Abstract
Rationale
Orexin knockout (KO) mice exhibit a phenotype that is similar to human narcolepsy, and monoamine-related compounds, such as psychostimulants and 5-HT uptake inhibitors, have been used for the treatment of narcoleptic disorders. However, little information is available regarding the pathophysiological features of orexin KO mice, particularly with respect to their narcoleptic-like disorder and how it is affected by monoamine-related compounds.
Objectives
The present study was designed to investigate both the nature of the neuronal changes in orexin KO mice and the therapeutic effects of monoamine-related compounds on the sleep disorder in orexin KO mice.
Results
A decrease in locomotor activity in the dark phase was observed in orexin KO mice, and psychostimulants and 5-HT-related compounds, such as 8-OH-DPAT (5-HT1A receptor agonist) and DOI (5-HT2 receptor agonist), inhibited this hypolocomotion. We also found that 5-HT1A receptor mRNA levels, but not those for 5-HT2 or dopamine receptors, were significantly decreased in the prefrontal cortex of orexin KO mice in the dark period and were accompanied by compromising the increase in 5-HT metabolite levels. In addition, the sleep disorder in orexin KO mice, as analyzed by a polysomnography during the dark period, was completely normalized by 8-OH-DPAT.
Conclusion
These results suggest that a dysfunction of 5-HT1A receptors is involved in the narcoleptic-like sleep dysfunction in orexin KO mice, and such dysfunction may participate in orexin deficiency-induced sleep disorders. Further, the use of 5-HT1A receptor agonist could be useful for treating the sleep disorder under a deficiency of orexin.
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Abbreviations
- EEG:
-
Electroencephalogram
- EMG:
-
Electromyogram
- KO:
-
Knockout
- MDMA:
-
3,4-Methylenedioxymethamphetamine
- REM:
-
Rapid eye movement
- RT-PCR:
-
Reverse transcription-polymerase chain reaction
- TBS:
-
Tris-buffered saline
- TBST:
-
TBS containing 0.05 % Tween 20
- WT:
-
Wild type
References
Banerjee D, Vitiello MV, Grunstein RR (2004) Pharmacotherapy for excessive daytime sleepiness. Sleep Med Rev 8:339–354
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
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
Dugovic C (1992) Functional activity of 5-HT2 receptors in the modulation of the sleep/wakefulness states. J Sleep Res 1:163–168
Fadel J, Deutch AY (2002) Anatomical substrates of orexin-dopamine interactions: lateral hypothalamic projections to the ventral tegmental area. Neuroscience 111:379–387
Fantegrossi WE, Reissig CJ, Katz EB, Yarosh HL, Rice KC, Winter JC (2008) Hallucinogen-like effects of N, N-dipropyltryptamine (DPT): possible mediation by serotonin 5-HT1A and 5-HT2A receptors in rodents. Pharmacol Biochem Behav 88:358–365
Green AR, Mechan AO, Elliott JM, O’Shea E, Colado MI (2003) The pharmacology and clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”). Pharmacol Rev 55:463–508
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
Hoyer D, Clarke DE, Fozard JR, Hartig PR, Martin GR, Mylecharane EJ, Saxena PR, Humphrey PP (1994) International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (serotonin). Pharmacol Rev 46:157–203
Hunsley MS, Palmiter RD (2004) Altered sleep latency and arousal regulation in mice lacking norepinephrine. Pharmacol Biochem Behav 78:765–773
Ito H, Yanase M, Yamashita A, Kitabatake C, Hamada A, Suhara Y, Narita M, Ikegami D, Sakai H, Yamazaki M, Narita M (2013) Analysis of sleep disorders under pain using an optogenetic tool: possible involvement of the activation of dorsal raphe nucleus-serotonergic neurons. Mol Brain 6:59
Jones BE (2000) Basic mechanisms of sleep-wake states. In: Kryger MH, Roth T, Dement WC (eds) Principles and practice of sleep medicine. Saunders, Philadelphia, pp 134–154
Kish SJ, Mamelak M, Slimovitch C, Dixon LM, Lewis A, Shannak K, DiStefano L, Chang LJ, Hornykiewicz O (1992) Brain neurotransmitter changes in human narcolepsy. Neurology 42:229–234
Kuczenski R, Segal DS (2001) Locomotor effects of acute and repeated threshold doses of amphetamine and methylphenidate: relative roles of dopamine and norepinephrine. J Pharmacol Exp Ther 296:876–883
Marona-Lewicka D, Kurrasch-Orbaugh DM, Selken JR, Cumbay MG, Lisnicchia JG, Nichols DE (2002) Re-evaluation of lisuride pharmacology: 5-hydroxytryptamine1A receptor-mediated behavioral effects overlap its other properties in rats. Psychopharmacology 164:93–107
Meguid MM, Fetissov SO, Varma M, Sato T, Zhang L, Laviano A, Rossi-Fanelli F (2000) Hypothalamic dopamine and serotonin in the regulation of food intake. Nutrition 16:843–857
Monti JM, Jantos H (1992) Dose-dependent effects of the 5-HT1A receptor agonist 8-OH-DPAT on sleep and wakefulness in the rat. J Sleep Res 1:169–175
Mori T, Ito S, Kuwaki T, Yanagisawa M, Sakurai T, Sawaguchi T (2010) Monoaminergic neuronal changes in orexin deficient mice. Neuropharmacology 58:826–832
Mori T, Uzawa N, Kazawa H, Watanabe H, Mochizuki A, Shibasaki M, Yoshizawa K, Suzuki T (2013) Differential substitution for the discriminative stimulus effects of 3,4-methylenedioxymethamphetamine and methylphenidate in rats. J Pharmacol Exp Ther 350:403–411
Nakamura T, Uramura K, Nambu T, Yada T, Goto K, Yanagisawa M, Sakurai T (2000) Orexin-induced hyperlocomotion and stereotypy are mediated by the dopaminergic system. Brain Res 873:181–187
Narita M, Mizoguchi H, Narita M, Nagase H, Suzuki T, Tseng LF (2001) Involvement of spinal protein kinase Cgamma in the attenuation of opioid mu-receptor-mediated G-protein activation after chronic intrathecal administration of [D-Ala2, N-MePhe4, Gly-Ol(5)]enkephalin. J Neurosci 21:3715–3720
Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E (2000) Hypocretin (orexin) deficiency in human narcolepsy. Lancet 355:39–40
Perrine SA, Miller JS (2008) Cocaine regulates protein kinsase B and glycogen synthase kinase-3 activity in selective regions of rat brain. J Neurochem 107:570–577
Peyron C, Tighe DK, van den Pol AN, de Lecea L, Heller HC, Sutcliffe JG, Kilduff TS (1998) Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci 18:9996–10015
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
Polter AM, Yang S, Jope RS, Li X (2012) Functional significance of glycogen synthase kinase-3 regulation by serotonin. Cell Signal 24:265–271
Rahmadi M, Narita M, Yamashita A, Imai S, Kuzumaki N, Suzuki T (2011) Sleep disturbance associated with an enhanced orexinergic system induced by chronic treatment with paroxetine and milnacipran. Synapse 65:652–657
Scammell TE, Willie JT, Guilleminault C, Siegel JM (2009) A consensus definition of cataplexy in mouse models of narcolepsy. Sleep 32:111–116
Siegel JM (2000) Brainstem mechanisms generating REM sleep. In: Kryger MH, Roth T, Dement WC (eds) Principles and practice of sleep medicine, Saunders Philadelphia. Saunders, Philadelphia, pp 112–133
Suzuki T, Shindo K, Miyatake M, Kurokawa K, Higashiyama K, Suzuki M, Narita M (2007) Lack of development of behavioral sensitization to methylphenidate in mice: correlation with reversible astrocytic activation. Eur J Pharmacol 574:39–48
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
Thorpy M (2007) Therapeutic advances in narcolepsy. Sleep Med 8:427–440
Thorpy MJ, Dauvilliers Y (2015) Clinical and practical considerations in the pharmacologic management of narcolepsy. Sleep Med 16:9–18
Willie JT, Chemelli RM, Sinton CM, Tokita S, Williams SC, Kisanuki YY, Marcus JN, Lee C, Elmquist JK, Kohlmeier KA, Leonard CS, Richardson JA, Hammer RE, Yanagisawa M (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
Acknowledgments
This work was supported in part by grants for Research on Regulatory Science of Pharmaceuticals and Medical Devices from the Ministry of Health, Labour and Welfare, Japan (MHLW) (Grant No: 15Emk0101001h0015) to TS and/or TM and EXT-Supported Program for the Strategic Research Foundation at Private Universities, 2014–2018, S1411019.
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The present study was conducted in accordance with the Guiding Principles for the Care and Use of Laboratory Animals (Hoshi University), as adopted by the Committee on Animal Research of Hoshi University, which is accredited by the Ministry of Education, Culture, Sports, Science, and Technology of Japan. Every effort was made to minimize the number and suffering of animals used in this experiments.
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Mori, T., Uzawa, N., Iwase, Y. et al. Narcolepsy-like sleep disturbance in orexin knockout mice are normalized by the 5-HT1A receptor agonist 8-OH-DPAT. Psychopharmacology 233, 2343–2353 (2016). https://doi.org/10.1007/s00213-016-4282-1
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DOI: https://doi.org/10.1007/s00213-016-4282-1