Skip to main content

Advertisement

SpringerLink
Log in

Microinjection of Adenosine into the Hypothalamic Ventrolateral Preoptic Area Enhances Wakefulness via the A1 Receptor in Rats

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Adenosine (AD) is a nucleic acid component that is critical for energy metabolism in the body. AD modulates numerous neural functions in the central nervous system, including the sleep-wake cycle. Previous studies have indicated that the A1 receptor (A1R) or A2A receptor (A2AR) may mediate the effects of AD on the sleep-wake cycle. The hypothalamic ventrolateral preoptic area (VLPO) initiates and maintains normal sleep. Histological studies have shown A1R are widely expressed in brain tissue, whereas A2AR expression is limited in the brain and undetectable in the VLPO. We hypothesize therefore, that AD modulates the sleep-wake cycle through A1R in the VLPO. In the present study, bilateral microinjection of AD or an AD transporter inhibitor (s-(4-nitrobenzyl)-6-thioinosine) into the VLPO of rats decreased non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. An A1R agonist (N6-cyclohexyladenosine) produced similar effects in the VLPO. Microinjection of an A1R antagonist (8-cyclopentyl-1,3-dimethylxanthine) into the VLPO enhanced NREM sleep and diminished AD-induced wakefulness. These data indicate that AD enhances wakefulness in the VLPO via A1R in rats.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Feldberg W, Sherwood SL (1954) Injections of drugs into the lateral ventricle of the cat. J Physiol 123:148–167

    PubMed  CAS  Google Scholar 

  2. Radulovacki M, Virus RM, Djuricic-Nedelson M, Green RD (1984) Adenosine analogs and sleep in rats. J Pharmacol Exp Ther 228:268–274

    PubMed  CAS  Google Scholar 

  3. Schwierin B, Borbély AA, Tobler I (1996) Effects of N6-cyclopentyladenosine and caffeine on sleep regulation in the rat. Eur J Pharmacol 300:163–171

    Article  PubMed  CAS  Google Scholar 

  4. Portas CM, Thakkar M, Rainnie DG, Greene RW, McCarley RW (1997) Role of adenosine in behavioral state modulation: a microdialysis study in the freely moving cat. Neuroscience 79:225–235

    Article  PubMed  CAS  Google Scholar 

  5. Yanik G, Glaum S, Radulovacki M (1987) The dose-response effects of caffeine on sleep in rats. Brain Res 403:177–180

    Article  PubMed  CAS  Google Scholar 

  6. Huston JP, Haas HL, Boix F, Pfister M, Decking U, Schrader J, Schwarting RK (1996) Extracellular adenosine levels in neostriatum and hippocampus during rest and activity periods of rats. Neuroscience 73:99–107

    Article  PubMed  CAS  Google Scholar 

  7. Porkka-Heiskanen T, Strecker RE, McCarley RW (2000) Brain site-specificity of extracellular adenosine concentration changes during sleep deprivation and spontaneous sleep: an in vivo microdialysis study. Neuroscience 99:507–517

    Article  PubMed  CAS  Google Scholar 

  8. Porkka-Heiskanen T, Strecker RE, Thakkar M, Bjorkum AA, Greene RW, McCarley RW (1997) Adenosine: a mediator of the sleep-inducing effects of prolonged wakefulness. Science 276:1265–1268

    Article  PubMed  CAS  Google Scholar 

  9. Satoh S, Matsumura H, Koike N, Tokunaga Y, Maeda T, Hayaishi O (1999) Region-dependent difference in the sleep-promoting potency of an adenosine A2A receptor agonist. Eur J Neurosci 11:1587–1597

    Article  PubMed  CAS  Google Scholar 

  10. Mendelson WB (2000) Sleep-inducing effects of adenosine microinjections into the medial preoptic area are blocked by flumazenil. Brain Res 852:479–481

    Article  PubMed  CAS  Google Scholar 

  11. Noor-Alam M, Kumar S, Rai S, Methippara M, Szymusiak R, Mcginty D (2009) Role of adenosine A1 receptor in the perifornical-lateral hypothalamic area in sleep-wake regulation in rats. Brain Res 1304:96–104

    Article  Google Scholar 

  12. Fredholm BB, IJzerman AP, Jacobson KA, Klotz KN, Linden J (2001) International Union of pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol Rev 53:527–552

    PubMed  CAS  Google Scholar 

  13. Thakkar MM, Engemann SC, Walsh KM, Sahota PK (2008) Adenosine and the homeostatic control of sleep: effects of A1 receptor blockade in the perifornical lateral hypothalamus on sleep-wakefulness. Neuroscience 153:875–880

    Article  PubMed  CAS  Google Scholar 

  14. Elmenhorst D, Meyer PT, Winz OH, Matusch A, Ermert J, Coenen HH, Basheer R, Haas HL, Zilles K, Bauer A (2007) Sleep deprivation increases A1 adenosine receptor binding in the human brain: a positron emission tomography study. J Neurosci 27:2410–2415

    Article  PubMed  CAS  Google Scholar 

  15. Coleman CG, Baghdoyan HA, Lydic R (2006) Dialysis delivery of an adenosine A2A agonist into the pontine reticular formation of C57BL/6 J mouse increases pontine acetylcholine release and sleep. J Neurochem 96:1750–1759

    Article  PubMed  CAS  Google Scholar 

  16. Satoh S, Matsumura H, Suzuki F, Hayaishi O (1996) Promotion of sleep mediated by the A2a-adenosine receptor and possible involvement of this receptor in the sleep induced by prostaglandin D2 in rats. Proc Natl Acad Sci USA 93:5980–5984

    Article  PubMed  CAS  Google Scholar 

  17. Methippara MM, Kumar S, Alam MN, Szymusiak R, McGinty D (2005) Effects on sleep of microdialysis of adenosine A1 and A2a receptor analogs into the lateral preoptic area of rats. Am J Physiol Regul Integr Comp Physiol 289:R1715–R1723

    Article  PubMed  CAS  Google Scholar 

  18. Huang ZL, Qu WM, Eguchi N, Chen JF, Schwarzschild MA, Fredholm BB, Urade Y, Hayaishi O (2005) Adenosine A2A, but not A1, receptors mediate the arousal effect of caffeine. Nat Neurosci 8:858–859

    Article  PubMed  CAS  Google Scholar 

  19. Lu J, Greco MA, Shiromani P, Saper CB (2000) Effect of lesions of the ventrolateral preoptic nucleus on NREM and REM sleep. J Neurosci 20:3830–3842

    PubMed  CAS  Google Scholar 

  20. Sherin JE, Shiromani PJ, McCarley RW, Saper CB (1996) Activation of ventrolateral preoptic neurons during sleep. Science 271:216–219

    Article  PubMed  CAS  Google Scholar 

  21. Gong H, Szymusiak R, King J, Steininger T, McGinty D (2000) Sleep-related c-Fos protein expression in the preoptic hypothalamus: effects of ambient warming. Am J Physiol Regul Integr Comp Physiol 279:R2079–R2088

    PubMed  CAS  Google Scholar 

  22. Szymusiak R, Alam N, Steininger TL, McGinty D (1998) Sleep-waking discharge patterns of ventrolateral preoptic/anterior hypothalamic neurons in rats. Brain Res 803:178–188

    Article  PubMed  CAS  Google Scholar 

  23. Gong H, McGinty D, Guzman-Marin R, Chew KT, Stewart D, Szymusiak R (2004) Activation of c-fos in GABAergic neurones in the preoptic area during sleep and in response to sleep deprivation. J Physiol 556:935–946

    Article  PubMed  CAS  Google Scholar 

  24. Sherin JE, Elmquist JK, Torrealba F, Saper CB (1998) Innervation of histaminergic tuberomammillary neurons by GABAergic and galaninergic neurons in the ventrolateral preoptic nucleus of the rat. J Neurosci 18:4705–4721

    PubMed  CAS  Google Scholar 

  25. Steininger TL, Gong H, McGinty D, Szymusiak R (2001) Subregional organization of preoptic area/anterior hypothalamic projections to arousal-related monoaminergic cell groups. J Comp Neurol 429:638–653

    Article  PubMed  CAS  Google Scholar 

  26. Yoshida K, McCormack S, España RA, Crocker A, Scammell TE (2006) Afferents to the orexin neurons of the rat brain. J Comp Neurol 494:845–861

    Article  PubMed  Google Scholar 

  27. Yaar R, Jones MR, Chen JF, Ravid K (2005) Animal models for the study of adenosine receptor function. J Cell Physiol 202:9–20

    Article  PubMed  CAS  Google Scholar 

  28. Dixon AK, Gubitz AK, Sirinathsinghji DJ, Richardson PJ, Freeman TC (1996) Tissue distribution of adenosine receptor mRNAs in the rat. Br J Pharmacol 118:1461–1468

    Article  PubMed  CAS  Google Scholar 

  29. Reppert SM, Weaver DR, Stehle JH, Rivkees SA (1991) Molecular cloning and characterization of a rat A1-adenosine receptor that is widely expressed in brain and spinal cord. Mol Endocrinol 5:1037–1048

    Article  PubMed  CAS  Google Scholar 

  30. Rivkees SA, Price SL, Zhou FC (1995) Immunohistochemical detection of A1 adenosine receptors in rat brain with emphasis on localization in the hippocampal formation, cerebral cortex, cerebellum, and basal ganglia. Brain Res 677:193–203

    Article  PubMed  CAS  Google Scholar 

  31. Rosin DL, Robeva A, Woodard RL, Guyenet PG, Linden J (1998) Immunohistochemical localization of adenosine A2A receptors in the rat central nervous system. J Comp Neurol 401:163–186

    Article  PubMed  CAS  Google Scholar 

  32. Huang ZL, Urade Y, Hayaishi O (2011) The role of adenosine in the regulation of sleep. Curr Top Med Chem 11:1047–1057

    Article  PubMed  CAS  Google Scholar 

  33. Zhang G, Wang L, Liu H, Zhang J (2004) Substance P promotes sleep in the ventrolateral preoptic area of rats. Brain Res 1028:225–232

    Article  PubMed  CAS  Google Scholar 

  34. Paxins G, Watson C (2007) The rat brain in stereotaxic coordinates. Academic Press, San Diego

    Google Scholar 

  35. Virus RM, Ticho S, Pilditch M, Radulovacki M (1990) A comparison of the effects of caffeine, 8-cyclopentyltheophylline, and alloxazine on sleep in rats. Possible roles of central nervous system adenosine receptors. Neuropsychopharmacology 3:243–249

    PubMed  CAS  Google Scholar 

  36. Marks GA, Shaffery JP, Speciale SG, Birabil CG (2003) Enhancement of rapid eye movement sleep in the rat by actions at A1 and A2a adenosine receptor subtypes with a differential sensitivity to atropine. Neuroscience 116:913–920

    Article  PubMed  CAS  Google Scholar 

  37. Strecker RE, Morairty SR, Thakkar MM, Porkka-Heiskanen T, Basheer R, Dauphin LJ, Rainnie DG, Greene RW, McCarley RW (2000) Adenosinergic modulation of basal forebrain andpreoptic/anterior hypothalamic neuronal activity in the control of behavioral state. Behav Brain Res 115:183–204

    Article  PubMed  CAS  Google Scholar 

  38. Thakkar MM, Delgiacco RA, Strecker RE, McCarley RW (2003) Adenosinergic inhibition of basal forebrain wakefulness-active neurons: a simultaneous unit recording and microdialysis study in freely behaving cats. Neuroscience 122:1107–1113

    Article  PubMed  CAS  Google Scholar 

  39. Urade Y, Eguchi N, Qu WM, Sakata M, Huang ZL, Chen JF, Schwarzschild MA, Fink JS, Hayaishi O (2003) Sleep regulation in adenosine A2A receptor-deficient mice. Neurology 61:S94–S96

    Article  PubMed  CAS  Google Scholar 

  40. Ralevic V, Burnstock G (1998) Receptors for purines and pyrimidines. Pharmacol Rev 50:413–492

    PubMed  CAS  Google Scholar 

  41. Obrietan K, Belousov AB, Heller HC, van den Pol AN (1995) Adenosine pre- and postsynaptic modulation of glutamate-dependent calcium activity in hypothalamic neurons. J Neurophysiol 74:2150–2162

    PubMed  CAS  Google Scholar 

  42. Morairty S, Rainnie D, McCarley R, Greene R (2004) Disinhibition of ventrolateral preoptic area sleep-active neurons by adenosine: a new mechanism for sleep promotion. Neuroscience 123:451–457

    Article  PubMed  CAS  Google Scholar 

  43. Chamberlin NL, Arrigoni E, Chou TC, Scammell TE, Greene RW, Saper CB (2003) Effects of adenosine on gabaergic synaptic inputs to identified ventrolateral preoptic neurons. Neuroscience 119:913–918

    Article  PubMed  CAS  Google Scholar 

  44. Gallopin T, Luppi PH, Cauli B, Urade Y, Rossier J, Hayaishi O, Lambolez B, Fort P (2005) The endogenous somnogen adenosine excites a subset of sleep-promoting neurons via A2A receptors in the ventrolateral preoptic nucleus. Neuroscience 134:1377–1390

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This research was supported by the National Natural Science Foundation of China (81071075 and 81271217), Doctoral Program Foundation of Institutions of Higher Education of China (20093420120004) and Plan for National Science Fund for Distinguished Young Scholars of Anhui Medical University (GJJQ-0801).

Author information

Authors and Affiliations

  1. Department of Neurology, The First Hospital of Anhui Medical University, Hefei, Anhui Province, People’s Republic of China

    Jin Zhang & Kai Wang

  2. Department of Physiology, School of Basic Medical Science, Anhui Medical University, Hefei, Anhui Province, People’s Republic of China

    Jin Zhang, Dou Yin, Fang Wu, Gongliang Zhang, Zhen Li & Liecheng Wang

  3. Department of Physiology, College of Traditional Chinese Medicine, Anhui Medical University, Hefei, Anhui Province, People’s Republic of China

    Chuanwei Jiang

Authors
  1. Jin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dou Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fang Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gongliang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chuanwei Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zhen Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Liecheng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kai Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Liecheng Wang or Kai Wang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, J., Yin, D., Wu, F. et al. Microinjection of Adenosine into the Hypothalamic Ventrolateral Preoptic Area Enhances Wakefulness via the A1 Receptor in Rats. Neurochem Res 38, 1616–1623 (2013). https://doi.org/10.1007/s11064-013-1063-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-013-1063-7

Keywords

Search

Navigation