Orexin neurons within the lateral hypothalamus play a crucial role in the promotion and maintenance of arousal. Studies have strongly suggested that orexin neurons are an important target in endogenous adenosine-regulated sleep homeostasis. Orexin A induces a robust increase in the firing activity of orexin neurons, while adenosine has an inhibitory effect. Whether the excitatory action of orexins in the lateral hypothalamus actually promotes wakefulness and reverses the sleep-producing effect of adenosine in vivo is less clear. In this study, electroencephalographic and electromyographic recordings were used to investigate the effects of orexin A and adenosine on sleep and wakefulness in rats. We found that microinjection of orexin A into the lateral hypothalamus increased wakefulness with a concomitant reduction of sleep during the first 3 h of post-injection recording, and this was completely blocked by a selective antagonist for orexin receptor 1, SB 334867. The enhancement of wakefulness also occurred after application of the excitatory neurotransmitter glutamate in the first 3 h post-injection. However, in the presence of the NMDA receptor antagonist APV, orexin A did not induce any change of sleep and wakefulness in the first 3 h. Further, exogenous application of adenosine into the lateral hypothalamus induced a marked increase of sleep in the first 3-h post-injection. No significant change in sleep and wakefulness was detected after adenosine application followed by orexin A administration into the same brain area. These findings suggest that the sleep-promoting action of adenosine can be reversed by orexin A applied to the lateral hypothalamus, perhaps by exciting glutamatergic input to orexin neurons via the action of orexin receptor 1.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 1998, 92: 573–585.
Sakurai T. The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness. Nat Rev Neurosci 2007, 8: 171–181.
Adamantidis AR, Zhang F, Aravanis AM, Deisseroth K, de Lecea L. Neural substrates of awakening probed with optogenetic control of hypocretin neurons. Nature 2007, 450: 420–424.
de Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE, et al. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci U S A 1998, 95: 322–327.
Sakurai T, Mieda M, Tsujino N. The orexin system: roles in sleep/wake regulation. Ann N Y Acad Sci 2010, 1200: 149–161.
Xia J, Chen X, Song C, Ye J, Yu Z, Hu Z. Postsynaptic excitation of prefrontal cortical pyramidal neurons by hypocretin-1/orexin A through the inhibition of potassium currents. J Neurosci Res 2005, 82: 729–736.
Xia JX, Fan SY, Yan J, Chen F, Li Y, Yu ZP, et al. Orexin A-induced extracellular calcium influx in prefrontal cortex neurons involves L-type calcium channels. J Physiol Biochem 2009, 65: 125–136.
Alexandre C, Andermann ML, Scammell TE. Control of arousal by the orexin neurons. Curr Opin Neurobiol 2013, 23: 752–759.
Li B, Chen F, Ye J, Chen X, Yan J, Li Y, et al. The modulation of orexin A on HCN currents of pyramidal neurons in mouse prelimbic cortex. Cereb Cortex 2010, 20: 1756–1767.
Chen XW, Mu Y, Huang HP, Guo N, Zhang B, Fan SY, et al. Hypocretin-1 potentiates NMDA receptor-mediated somatodendritic secretion from locus ceruleus neurons. J Neurosci 2008, 28: 3202–3208.
Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, Lee C, et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 1999, 98: 437–451.
Sasaki K, Suzuki M, Mieda M, Tsujino N, Roth B, Sakurai T. Pharmacogenetic modulation of orexin neurons alters sleep/ wakefulness states in mice. PLoS One 2011, 6: e20360.
Tabuchi S, Tsunematsu T, Kilduff TS, Sugio S, Xu M, Tanaka KF, et al. Influence of inhibitory serotonergic inputs to orexin/ hypocretin neurons on the diurnal rhythm of sleep and wakefulness. Sleep 2013, 36: 1391–1404.
Zhang XY, Yu L, Zhuang QX, Zhu JN, Wang JJ. Central functions of the orexinergic system. Neurosci Bull 2013, 29: 355–365.
Li Y, Gao XB, Sakurai T, van den Pol AN. Hypocretin/Orexin excites hypocretin neurons via a local glutamate neuron-A potential mechanism for orchestrating the hypothalamic arousal system. Neuron 2002, 36: 1169–1181.
Xia J, Chen F, Ye J, Yan J, Wang H, Duan S, et al. Activity-dependent release of adenosine inhibits the glutamatergic synaptic transmission and plasticity in the hypothalamic hypocretin/orexin neurons. Neuroscience 2009, 162: 980–988.
Alam MN, Kumar S, Rai S, Methippara M, Szymusiak R, McGinty D. Role of adenosine A(1) receptor in the perifornical-lateral hypothalamic area in sleep-wake regulation in rats. Brain Res 2009, 1304: 96–104.
Rai S, Kumar S, Alam MA, Szymusiak R, McGinty D, Alam MN. A1 receptor mediated adenosinergic regulation of perifornical-lateral hypothalamic area neurons in freely behaving rats. Neuroscience 2010, 167: 40–48.
Thakkar MM, Engemann SC, Walsh KM, Sahota PK. Adenosine and the homeostatic control of sleep: effects of A1 receptor blockade in the perifornical lateral hypothalamus on sleep-wakefulness. Neuroscience 2008, 153: 875–880.
Chen L, Thakkar MM, Winston S, Bolortuya Y, Basheer R, McCarley RW. REM sleep changes in rats induced by siRNA-mediated orexin knockdown. Eur J Neurosci 2006, 24: 2039–2048.
Jia X, Yan J, Xia J, Xiong J, Wang T, Chen Y, et al. Arousal effects of orexin A on acute alcohol intoxication-induced coma in rats. Neuropharmacology 2012, 62: 775–783.
Paxinos G, Waston C. The Rat Brain in Stereotaxic Coordinates. San Diego, 1998.
Huang ZL, Qu WM, Li WD, Mochizuki T, Eguchi N, Watanabe T, et al. Arousal effect of orexin A depends on activation of the histaminergic system. Proc Natl Acad Sci U S A 2001, 98: 9965–9970.
Huang ZL, Sato Y, Mochizuki T, Okada T, Qu WM, Yamatodani A, et al. Prostaglandin E2 activates the histaminergic system via the EP4 receptor to induce wakefulness in rats. J Neurosci 2003, 23: 5975–5983.
Oishi Y, Huang ZL, Fredholm BB, Urade Y, Hayaishi O. Adenosine in the tuberomammillary nucleus inhibits the histaminergic system via A1 receptors and promotes non-rapid eye movement sleep. Proc Natl Acad Sci U S A 2008, 105: 19992–19997.
Kushikata T, Hirota K, Yoshida H, Kudo M, Lambert DG, Smart D, et al. Orexinergic neurons and barbiturate anesthesia. Neuroscience 2003, 121: 855–863.
Liu ZW, Gao XB. Adenosine inhibits activity of hypocretin/ orexin neurons by the A1 receptor in the lateral hypothalamus: a possible sleep-promoting effect. J Neurophysiol 2007, 97: 837–848.
Dong H, Niu J, Su B, Zhu Z, Lv Y, Li Y, et al. Activation of orexin signal in basal forebrain facilitates the emergence from sevoflurane anesthesia in rat. Neuropeptides 2009, 43: 179–185.
Eriksson KS, Sergeeva O, Brown RE, Haas HL. Orexin/ hypocretin excites the histaminergic neurons of the tuberomammillary nucleus. J Neurosci 2001, 21: 9273–9279.
Chen L, McKenna JT, Bolortuya Y, Winston S, Thakkar MM, Basheer R, et al. Knockdown of orexin type 1 receptor in rat locus coeruleus increases REM sleep during the dark period. Eur J Neurosci 2010, 32: 1528–1536.
Alam MA, Mallick BN. Glutamic acid stimulation of the perifornical-lateral hypothalamic area promotes arousal and inhibits non-REM/REM sleep. Neurosci Lett 2008, 439: 281–286.
Li FW, Deurveilher S, Semba K. Behavioural and neuronal activation after microinjections of AMPA and NMDA into the perifornical lateral hypothalamus in rats. Behav Brain Res 2011, 224: 376–386.
Rainnie DG, Grunze HC, McCarley RW, Greene RW. Adenosine inhibition of mesopontine cholinergic neurons: implications for EEG arousal. Science 1994, 263: 689–692.
Porkka-Heiskanen T, Strecker RE, McCarley RW. Brain sitespecificity of extracellular adenosine concentration changes during sleep deprivation and spontaneous sleep: an in vivo microdialysis study. Neuroscience 2000, 99: 507–517.
Zhang N, Liu HT. Effects of sleep deprivation on cognitive functions. Neurosci Bull 2008, 24: 45–48.
Landolt HP, Retey JV, Tonz K, Gottselig JM, Khatami R, Buckelmuller I, et al. Caffeine attenuates waking and sleep electroencephalographic markers of sleep homeostasis in humans. Neuropsychopharmacology 2004, 29: 1933–1939.
Daly JW, Fredholm BB. Caffeine—an atypical drug of dependence. Drug Alcohol Depend 1998, 51: 199–206.
About this article
Cite this article
Cun, Y., Tang, L., Yan, J. et al. Orexin A attenuates the sleep-promoting effect of adenosine in the lateral hypothalamus of rats. Neurosci. Bull. 30, 877–886 (2014). https://doi.org/10.1007/s12264-013-1442-8
- lateral hypothalamus