A commentary on the neurobiology of the hypocretin/orexin system

Neuropsychopharmacology

Volumn 25, Issue 5, 2001, Pages S5-S13

  Mignot, Emmanuel ^a  

^a Stanford California and Cofounder   (United States)

Author keywords

Energy metabolism; Hypocretin; Mood regulation; Narcolepsy; Orexin; Sleep

Indexed keywords

G PROTEIN COUPLED RECEPTOR; NEUROPEPTIDE; NEUROTRANSMITTER; OREXIN;

APPETITE; BEHAVIOR; CELLULAR DISTRIBUTION; CIRCADIAN RHYTHM; DOG; ENERGY METABOLISM; EXCITATORY POSTSYNAPTIC POTENTIAL; GENETIC CODE; HUMAN; HYPOTHALAMUS; MONOAMINE NERVE CELL; NARCOLEPSY; NEUROBIOLOGY; NEUROENDOCRINE SYSTEM; NEUROTRANSMISSION; NONHUMAN; PRIORITY JOURNAL; PSYCHIATRY; REVIEW; SLEEP DEPRIVATION; SLEEP DISORDER; SLEEP PATTERN; WAKEFULNESS;

ANIMALS; APPETITE REGULATION; CARRIER PROTEINS; CIRCADIAN RHYTHM; ENERGY METABOLISM; HUMANS; HYPOTHALAMUS; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; NARCOLEPSY; NEUROPEPTIDES; NEUROTRANSMITTER AGENTS; SLEEP;

EID: 0034782624     PISSN: 0893133X     EISSN: 1740634X     Source Type: Journal    
DOI: 10.1016/S0893-133X(01)00316-5     Document Type: Article

References (96)

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2. Baker TL, Dement WC (1985): Canine narcolepsy-cataplexy syndrome: evidence for an inherited monoaminergic-cholinergic imbalance. In DJ McGinty, R Drucker-Colin, A Morisson, PL Parmengiani (eds), Brain mechanisms of sleep. New York, Raven Press, l99-233.
3. Bernasconi R, Mathivet P, Bischoff S, Marescaux C (1999): Gamma-hydroxybutyric acid: an endogenous neuro-modulator with abuse potential? Trends PharmacolSci 20:135-141
4. Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, Lee C, Richardson JA, Williams SC, Xiong Y, Kisanuki Y, Fitch TE, Nakazato M, Hammer RE, Saper CB, Yanagisawa M (1999): Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98:437-451
5. Dantz B, Edgar DM, Dement WC (1994): Circadian rhythms in narcolepsy: studies on a 90 minute day. Electroen-cephalogrClinNeurophysiol 90:24-35
6. de Lecea L, Kilduff TS, Peyron C, Gao X-B, Foye PE, Daniel-son pE, Fukuhara C, Battenberg ELF, Gautvik VT, Bar-lett FS, Frankel WN, van den Pol AN, Bloom FE, Gautvik M, Sutcliffe JG (1998): The hypocretins: Hypo-thalamus-specific peptides with neuroexcitatoryactiv-ity. ProcNatlAcadSci USA 95:322-327
7. Edgar DM, Dement WC, Fuller CA (1993): Effect of SCN lesions on sleep in squirrel monkeys: evidence for oppo-nent processes in sleep-wake regulation. J Neurosci 13:1065-1079
8. Estabrooke IV, McCarthy MT, Ko E, Chou TC, Chemelli RM, Yanagisawa M, Saper CB, Scammell TE (2001): Fos expression in orexin neurons varies with behavioral state. J Neurosci 21:1656-1662
9. Fujiki N, Yoshida Y, Ripley B, Honda K, Mignot E, Nishino S (2001a): Changes in CSF hypocretin-1 (orexin A) levels in rats across 24 hours and in response to food deprivation. Neuroreport 12:993-997
10. Fujiki N, Yoshida Y, Ripley B, Mignot E, Nishino S (2001b): Effect of systemic and central administration of hypo-cretin-1 in narcoleptic (hcrtr2 mutated) and control dogs. Sleep 24 (suppl):A96-A97
11. Gillin JC (1983): The sleep therapies of depression. Prog Neuropsychopharmacol Biol Psychiatry 7:351-364
12. 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 USA 96:10911-10916
13. Hara J, Beuckmann CT, Nambu T, Willie JT, Chemelli RM, Sinton CM, Sugiyama F, Yagami K, Goto K, Yanagisawa M, Sakurai T (2001): Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron 30:345-354
14. Higushi T, Takahashi Y, Takahashi K, Nimi Y, Miyasita A (1979): Twenty-four hour secretatory patterns of growth hormone, prolactive, and cortisol in narcolepsy. J Clin Endocrinol Metabolism 49:197-204
15. Hungs M, Mignot E (2001): Hypocretin/orexin, sleep and narcolepsy. Bioessays 23:397-408
16. Kilduff TS, Peyron C (2000): The hypocretin/orexin ligand-receptor system: implications for sleep and sleep disorders. Trends Neurosci 23:359-365
17. Kisanuki YY, Chemelli RM, Sinton CM, Williams SC, Rich-ardson JA, Hammer RE, Yanagisawa M (2000): The role of orexin receptor Type-1 (OX1R) in the regulation of sleep. Sleep 23(Suppl. 2):A91
18. 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
19. Lubkin M, Stricker-KrongradA (1998): Independent feeding and metabolic actions of orexins in mice. Biochem Bio-phys Res Commun 253:241-245
20. McCarley RW, Massaquoi SG (1992): Neurobiological struc-ture of the revised limit cycle reciprocal interaction model of REM cycle control. J Sleep Res 1:132-137
21. Marcus JN, Aschkenasi CJ, Lee CE, Chemelli RM, Saper CB, Yanagisawa M, Elmquist JK (2001): Differential expression of orexin receptors 1 and 2 in the rat brain. J Comp Neurol 435:6-25
22. Mignot E, Renaud A, Nishino S, Arrigoni J, Guilleminault C, Dement WC (1993a): Canine cataplexy is preferentially controlled by adrenergic mechanisms: evidence using monoamine selective uptake inhibitors and release enhancers. Psychopharmacology 113:76-82
23. Mignot E, Nishino S, Sharp LH, Arrigoni J, Siegel JM, Reid MS, Edgar DM, Ciaranello RD, Dement WC (1993b): Heterozygosity at the canarc-1 locus can confer suscep-tibility for narcolepsy: induction of cataplexy in het-erozygous asymptomatic dogs after administration of a combination of drugs acting on monoaminergic and cholinergic systems. J Neurosci 13:1057-1064
24. Mignot E (1998): Genetic and familial aspects of narcolepsy. Neurology 50(Suppl 1):S16-S22
25. Mignot E, Lin L, Rogers W, Honda Y, Qiu X, Lin X, Okun M, Hohjoh H, Miki T, Hsu S, Leffell M, Grumet F, Fernan-dez-Vina M, Honda M, Risch N (2001): Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cata-plexy in three ethnic groups. Am J Hum Genet 68:686-699
26. Mignot E (2001): A hundred years of narcolepsy research. Arch ItalBiol 139:207-220
27. Miller JD, Faull KF, Bowersox SS, Dement WC (1990): CNS monoamines and their metabolites in canine narco-lepsy: a replication study. Brain Res 509:169-171
28. Nakamura T, Uramura K, Nambu T, Yada T, Goto K, Yanag-isawa M, Sakurai T (2000): Orexin-induced hyperlocomo-tion and stereotypy are mediated by the dopaminergic system. Brain Res 873:181-187
29. Nishino S, Mignot E (1997): Pharmacological aspects of human and canine narcolepsy. ProgNeurobiol 52:27-78
30. Nishino S, Mao J, Sampathkumaran R, Shelton J, Mignot E (1998): Increased dopaminergic transmission mediates the wake-promoting effects of CNS stimulants. Sleep Res Online 1:49-61
31. Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E (2000): Hypocretin (orexin) deficiency in human narco-lepsy. Lancet 355:39-40
32. Nishino S, Honda K, Fujuki N, Wurtz SW, Chang M, Sakurai E, Kato M, Watanabe T, Mignot E, Yanai (2001): The role of histamine in a hypocretin (orexin) deficient sleep disorder narcolepsy. Sleep 24(suppl): A23-A24
33. Overeem S, Mignot E, Van Djik G, Lammers (2001): Narco-lepsy: Clinical features, new pathophysiologic insight and future perspectives. J Clin Neurophysiology 18: 78-105
34. 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 early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nature Med 6:991-997
35. Rechtschaffen A, Bergmann BM (1995): Sleep deprivation in the rat by the disk-over-water method. Behav Brain Res 69:55-63.
36. Ripley B, Fujiki N, Okura M, Mignot E, Nishino S (2001a): Hypocretin Levels in Sporadic and Familial Canine nar-colepsy. Neurobiol Dis 8:525-534
37. Ripley B, Benson KL, Zarcone VP, Mignot E, Nishino S (2001b): CSF hypocretin-1 levels in schizophrenics and controls: relationship to sleep architecture. Sleep 24 (suppl):A117
38. Rodgers RJ, Halford JC, Nunes de Souza RL, Canto de Souza AL, Piper DC, Arch JR, Upton N, Porter RA, Johns A, Blundell JE (2001): SB-334867, a selective orexin-1 recep-tor antagonist, enhances behavioral satiety and blocks the hyperphagic effect of orexin-A in rats. Eur J Neuro-sci 13:1444-1452
39. Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richardson 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 neuropep-tides and G protein-coupled receptors that regulate feeding behavior. Cell 92:573-585
40. Samson WK, Goswell B, Chang JK, Resch ZT, Murphy TC (1999): Cardiovascular regulatory actions of the hypo-cretins in the brain. Brain Res 831:248-253
41. Shirasaka T, Nakazato M, Matsukura S, Takasaki M, Kannan H (1999): Sympathetic and cardiovascular actions of orexins in conscious rats. Am J Physiol 277:R1780-R1785
42. Schuld A, Hebebrand J, Geller F, Pollmacher T (2000): Increased body-mass index in patients with narcolepsy. Lancet 355:1274-1275
43. Sutcliffe JG, de Lecea L (2000): The hypocretins: excitatory neu-romodulatory peptides for multiple homeostatic systems, including sleep and feeding. J Neurosci Res 62:161-168.
44. Thannickal TC, Moore RY, Nienhuis R, Ramanathan L, Gulyani S, Aldrich M, Cornford M, Siegel JM (2000): Reduced number of hypocretin neurons in human nar-colepsy. Neuron 27:469-474
45. Tokita S, Chemelli RM, Willie WT, Yanagisawa M (2001): Behavioral characterization of orexin-2 receptor knockout mice. Sleep 24(suppl): A21
46. 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
47. Wisor JP, Nishino S, Sora I, Uhl GH, Mignot E, Edgar DM (2001): Dopaminergic role in stimulant-induced wakefulness. J Neurosci 21:1787-1794
48. Yoshida Y, Fujuki N, Nakajima T, Ripley B, Matsummara H, Yonega H, Mignot E, Nishino S (2002): Fluctuation of extracellular hypocretin-1 (orexin-A) levels in the rat in relation to the light dark cycle and sleep/wake activi-ties. Eur J Neurosci (in press)
49. Abrahamson EE, Leak RK, Moore RY (2001): The suprachi-asmatic nucleus projects to posterior hypothalamic arousal systems. Neuroreport 12:435-440
50. Baker TL, Dement WC (1985): Canine narcolepsy-cataplexy syndrome: evidence for an inherited monoaminergic-cholinergic imbalance. In DJ McGinty, R Drucker-Colin, A Morisson, PL Parmengiani (eds), Brain mechanisms of sleep. New York, Raven Press, l99-233.
51. Bernasconi R, Mathivet P, Bischoff S, Marescaux C (1999): Gamma-hydroxybutyric acid: an endogenous neuro-modulator with abuse potential? Trends PharmacolSci 20:135-141
52. Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, Lee C, Richardson JA, Williams SC, Xiong Y, Kisanuki Y, Fitch TE, Nakazato M, Hammer RE, Saper CB, Yanagisawa M (1999): Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98:437-451
53. Dantz B, Edgar DM, Dement WC (1994): Circadian rhythms in narcolepsy: studies on a 90 minute day. Electroen-cephalogrClinNeurophysiol 90:24-35
54. de Lecea L, Kilduff TS, Peyron C, Gao X-B, Foye PE, Daniel-son pE, Fukuhara C, Battenberg ELF, Gautvik VT, Bar-lett FS, Frankel WN, van den Pol AN, Bloom FE, Gautvik M, Sutcliffe JG (1998): The hypocretins: Hypo-thalamus-specific peptides with neuroexcitatoryactiv-ity. ProcNatlAcadSci USA 95:322-327
55. Edgar DM, Dement WC, Fuller CA (1993): Effect of SCN lesions on sleep in squirrel monkeys: evidence for oppo-nent processes in sleep-wake regulation. J Neurosci 13:1065-1079
56. Estabrooke IV, McCarthy MT, Ko E, Chou TC, Chemelli RM, Yanagisawa M, Saper CB, Scammell TE (2001): Fos expression in orexin neurons varies with behavioral state. J Neurosci 21:1656-1662
57. Fujiki N, Yoshida Y, Ripley B, Honda K, Mignot E, Nishino S (2001a): Changes in CSF hypocretin-1 (orexin A) levels in rats across 24 hours and in response to food deprivation. Neuroreport 12:993-997
58. Fujiki N, Yoshida Y, Ripley B, Mignot E, Nishino S (2001b): Effect of systemic and central administration of hypo-cretin-1 in narcoleptic (hcrtr2 mutated) and control dogs. Sleep 24 (suppl):A96-A97
59. Gillin JC (1983): The sleep therapies of depression. Prog Neuropsychopharmacol Biol Psychiatry 7:351-364
60. 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. ProcNatlAcadSci USA 96:10911-10916
61. Hara J, Beuckmann CT, Nambu T, Willie JT, Chemelli RM, Sinton CM, Sugiyama F, Yagami K, Goto K, Yanagisawa M, Sakurai T (2001): Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron 30:345-354
62. Higushi T, Takahashi Y, Takahashi K, Nimi Y, Miyasita A (1979): Twenty-four hour secretatory patterns of growth hormone, prolactive, and cortisol in narcolepsy. J Clin Endocrinol Metabolism 49:197-204
63. Hungs M, Mignot E (2001): Hypocretin/orexin, sleep and narcolepsy. Bioessays 23:397-408
64. Kilduff TS, Peyron C (2000): The hypocretin/orexin ligand-receptor system: implications for sleep and sleep disorders. Trends Neurosci 23:359-365
65. Kisanuki YY, Chemelli RM, Sinton CM, Williams SC, Rich-ardson JA, Hammer RE, Yanagisawa M (2000): The role of orexin receptor Type-1 (OX1R) in the regulation of sleep. Sleep 23(Suppl. 2):A91
66. 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
67. Lubkin M, Stricker-KrongradA (1998): Independent feeding and metabolic actions of orexins in mice. Biochem Bio-phys Res Commun 253:241-245
68. McCarley RW, Massaquoi SG (1992): Neurobiological struc-ture of the revised limit cycle reciprocal interaction model of REM cycle control. J Sleep Res 1:132-137
69. Marcus JN, Aschkenasi CJ, Lee CE, Chemelli RM, Saper CB, Yanagisawa M, Elmquist JK (2001): Differential expression of orexin receptors 1 and 2 in the rat brain. J Comp Neurol 435:6-25
70. Mignot E, Renaud A, Nishino S, Arrigoni J, Guilleminault C, Dement WC (1993a): Canine cataplexy is preferentially controlled by adrenergic mechanisms: evidence using monoamine selective uptake inhibitors and release enhancers. Psychopharmacology 113:76-82
71. Mignot E, Nishino S, Sharp LH, Arrigoni J, Siegel JM, Reid MS, Edgar DM, Ciaranello RD, Dement WC (1993b): Heterozygosity at the canarc-1 locus can confer suscep-tibility for narcolepsy: induction of cataplexy in het-erozygous asymptomatic dogs after administration of a combination of drugs acting on monoaminergic and cholinergic systems. J Neurosci 13:1057-1064
72. Mignot E (1998): Genetic and familial aspects of narcolepsy. Neurology 50(Suppl 1):S16-S22
73. Mignot E, Lin L, Rogers W, Honda Y, Qiu X, Lin X, Okun M, Hohjoh H, Miki T, Hsu S, Leffell M, Grumet F, Fernan-dez-Vina M, Honda M, Risch N (2001): Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cata-plexy in three ethnic groups. Am J Hum Genet 68:686-699
74. Mignot E (2001): A hundred years of narcolepsy research. Arch ItalBiol 139:207-220
75. Miller JD, Faull KF, Bowersox SS, Dement WC (1990): CNS monoamines and their metabolites in canine narco-lepsy: a replication study. Brain Res 509:169-171
76. Nakamura T, Uramura K, Nambu T, Yada T, Goto K, Yanag-isawa M, Sakurai T (2000): Orexin-induced hyperlocomo-tion and stereotypy are mediated by the dopaminergic system. Brain Res 873:181-187
77. Nishino S, Mignot E (1997): Pharmacological aspects of human and canine narcolepsy. ProgNeurobiol 52:27-78
78. Nishino S, Mao J, Sampathkumaran R, Shelton J, Mignot E (1998): Increased dopaminergic transmission mediates the wake-promoting effects of CNS stimulants. Sleep Res Online 1:49-61
79. Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E (2000): Hypocretin (orexin) deficiency in human narco-lepsy. Lancet 355:39-40
80. Nishino S, Honda K, Fujuki N, Wurtz SW, Chang M, Sakurai E, Kato M, Watanabe T, Mignot E, Yanai (2001): The role of histamine in a hypocretin (orexin) deficient sleep disorder narcolepsy. Sleep 24(suppl): A23-A24
81. Overeem S, Mignot E, Van Djik G, Lammers (2001): Narco-lepsy: Clinical features, new pathophysiologic insight and future perspectives. J Clin Neurophysiology 18: 78-105
82. 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 early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nature Med 6:991-997
83. Rechtschaffen A, Bergmann BM (1995): Sleep deprivation in the rat by the disk-over-water method. Behav Brain Res 69:55-63.
84. Ripley B, Fujiki N, Okura M, Mignot E, Nishino S (2001a): Hypocretin Levels in Sporadic and Familial Canine nar-colepsy. Neurobiol Dis 8:525-534
85. Ripley B, Benson KL, Zarcone VP, Mignot E, Nishino S (2001b): CSF hypocretin-1 levels in schizophrenics and controls: relationship to sleep architecture. Sleep 24 (suppl):A117
86. Rodgers RJ, Halford JC, Nunes de Souza RL, Canto de Souza AL, Piper DC, Arch JR, Upton N, Porter RA, Johns A, Blundell JE (2001): SB-334867, a selective orexin-1 recep-tor antagonist, enhances behavioral satiety and blocks the hyperphagic effect of orexin-A in rats. Eur J Neuro-sci 13:1444-1452
87. Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richardson 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 neuropep-tides and G protein-coupled receptors that regulate feeding behavior. Cell 92:573-585
88. Samson WK, Goswell B, Chang JK, Resch ZT, Murphy TC (1999): Cardiovascular regulatory actions of the hypo-cretins in the brain. Brain Res 831:248-253
89. Shirasaka T, Nakazato M, Matsukura S, Takasaki M, Kannan H (1999): Sympathetic and cardiovascular actions of orexins in conscious rats. Am J Physiol 277:R1780-R1785
90. Schuld A, Hebebrand J, Geller F, Pollmacher T (2000): Increased body-mass index in patients with narcolepsy. Lancet 355:1274-1275
91. Sutcliffe JG, de Lecea L (2000): The hypocretins: excitatory neu-romodulatory peptides for multiple homeostatic systems, including sleep and feeding. J Neurosci Res 62:161-168.
92. Thannickal TC, Moore RY, Nienhuis R, Ramanathan L, Gulyani S, Aldrich M, Cornford M, Siegel JM (2000): Reduced number of hypocretin neurons in human nar-colepsy. Neuron 27:469-474
93. Tokita S, Chemelli RM, Willie WT, Yanagisawa M (2001): Behavioral characterization of orexin-2 receptor knockout mice. Sleep 24(suppl): A21
94. 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
95. Wisor JP, Nishino S, Sora I, Uhl GH, Mignot E, Edgar DM (2001): Dopaminergic role in stimulant-induced wakefulness. J Neurosci 21:1787-1794
96. Yoshida Y, Fujuki N, Nakajima T, Ripley B, Matsummara H, Yonega H, Mignot E, Nishino S (2002): Fluctuation of extracellular hypocretin-1 (orexin-A) levels in the rat in relation to the light dark cycle and sleep/wake activi-ties. Eur J Neurosci (in press)