Past Projects

Our lab contributed to the series of discoveries in the pathophysiology of narcolepsy (see publications presented by the Center for Narcolepsy). In addition, we have:

  1. Identified the major neurotransmitter systems (i.e. adrenergic alpha-1b, alpha-2, dopaminergic D2/3 and cholinergic M2/3 receptor mechanisms) critical for pharmacological control of cataplexy in narcolepsy [1, 2, 3, 4, 5].
  2. Demonstrated preferential involvement of the adrenergic system for mediating anticataplectic effects of tricyclic antidepressants [6].
  3. Identified the presynaptic enhancement of dopaminergic system as the major mode of action of wake-promoting compounds currently available (amphetamine and modafinil) [7, 8, 9].
  4. Found that canine narcolepsy displays periodic leg movements during sleep (PLMS), similar to sleep related involuntary movements seen in human PLMS [10].
  5. Demonstrated that the midbrain (A9 and A10) and diencephalic (A11) dopaminergic nuclei are involved in the regulation of cataplexy in the canine model [11].
  6. Performed detailed analysis of sleep abnormalities in canine narcolepsy and cataplexy [12] and murine models of narcolepsy [13]. These results gave significant insights towards the primary symptoms of narcolepsy. 
  7. Characterized the diurnal fluctuation of hypocretin-1 in the CSF and extracellular microdialysis perfusates in freely-moving rats and proposed the model for the regulation of wake and sleep by the hypocretin system [14, 15].
  8. Demonstrated the interaction between the hypocretin and histamine systems and their involvement in sleep regulation [16, 17]. 
  9. Reported the histamine deficiency in hypocretin receptor 2-mutated narcoleptic Dobermans [18], as well as in human narcolepsy and other hypersomnia of central origins [19, 20].
  10. Conduct studies of hypocretin replacement therapy in hypocretin-receptor-mutated and ligand-deficient narcoleptic dogs [21].
  11. Proposed that narcolepsy may be a unique disease model to study links among fundamental hypothalamic functions in health. and disease [22]. 
  12. Characterized sleep phenotypes of a murine model human short sleeper (i.e. transgenic mouse of a human mutation in a transcriptional repressor (hDEC2-P385R) [23].

References:

  1. Nishino, S., et al. (1991). Dopamine D2 mechanisms in canine narcolepsy. J Neurosci 11: 2666-2671. 
  2. Nishino, S., et al. (1990). Effects of central alpha-2 adrenergic compounds on canine narcolepsy, a disorder of rapid eye movement sleep. J Pharmacol Exp Ther 253: p. 1145-1152. 
  3. Nishino, S., et al. (1993). Further characterization of the alpha-1 receptor subtype involved in the control of cataplexy in canine narcolepsy. J Pharmacol Exp Ther 264: p. 1079-1084. 
  4. Reid, M.S., et al. (1994). Cholinergic mechanisms in canine narcolepsy: I. Modulation of cataplexy via local drug administration into pontine reticular formation. Neuroscience 59: p. 511-522. 
  5. Nishino, S., et al. (1995). Muscle atonia is triggered by cholinergic stimulation of the basal forebrain: implication for the pathophysiology of canine narcolepsy. J Neurosci 15(7 Pt 1): p. 4806-4814. 
  6. Nishino, S., et al. (1993). Desmethyl metabolites of serotonergic uptake inhibitors are more potent for suppressing canine cataplexy than their parent compounds. Sleep 16(8): p. 706-12. 
  7. Nishino, S., et al. (1998). Increased dopaminergic transmission mediates the wake-promoting effects of CNS stimulants. Sleep Research Online 1: p. 49-61. http://www.sro.org/1998/Nishino/49/.
  8. Kanbayashi, T., et al. (1997). Differential effects of D-and L-amphetamine isomers on dopaminergic trasmission: Implication for the control of alertness in canine narcolepsy. Sleep Res 26: p. 383.
  9. Wisor, J.P., et al. (2001). Dopaminergic role in stimulant-induced wakefulness. J Neurosci 21(5): p. 1787-94. 
  10. Okura, M., et al. (2001). Narcoleptic canines display periodic leg movements during sleep. Psychiatry Clin Neurosci 55(3): p. 243-4. 
  11. Okura, M., et al. (2004). The roles of midbrain and diencephalic dopamine cell groups in the regulation of cataplexy in narcoleptic Dobermans. Neurobiol Dis 16(1): p. 274-82. 
  12. Nishino, S., et al. (2000). Is narcolepsy REM sleep disorder? Analysis of sleep abnormalities in narcoleptic Dobermans. Neuroscience Research 38(4): p. 437-446. 
  13. Fujiki, N., et al. (2007). Specificity of direct transition from wake to REM sleep in orexin/ataxin-3 transgenic narcoleptic mice. Exp Neurol 217(1): p. 46-54. 
  14. Yoshida, Y., et al. (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(7): p. 1075-81. 
  15. Fujiki, N., et al. (2001). Changes in CSF hypocretin-1 (orexin A) levels in rats across 24 hours and in response to food deprivation. NeuroReport 12(5): p. 993-7.

  16. Yoshida, Y., et al. (2005). Vigilance Change, Hypocretin And Histamine Release In Rats Before And After A Histamine Synthesis Blocker (Alpha-FMH) Administration. Sleep 28:A18.

  17. Soya, A., et al. (2008). CSF histamine levels in rats reflect the central histamine neurotransmission. Neurosci let 430(3):p. 224-229.
  18. Nishino, S., et al. (2001). Decreased brain histamine contents in hypocretin/orexin receptor-2 mutated narcoleptic dogs. Neurosci Lett 313(3): p. 125-8. 
  19. Nishino, S., et al. (2009). I. Decreased CSF histamine in narcolepsy with and without low CSF hypocretin-1 in comparison to healthy controls. Sleep 32(2): p. 181-187.
  20. Kanbayashi, T., et al. (2008). II. CSF histamine contents in narcolepsy, idiopathic hypersomnia and obstructive sleep apnea syndrome. Sleep 32(2):p. 175-180.
  21. Fujiki, N., et al. (2003). Effects of IV and ICV hypocretin-1 (orexin A) in hypocretin receptor-2 gene mutated narcoleptic dogs and IV hypocretin-1 replacement therapy in a hypocretin ligand deficient narcoleptic dog. Sleep 6(8): p. 953-959. 
  22. Nishino, S. (2003). The hypocretin/orexin system in health and disease. Biol Psychiatry 54(2): p. 87-95. 
  23. He, Y., et al. (2009). The transcriptional repressor DEC2 regulates sleep length in mammals. Science 325(5942):p. 866-870.
  24. Nishino, S., et al. (2004). In Charney DS, Nestler EJ, (eds.) The neurobiology of sleep in relation to mental illness, Neurobiology of Mental Illness, Oxford University Press, New York, 1160-1179.
  25. Fujiki, N., et al. (2005). Attenuated amphetamine induced locomotor sensitization in hypocretin/orexin-deficient narcoleptic mice. Sleep 28(Abstract Supplement ): p. A219.
  26. Fujiki, N., et al. (2006). Sex difference in body weight gain and leptin signaling in hypocretin/orexin deficient mouse models. Peptides 27(9):2326-2331. 
  27. Okuro, M., et al. (2009). A mice model of PTSD: Psychological stress but not physical stress enhances REM sleep. Sleep, Jun; 32, A353-354.

  28. Nishino, S., et al. (2009). Hypocretin neurotransmission differentiates rem sleep changes by physical and psychological stresses. Sleep, 2009, Jun; 32, A354