci. 21, 1656–1662.
Zeitzer J. M., Buckmaster C. L., Lyons D. M., and Mignot E. (2004) Locomotor-dependent and -independent components to hypocretin-1 (orexin A) regulation in sleep-wake consolidating monkeys. J. Physiol. 557, 1045–1053.
Balasko M., Szelenyi Z., and Szekely M. (1999) Central thermoregulatory effects of neuropeptide Y and orexin A in rats. Acta. Physiol. Hung. 86, 219–222.
Yoshimichi G., Yoshimatsu H., Masaki T., and Sakata T. (2001) Orexin-A regulates body temperature in coordination with arousal status. Exp. Biol. Med. (Maywood) 226, 468–476.
Dun N. J., Le Dun S., Chen C. T., Hwang L. L., Kwok E. H., and Chang J. K. (2000) Orexins: a role in medullary sympathetic outflow. Regul. Pept. 96, 65–70.
Shirasaka T., Nakazato M., Matsukura S., Takasaki M., and Kannan H. (1999) Sympathetic and cardiovascular actions of orexins in conscious rats. Am. J. Physiol. 277, R1780-R1785.
Kayaba Y., Nakamura A., Kasuya Y., et al. (2003) Attenuated defense response and low basal blood pressure in orexin knockout mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. 285, R581-R593.
Blanco M., Garcia-Caballero T., Fraga M., et al. (2002) Cellular localization of orexin receptors in human adrenal gland, adrenocortical adenomas and pheochromocytomas. Regul. Pept. 104, 161–165.
Lopez M., Senaris R., Gallego R., et al. (1999) Orexin receptors are expressed in the adrenal medulla of the rat. Endocrinology 140, 5991–5994.
Nanmoku T., Isobe K., Sakurai T., et al. (2002) Effects of orexin on cultured porcine adrenal medullary and cortex cells. Regul. Pept. 104, 125–130.
Sakamoto F., Yamada S., and 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. Regul. Pept. 118, 183–191.
Samson W. K., Taylor M. M., Follwell M., and Ferguson A. V. (2002) Orexin actions in hypothalamic paraventricular nucleus: physiological consequences and cellular correlates. Regul. Pept. 104, 97–103.
Kuru M., Ueta Y., Serino R., et al. (2000) Centrally administered orexin/hypocretin activates HPA axis in rats. Neuroreport 11, 1977–1980.
Ida T., Nakahara K., Murakami T., Hanada R., Nakazato M., and Murakami N. (2000) Possible involvement of orexin in the stress reaction in rats. Biochem. Biophys. Res. Commun. 270, 318–323.
Ida T., Nakahara K., Kuroiwa T., et al. (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.
Jaszberenyi M., Bujdoso E., Pataki I.. and Telegdy G. (2000) Effects of orexins on the hypothalamic-pituitary-adrenal system. J. Neuroendocrinol. 12, 1174–1178.
Espana R. A., Valentino R. J., and Berridge C. W. (2002) Fos expression in hypocretin-1 receptor-bearing and hypocretin-synthesizing neurons: effects of diurnal and nocturnal waking, stress and hcrt-1 administration. Abstract Viewer/Itinerary Planner. Society for Neuroscience., Program No. 776.5.
Martins P. J., D’Almeida V., Pedrazzoli M., Lin L., Mignot E., and Tufik S. (2004) Increased hypocretin-1 (orexin-a) levels in cerebrospinal fluid of rats after short-term forced activity. Regul. Pept. 117, 155–158.
Reyes T. M., Walker J. R., DeCino C., Hogenesch J. B., and Sawchenko P. E. (2003) Categorically distinct acute stressors elicit dissimilar transcriptional profiles in the paraventricular nucleus of the hypothalamus. J. Neurosci. 23, 5607–5616.
Stricker-Krongrad A., Richy S., and Beck B. (2002) Orexins/hypocretins in the ob/ob mouse: hypothalamic gene expression, peptide content and metabolic effects. Regul. Pept. 104, 11–20.
Winsky-Sommerer R., Yamanaka A., Diano S., et al. (2004) Interaction between the corticotropin-releasing factor system and hypocretins (orexins): a novel circuit mediating stress response. J. Neurosci. 24, 11,439–11,448.
Samson W. K. and Taylor M. M. (2001) Hypocretin/orexin suppresses corticotroph responsiveness in vitro. Am. J. Physiol. Regul. Integr. Comp. Physiol. 281, R1140–1145.
Lu X. Y., Bagnol D., Burke S., Akil H., and Watson S. J. (2000) Differential distribution and regulation of OX1 and OX2 orexin/hypocretin receptor messenger RNA in the brain upon fasting. Horm. Behav. 37, 335–344.
Shirasaka T., Miyahara S., Kunitake T., et al. (2001) Orexin depolarizes rat hypothalamic paraventricular nucleus neurons. Am. J. Physiol. Regul. Integr. Comp. Physiol. 281, R1114-R1118.
Follwell M. J. and Ferguson A. V. (2002) Cellular mechanisms of orexin actions on paraventricular nucleus neurones in rat hypothalamus. J. Physiol. 545, 855–867.
Horvath T. L., Diano S., and van den Pol A. N. (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.
Heilig M. (2004) The NPY system in stress, anxiety and depression. Neuropeptides 38, 213–224.
Adrian T. E., Allen J. M., Bloom S. R., et al. (1983) Neuropeptide Y distribution in human brain. Nature 306, 584–586.
Baldo B. A., Daniel R. A., Berridge C. W., and Kelley A. E. (2003) Overlapping distributions of orexin/hypocretin- and dopamine-beta-hydroxylase immunoreactive fibers in rat brain regions mediating arousal, motivation, and stress. J. Comp. Neurol. 464, 220–237.
Naveilhan P., Canals J. M., Valjakka A., Vartiainen J., Arenas E., and Ernfors P. (2001) Neuropeptide Y alters sedation through a hypothalamic Y1-mediated mechanism. Eur. J. Neurosci. 13, 2241–2246.
Bannon A. W., Seda J., Carmouche M., et al. (2000) Behavioral characterization of neuropeptide Y knockout mice. Brain Res. 868, 79–87.
Palmiter R. D., Erickson J. C., Hollopeter G., Baraban S. C., and Schwartz M. W. (1998) Life without neuropeptide Y. Rec. Prog. Horm. Res. 53, 163–199.
Karlsson R. M., Holmes A., Heilig M., and Crawley J. N. (2005) Anxiolytic-like actions of centrally-administered neuropeptide Y, but not galanin, in C57BL/6J mice. Pharmacol. Biochem. Behav. 80, 427–436.
Fu L. Y., Acuña-Goycolea C.. and van den Pol A. N. (2004) Neuropeptide Y inhibits hypocretin/orexin neurons by multiple presynaptic and postsynaptic mechanisms: tonic depression of the hypothalamic arousal system. J. Neurosci. 24, 8741–8751.
Kalivas P. W. and McFarland K. (2003) Brain circuitry and the reinstatement of cocaine-seeking behavior. Psychopharmacology (Berl.) 168, 44–56.
Koob G. F. (1999) Stress, corticotropin-releasing factor, and drug addiction. Ann. NY Acad. Sci. 897, 27–45.
Koob G. F., Sanna P. P., and Bloom F. E. (1998) Neuroscience of addiction. Neuron 21, 467–476.
Koob G. F. (2000) Neurobiology of addiction. Toward the development of new therapies. Ann. NY Acad. Sci. 909, 170–185.
Koob G. F. (1999) The role of the striatopallidal and extended amygdala systems in drug addiction. Ann. NY Acad. Sci. 877, 445–460.
Korotkova T. M., Eriksson K. S., Haas H. L., and Brown R. E. (2002) Selective excitation of GABAergic neurons in the substantia nigra of the rat by orexin/hypocretin in vitro. Regul. Pept. 104, 83–89.
Martin G., Fabre V., Siggins G. R., and de Lecea L. (2002) Interaction of the hypocretins with neurotransmitters in the nucleus accumbens. Regul. Pept. 104, 111–117.
Fadel J. and Deutch A. Y. (2002) Anatomical substrates of orexin-dopamine interactions: lateral hypothalamic projections to the ventral tegmental area. Neuroscience 111, 379–387.
Olds J. and Milner P. (1954) Positive reinforcement produced by electrical stimulation of septal area and other regions of rat brain. J. Comp. Physiol. Psychol. 47, 419–427.
Anand B. K. and Brobeck J. R. (1951) Localization of a feeding center in the hypothalamus of the rat. Proc. Soc. Exp. Biol. Med. 77, 323,324.
Gallistel C. R., Shizgal P., and Yeomans J. S. (1981) A portrait of the substrate for self-stimulation. Psychol. Rev. 88, 228–273.
Sarnyai Z., Shaham Y., and Heinrichs S. C. (2001) The role of corticotropin-releasing factor in drug addiction. Pharmacol. Rev. 53, 209–243.
Stricker-Krongrad A. and Beck B. (2002) Modulation of hypothalamic hypocretin/orexin mRNA expression by glucocorticoids. Biochem. Biophys. Res. Commun. 296, 129–133.
Boutrel B., Kenny P. J., Winsky-Sommerer R., Markou A., Koob G. F., and de Lecea L. (2003) Soc. Neurosci. Abstr. 879.7.
Macey D. J., Koob G. F. and Markou A. (2000) CRF and urocortin decreased brain stimulation reward in the rat: reversal by a CRF receptor antagonist. Brain Res. 866, 82–91.
Georgescu D., Zachariou V., Barrot M., et al. (2003) Involvement of the lateral hypothalamic peptide orexin in morphine dependence and withdrawal. J. Neurosci. 23, 3106–3111.
Heinrichs S. C. and Koob G. F. (2004) Corticotropin-releasing factor in brain: a role in activation, arousal, and affect regulation. J. Pharmacol. Exp. Ther. 311, 427–440.
Aston-Jones G. and Harris G. C. (2004) Brain substrates for increased drug seeking during protracted withdrawal. Neuropharmacology 47(Suppl 1), 167–179.
Shalev U., Morales M., Hope B., Yap J. and Shaham Y. (2001) Time-dependent changes in extinction behavior and stress-induced reinstatement of drug seeking following withdrawal from heroin in rats. Psychopharmacology (Berl.) 156, 98–107.
Lopez M., Seoane L., Garcia M. C., et al. (2000) Leptin regulation of prepro-orexin and orexin receptor mRNA levels in the hypothalamus. Biochem. Biophys. Res. Commun. 269, 41–45.
Yamamoto Y., Ueta Y., Date Y., et al. (1999) Down regulation of the prepro-orexin gene expression in genetically obese mice. Brain Res. Mol. Brain Res. 65, 14–22.
Cai X. J., Lister C. A., Buckingham R. E., et al. (2000) Down-regulation of orexin gene expression by severe obesity in the rats: studies in Zucker fatty and zucker diabetic fatty rats and effects of rosiglitazone. Brain Res. Mol. Brain Res. 77, 131–137.
Komaki G., Matsumoto Y., Nishikata H., et al. (2001) Orexin-A and leptin change inversely in fasting non-obese subjects. Eur. J. Endocrinol. 144, 645–651.
Rauch M., Riediger T., Schmid H. A., and Simon E. (2000) Orexin A activates leptin-responsive neurons in the arcuate nucleus. Pflugers Arch. 440, 699–703.
Thiele T. E., Sparta D. R., Hayes D. M., and Fee J. R. (2004) A role for neuropeptide Y in neurobiological responses to ethanol and drugs of abuse. Neuropeptides 38, 235–243.
Valdez G. R. and Koob G. F. (2004) Allostasis and dysregulation of corticotropin-releasing factor and neuropeptide Y systems: implications for the development of alcoholism. Pharmacol. Biochem. Behav. 79, 671–689.
Koob G. F. (2003) Alcoholism: allostasis and beyond. Alcohol Clin. Exp. Res. 27, 232–243.
Roy A. and Pandey S. C. (2002) The decreased cellular expression of neuropeptide Y protein in rat brain structures during ethanol withdrawal after chronic ethanol exposure. Alcohol Clin. Exp. Res. 26, 796–803.
Thiele T. E., Marsh D. J., Ste Marie L., Bernstein I. L., and Palmiter R. D. (1998) Ethanol consumption and resistance are inversely related to neuropeptide Y levels. Nature 396, 366–369.
Koob G. F., Ahmed S. H., Boutrel B., et al. (2004) Neurobiological mechanisms in the transition from drug use to drug dependence. Neurosci. Biobehav. Rev. 27, 739–749.
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Winsky-Sommerer, R., Boutrel, B. & de Lecea, L. Stress and arousal. Mol Neurobiol 32, 285–294 (2005). https://doi.org/10.1385/MN:32:3:285
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DOI: https://doi.org/10.1385/MN:32:3:285