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Gene Review

Hcrt  -  hypocretin

Rattus norvegicus

Synonyms: Hypocretin, Orexin, Ox, Ppox
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Disease relevance of Hcrt


Psychiatry related information on Hcrt


High impact information on Hcrt

  • Orexin/hypocretin-containing neurons in the lateral hypothalamus project to the VTA, and behavioral studies have suggested that orexin neurons play an important role in motivation, feeding, and adaptive behaviors [8].
  • We found that Hcrt cells have broad action potentials with elongated later positive deflections that distinguish them from adjacent antidromically identified cells [5].
  • By this mechanism, the hypocretin projection to prefrontal cortex may play a larger role in prefrontal or "executive" aspects of alertness and attention than previously anticipated [9].
  • Hypocretin-containing neurons project throughout the brain, with a prominent input to basal forebrain structures involved in motivation, reward, and stress [10].
  • Hypocretin-induced reinstatement of cocaine seeking was prevented by blockade of noradrenergic and corticotropin-releasing factor systems, suggesting that Hcrt-1 reinstated drug seeking through induction of a stress-like state [10].

Chemical compound and disease context of Hcrt

  • Orexin/hypocretin neurons in the lateral hypothalamus and adjacent perifornical area (LH/PFA) innervate midbrain dopamine (DA) neurons that project to corticolimbic sites and subserve psychostimulant-induced locomotor activity [11].
  • Using two-photon imaging in prefrontal brain slices, we show that nicotine and the wakefulness neuropeptide hypocretin (orexin) excite the same identified synapses of the thalamocortical arousal pathway within the prefrontal cortex [12].
  • CONCLUSION: The present data indicate that a large fall in plasma glucose in early phase of acute hypoglycemia does not represent an appropriate stimulus for massive activation of HCRT neurons in the LHA of rats [4].

Biological context of Hcrt

  • Evidence for a role for Hcrt in food intake regulation is inconsistent [6].
  • These results indicate that the Hcrt system modulates ingestive behaviors but does not play a necessary role in the entrainment or expression of food-anticipatory circadian rhythms [13].
  • Our previous experimental work on these neurons showed that they may be involved in energy metabolism and water balance, which is in agreement with the current literature about Hcrt functions [14].
  • The high concentration of unconjugated saporin produced some loss of neuronal nuclei-immunoreactive (NeuN-ir) neurons and hypocretin immunoreactive neurons, but only a transient increase in non-rapid eye movement sleep [15].
  • Hypocretin 2 (orexin B) is a hypothalamic neuropeptide thought to be involved in regulating energy homeostasis, autonomic function, arousal, and sensory processing [16].

Anatomical context of Hcrt


Associations of Hcrt with chemical compounds

  • Hcrt also has a major role in modulating the release of glutamate and other amino acid transmitters [6].
  • To see if these neurons are similarly or differentially modulated by neurotransmitters of the major brainstem arousal systems, the effects of noradrenaline (NA) and carbachol, a cholinergic agonist, were examined on identified Hcrt/Orx and MCH neurons in rat hypothalamic slices [21].
  • This result together with the previously reported stimulation of Hcrt expression by insulin confirms that Hcrt neurons, but not MCH neurons, are sensitive to glucose availability and suggests that they respond through different mechanisms and/or different pathways to intracellular glucopenia and hypoglycemic conditions [22].
  • Thus Hcrt effects within the septum should increase hippocampal acetylcholine release and thereby promote hippocampal arousal [23].
  • The Hcrt effect was dependent on external Na(+), reduced by external Ba(2+), and also reduced in recordings with CsCl-containing electrodes, suggesting a dual underlying ionic mechanism that involved inhibition of a K(+) current, presumably an inward rectifier, and a Na(+)-dependent component [23].

Regulatory relationships of Hcrt


Other interactions of Hcrt


Analytical, diagnostic and therapeutic context of Hcrt

  • We confirmed by in situ hybridization that prepro-Hcrt/OX mRNA expression is restricted to the lateral hypothalamus area with extension to the perifornical nucleus and the posterior hypothalamic area [17].
  • Lateral hypothalamic prepro-Hcrt/OX mRNA expression was decreased by 50% after adrenalectomy (99.8+/-5.0 vs 49.2+/-4.4 nCi/g, p<0.01) [17].
  • In the present in vivo microdialysis study we have investigated the effect of intravenous administration of Hcrt-1 (orexin-A) to anaesthetized rats on glutamate and GABA release in the amygdala, a region with moderate Hcrt innervation, and in the cerebellar cortex, a region with sparse or no Hcrt innervation [18].
  • The roles played by these peptide/protein in OX/Hcrt neurons are still unclear.Double immunocytochemical stainings highlight putative somasomatic, axosomatic and axodendritic contacts between OX/Hcrt and MCH neurons [29].
  • Stereological analysis of the hypothalamic hypocretin/orexin neurons in an animal model of depression [30].


  1. Transplantation of hypocretin neurons into the pontine reticular formation: preliminary results. Arias-Carrión, O., Murillo-Rodriguez, E., Xu, M., Blanco-Centurion, C., Drucker-Colín, R., Shiromani, P.J. Sleep. (2004) [Pubmed]
  2. Increased and decreased muscle tone with orexin (hypocretin) microinjections in the locus coeruleus and pontine inhibitory area. Kiyashchenko, L.I., Mileykovskiy, B.Y., Lai, Y.Y., Siegel, J.M. J. Neurophysiol. (2001) [Pubmed]
  3. Increased hypocretin-1 levels in cerebrospinal fluid after REM sleep deprivation. Pedrazzoli, M., D'Almeida, V., Martins, P.J., Machado, R.B., Ling, L., Nishino, S., Tufik, S., Mignot, E. Brain Res. (2004) [Pubmed]
  4. Activation of FOS in hypocretin neurons of the rat by insulin-induced hypoglycemia. Kiss, A., Jezova, D., Mikkelsen, J.D. Endocrine regulations. (2004) [Pubmed]
  5. Behavioral correlates of activity in identified hypocretin/orexin neurons. Mileykovskiy, B.Y., Kiyashchenko, L.I., Siegel, J.M. Neuron (2005) [Pubmed]
  6. Hypocretin (orexin): role in normal behavior and neuropathology. Siegel, J.M. Annual review of psychology. (2004) [Pubmed]
  7. The hypocretins: excitatory neuromodulatory peptides for multiple homeostatic systems, including sleep and feeding. Sutcliffe, J.G., de Lecea, L. J. Neurosci. Res. (2000) [Pubmed]
  8. Orexin A in the VTA is critical for the induction of synaptic plasticity and behavioral sensitization to cocaine. Borgland, S.L., Taha, S.A., Sarti, F., Fields, H.L., Bonci, A. Neuron (2006) [Pubmed]
  9. Hypocretin (orexin) induces calcium transients in single spines postsynaptic to identified thalamocortical boutons in prefrontal slice. Lambe, E.K., Aghajanian, G.K. Neuron (2003) [Pubmed]
  10. Role for hypocretin in mediating stress-induced reinstatement of cocaine-seeking behavior. Boutrel, B., Kenny, P.J., Specio, S.E., Martin-Fardon, R., Markou, A., Koob, G.F., de Lecea, L. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  11. Dopaminergic regulation of orexin neurons. Bubser, M., Fadel, J.R., Jackson, L.L., Meador-Woodruff, J.H., Jing, D., Deutch, A.Y. Eur. J. Neurosci. (2005) [Pubmed]
  12. Hypocretin and nicotine excite the same thalamocortical synapses in prefrontal cortex: correlation with improved attention in rat. Lambe, E.K., Olausson, P., Horst, N.K., Taylor, J.R., Aghajanian, G.K. J. Neurosci. (2005) [Pubmed]
  13. Food- and light-entrained circadian rhythms in rats with hypocretin-2-saporin ablations of the lateral hypothalamus. Mistlberger, R.E., Antle, M.C., Kilduff, T.S., Jones, M. Brain Res. (2003) [Pubmed]
  14. Preprohypocretin (orexin) and prolactin-like immunoreactivity are coexpressed by neurons of the rat lateral hypothalamic area. Risold, P.Y., Griffond, B., Kilduff, T.S., Sutcliffe, J.G., Fellmann, D. Neurosci. Lett. (1999) [Pubmed]
  15. Effects of lateral hypothalamic lesion with the neurotoxin hypocretin-2-saporin on sleep in Long-Evans rats. Gerashchenko, D., Blanco-Centurion, C., Greco, M.A., Shiromani, P.J. Neuroscience (2003) [Pubmed]
  16. Selective enhancement of excitatory synaptic activity in the rat nucleus tractus solitarius by hypocretin 2. Smith, B.N., Davis, S.F., Van Den Pol, A.N., Xu, W. Neuroscience (2002) [Pubmed]
  17. Modulation of hypothalamic hypocretin/orexin mRNA expression by glucocorticoids. Stricker-Krongrad, A., Beck, B. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  18. Intravenously administered hypocretin-1 alters brain amino acid release: an in vivo microdialysis study in rats. John, J., Wu, M.F., Kodama, T., Siegel, J.M. J. Physiol. (Lond.) (2003) [Pubmed]
  19. Hypocretin/orexin suppresses corticotroph responsiveness in vitro. Samson, W.K., Taylor, M.M. Am. J. Physiol. Regul. Integr. Comp. Physiol. (2001) [Pubmed]
  20. Hypocretin increases impulse flow in the septohippocampal GABAergic pathway: implications for arousal via a mechanism of hippocampal disinhibition. Wu, M., Zhang, Z., Leranth, C., Xu, C., van den Pol, A.N., Alreja, M. J. Neurosci. (2002) [Pubmed]
  21. Opposite effects of noradrenaline and acetylcholine upon hypocretin/orexin versus melanin concentrating hormone neurons in rat hypothalamic slices. Bayer, L., Eggermann, E., Serafin, M., Grivel, J., Machard, D., Muhlethaler, M., Jones, B.E. Neuroscience (2005) [Pubmed]
  22. Alteration of the expression of the hypocretin (orexin) gene by 2-deoxyglucose in the rat lateral hypothalamic area. Bayer, L., Colard, C., Nguyen, N.U., Risold, P.Y., Fellmann, D., Griffond, B. Neuroreport (2000) [Pubmed]
  23. Hypocretin/orexin innervation and excitation of identified septohippocampal cholinergic neurons. Wu, M., Zaborszky, L., Hajszan, T., van den Pol, A.N., Alreja, M. J. Neurosci. (2004) [Pubmed]
  24. Synaptic interaction between hypocretin (orexin) and neuropeptide Y cells in the rodent and primate hypothalamus: a novel circuit implicated in metabolic and endocrine regulations. Horvath, T.L., Diano, S., van den Pol, A.N. J. Neurosci. (1999) [Pubmed]
  25. Activation of a subpopulation of orexin/hypocretin-containing hypothalamic neurons by GABAA receptor-mediated inhibition of the nucleus accumbens shell, but not by exposure to a novel environment. Baldo, B.A., Gual-Bonilla, L., Sijapati, K., Daniel, R.A., Landry, C.F., Kelley, A.E. Eur. J. Neurosci. (2004) [Pubmed]
  26. Both corticotropin releasing factor and neuropeptide Y are involved in the effect of orexin (hypocretin) on the food intake in rats. Ida, T., Nakahara, K., Kuroiwa, T., Fukui, K., Nakazato, M., Murakami, T., Murakami, N. Neurosci. Lett. (2000) [Pubmed]
  27. Leptin receptor- and STAT3-immunoreactivities in hypocretin/orexin neurones of the lateral hypothalamus. Håkansson, M., de Lecea, L., Sutcliffe, J.G., Yanagisawa, M., Meister, B. J. Neuroendocrinol. (1999) [Pubmed]
  28. Effect of 2-mercaptoacetate and 2-deoxy-D-glucose administration on the expression of NPY, AGRP, POMC, MCH and hypocretin/orexin in the rat hypothalamus. Sergeyev, V., Broberger, C., Gorbatyuk, O., Hökfelt, T. Neuroreport (2000) [Pubmed]
  29. Orexin/hypocretin neurons: chemical phenotype and possible interactions with melanin-concentrating hormone neurons. Bayer, L., Mairet-Coello, G., Risold, P.Y., Griffond, B. Regul. Pept. (2002) [Pubmed]
  30. Stereological analysis of the hypothalamic hypocretin/orexin neurons in an animal model of depression. Allard, J.S., Tizabi, Y., Shaffery, J.P., Trouth, C.O., Manaye, K. Neuropeptides (2004) [Pubmed]
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