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Cellular and Molecular Neurobiology

, Volume 31, Issue 8, pp 1245–1255 | Cite as

Alterations in Serotonin Receptors and Transporter Immunoreactivities in the Hippocampus in the Rat Unilateral Hypoxic-induced Epilepsy Model

  • Sung-Jin An
  • Duk-Soo Kim
Original Research

Abstract

Unilateral hypoxic-ischemia results in the frequent occurrence of interictal spikes, and occasionally sustained ictal discharges accompanied by a reduction in paired-pulse inhibition within the non-lesioned dentate gyrus. To elucidate the roles of serotonin (5-hydroxytryptamine [5-HT]) in an epileptogenic insult, we investigated the changes in 5-HT receptors and serotonin transporter (5-HTT) immunoreactivities within the lesioned and contralateral hippocampus following unilateral hypoxic-ischemia. During epileptogenic periods following hypoxic-ischemia, both 5-HT1A and 5HT1B receptor immunoreactivities were decreased within the lesioned and the non-lesioned hippocampus. However, 5-HTT immunoreactivity was transiently increased within the hippocampus bilaterally. These findings indicate that alteration of the 5-HT system results in a “diaschisis” pattern, and may contribute to neuronal death and the development of emotional disorders in epileptic patients accompanied by psychological stress.

Keywords

5-HT1A receptor 5HT1B receptor 5-HTT Hippocampus Hypoxic-ischemia Epilepsy 

Notes

Acknowledgment

This study was supported by a grant of the National Research Foundation of Korea (grant number 2009-0093812).

References

  1. Amara SG, Kuhar MJ (1993) Neurotransmitter transporters: recent progress. Annu Rev Neurosci 16:73–93PubMedCrossRefGoogle Scholar
  2. Azmitia EC, Gannon PJ, Kheck NM, Whitaker-Azmitia PM (1996) Cellular localization of the 5-HT1A receptor in primate brain neurons and glial cells. Neuropsychopharmacology 14:35–46PubMedCrossRefGoogle Scholar
  3. Bergamasco B, Benna P, Ferrero P, Gabinelli R (1984) Neonatal hypoxia and epileptic risk: a clinical prospective study. Epilepsia 25:131–136PubMedCrossRefGoogle Scholar
  4. Boeijinga PH, Boddeke HW (1993) Serotonergic modulation of neurotransmission in the rat subicular cortex in vitro: a role for 5-HT1B receptors. Naunyn Schmiedebergs Arch Pharmacol 348:553–557PubMedCrossRefGoogle Scholar
  5. Calvert JW, Yin W, Patel M, Badr A, Mychaskiw G, Parent AD, Zhang JH (2002) Hyperbaric oxygenation prevented brain injury induced by hypoxia–ischemia in a neonatal rat model. Brain Res 951:1–8PubMedCrossRefGoogle Scholar
  6. Chalmers DT, Watson SI (1991) Comparative anatomical distribution of 5-HT lA receptor mRNA and 5-HTlA binding in rat brain -a combined in situ hybridisation/in vitro receptor autoradiographic study. Brain Res 561:51–60PubMedCrossRefGoogle Scholar
  7. Colino A, Halliwell JV (1987) Differential modulation of three separate K+-conductances in hippocampal CA1 neurons by serotonin. Nature 328:73–77PubMedCrossRefGoogle Scholar
  8. Damsma G, Boisvert DP, Mudrick LA, Wenkstern D, Fibiger HC (1990) Effects of transient forebrain ischemia and pargyline on extracellular concentrations of dopamine, serotonin, and their metabolites in the rat striatum as determined by in vivo microdialysis. J Neurochem 54:801–808PubMedCrossRefGoogle Scholar
  9. Davies MF, Deisz RA, Prince DA, Peroutka SJ (1987) Two distinct effects of 5-hydroxytryptamine on single cortical neurons. Brain Res 423:347–352PubMedCrossRefGoogle Scholar
  10. De Vry J, Jentzsch KR (1998) Discriminative stimulus properties of the 5-HT1A receptor agonist BAY x3702 in the rat. Eur J Pharmacol 357:1–8PubMedCrossRefGoogle Scholar
  11. Giovacchini G, Toczek MT, Bonwetsch R, Bagic A, Lang L, Fraser C, Reeves-Tyer P, Herscovitch P, Eckelman WC, Carson RE, Theodore WH (2005) 5-HT1A receptors are reduced in temporal lobe epilepsy after partial-volume correction. J Nucl Med 46:1128–1135PubMedGoogle Scholar
  12. Globus MY, Wester P, Busto R, Dietrich WD (1992) Ischemia-induced extracellular release of serotonin plays a role in CA1 neuronal cell death in rats. Stroke 23:1595–1601PubMedCrossRefGoogle Scholar
  13. Hansson SR, Mezey E, Hoffman BJ (1998) Serotonin transporter messenger RNA in the developing rat brain: early expression in serotonergic neurons and transient expression in non-serotonergic neurons. Neuroscience 83:1185–1201PubMedCrossRefGoogle Scholar
  14. 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 46:157–203PubMedGoogle Scholar
  15. Jackson GD, Chambers BR, Berkovic SF (1999) Hippocampal sclerosis:development in adult life. Dev Neurosci 21:207–214PubMedCrossRefGoogle Scholar
  16. Kang TC, Park SK, Hwang IK, An SJ, Won MH (2004a) GABA(B) receptor-mediated regulation of P2X7 receptor expression in the gerbil hippocampus. Brain Res Mol Brain Res 121:12–18PubMedCrossRefGoogle Scholar
  17. Kang TC, Park SK, Hwang IK, An SJ, Won MH (2004b) Altered Na+-K+ ATPase immunoreactivity within GABAergic neurons in the gerbil hippocampal complex induced by spontaneous seizure and vigabatrin treatment. Neurochem Int 45:179–187PubMedCrossRefGoogle Scholar
  18. Kang TC, Kim DS, Kwak SE, Kim JE, Kim DW, Kang JH, Won MH, Kwon OS, Choi SY (2005) Valproic acid reduces enhanced vesicular glutamate transporter immunoreactivities in the dentate gyrus of the seizure prone gerbil. Neuropharmacology 49:912–921PubMedCrossRefGoogle Scholar
  19. Kim DS, Kwak SE, Kim JE, Won MH, Choi HC, Song HK, Kwon OS, Kim YI, Choi SY, Kang TC (2005) Bilateral enhancement of excitation via up-regulation of vesicular glutamate transporter subtype 1, not subtype 2, immunoreactivity in the unilateral hypoxic epilepsy model. Brain Res 1055:122–130PubMedCrossRefGoogle Scholar
  20. Kim DS, Kim JE, Kwak SE, Choi HC, Song HK, Kim YI, Choi SY, Kang TC (2007a) Up-regulated astroglial TWIK-related acid-sensitive K+ channel-1 (TASK-1) in the hippocampus of seizure-sensitive gerbils: a target of anti-epileptic drugs. Brain Res 1185:346–358PubMedCrossRefGoogle Scholar
  21. Kim DS, Kim JE, Kwak SE, Won MH, Kang TC (2007b) Seizure activity affects neuroglial Kv1 channel immunoreactivities in the gerbil hippocampus. Brain Res 1151:17–187CrossRefGoogle Scholar
  22. Kim JE, Kwak SE, Kang TC (2009) Upregulated TWIK-related acid-sensitive K+ channel-2 in neurons and perivascular astrocytes in the hippocampus of experimental temporal lobe epilepsy. Epilepsia 50:654–663PubMedCrossRefGoogle Scholar
  23. Koh S, Jensen FE (2001) Topiramate blocks perinatal hypoxia-induced seizures in rat pups. Ann Neurol 50:366–372PubMedCrossRefGoogle Scholar
  24. Kotila M, Waltimo O (1992) Epilepsy after stroke. Epilepsia 33:495–498PubMedCrossRefGoogle Scholar
  25. Kozuka M, Iwata N (1995) Changes in levels of monoamines and their metabolites in incompletely ischemic brains of spontaneously hypertensive rats. Neurochem Res 20:1429–1435PubMedCrossRefGoogle Scholar
  26. Kwak SE, Kim JE, Kim DS, Jung JY, Won MH, Kwon OS, Choi SY, Kang TC (2005) Effects of GABAergic transmissions on the immunoreactivities of calcium binding proteins in the gerbil hippocampus. J Comp Neurol 485:153–164PubMedCrossRefGoogle Scholar
  27. Levine S (1960) Anoxic-ischemic encephalopathy in rats. Am J Pathol 36:1–14PubMedGoogle Scholar
  28. Lucki I (1998) The spectrum of behaviors influenced by serotonin. Biol Psychiatry 44:151–162PubMedCrossRefGoogle Scholar
  29. Manukhin BN, Volina EV, Markova LN, Rakic L, Buznikov GA (1981) Biogenic monoamines in early embryos of sea urchins. Dev Neurosci 4:322–328PubMedCrossRefGoogle Scholar
  30. Mathern GW, Price G, Rosales C, Pretorius JK, Lozada A, Mendoza D (1998) Anoxia during kainate status epilepticus shortens behavioral convulsions but generates hippocampal neuron loss and supragranular mossy fiber sprouting. Epilepsy Res 30:133–151PubMedCrossRefGoogle Scholar
  31. Matsuyama S, Nei K, Tanaka C (1996) Regulation of glutamate release via NMDA and 5-HT1A receptors in guinea pig dentate gyrus. Brain Res 728:175–180PubMedCrossRefGoogle Scholar
  32. Meldrum BS (2002) Concept of activity-induced cell death in epilepsy: historical and contemporary perspectives. Prog Brain Res 135:3–11PubMedCrossRefGoogle Scholar
  33. Meschaks A, Lindstrom P, Halldin C, Farde L, Savic I (2005) Regional reductions in serotonin 1A receptor binding in juvenile myoclonic epilepsy. Arch Neurol 62:946–950PubMedCrossRefGoogle Scholar
  34. Nakata N, Kato H, Kogure K (1992) Protective effects of serotonin reuptake inhibitors, citalopram and clomipramine, against hippocampal CA1 neuronal damage following transient ischemia in the gerbil. Brain Res 590:48–52PubMedCrossRefGoogle Scholar
  35. Nakata N, Suda H, Izumi J, Tanaka Y, Ikeda Y, Kato H, Itoyama Y, Kogure KL (1997) Role of hippocampal serotonergic neurons in ischemic neuronal death. Behav Brain Res 83:217–220PubMedCrossRefGoogle Scholar
  36. Nellgard B, Wieloch T (1992) Postischemic blockade of AMPA but not NMDA receptors mitigates neuronal damage in the rat brain following transient severe cerebral ischemia. J Cereb Blood Flow Metab 12:2–11PubMedCrossRefGoogle Scholar
  37. Owens MJ, Nemeroff CB (1994) Role of serotonin in the pathophysiology of depression: focus on the serotonin transporter. Clin Chem 40:288–295PubMedGoogle Scholar
  38. Peroutka SI (1993) 5-Hydroxytryptamine receptors. J Neurochem 60:408–416PubMedCrossRefGoogle Scholar
  39. Phebus LA, Clemens JA (1989) Effects of transient, global, cerebral ischemia on striatal extracellular dopamine, serotonin and their metabolites. Life Sci 44:1335–1342PubMedCrossRefGoogle Scholar
  40. Pulsinelli W, Sarokin A, Buchan A (1993) Antagonism of the NMDA and non-NMDA receptors in global versus focal brain ischemia. Prog Brain Res 96:125–135PubMedCrossRefGoogle Scholar
  41. Quirion R, Richard J (1987) Differential effects of selective lesions of cholinergic and dopaminergic neurons on serotonin-type 1 receptors in rat brain. Synapse 1:124–130PubMedCrossRefGoogle Scholar
  42. Raiteri M, Maura G, Barzizza A (1991) Activation of presynaptic 5-hydroxytryptamine1-like receptors on glutamatergic terminals inhibits N-methyl-aspartate-induced cyclic GMP production in rat cerebellar slices. J Pharmacol Exp Ther 257:1184–1188PubMedGoogle Scholar
  43. Rasmussen K, Aghajanian GK (1990) Serotonin excitation of facial motoneurons: receptor subtype characterization. Synapse 5:324–332PubMedCrossRefGoogle Scholar
  44. Raymond JR, Mukhin YV, Gettys TW, Garnovskaya MN (1999) The recombinant 5-HT1A receptor: G protein coupling and signalling pathways. Br J Pharmacol 127:1751–1764PubMedCrossRefGoogle Scholar
  45. Rice JE 3rd, Vannucci RC, Brierley JB (1981) The influence of immaturity on hypoxic-ischemic brain damage in the rat. Ann Neurol 9:131–141PubMedCrossRefGoogle Scholar
  46. Richards DA, Obrenovitch TP, Symon L, Curzon G (1993) Extracellular dopamine and serotonin in the rat striatum during transient ischaemia of different severities: a microdialysis study. J Neurochem 60:128–136PubMedCrossRefGoogle Scholar
  47. Segal M (1980) The action of serotonin in the rat hippocampal slice preparation. J Physiol 303:423–439PubMedGoogle Scholar
  48. Tanaka E, North RA (1993) Actions of 5-hydroxytryptamine on neurons of the rat cingulate cortex. J Neurophysiol 69:1749–1757PubMedGoogle Scholar
  49. Veenstra-Vander Weele J, GMJr Anderson, Cook EH (2000) Pharmacogenetics and the serotonin system: initial studies and future directions. Eur J Pharmacol 410:165–181CrossRefGoogle Scholar
  50. Waeber C, Dietl MM, Hoyer D, Palacios JM (1989) 5-HT1 receptors in the vertebrate brain. Regional distribution examined by autoradiography. Naunyn Schmiedebergs Arch Pharmacol 340:486–494PubMedGoogle Scholar
  51. Witte OW, Bidmon HJ, Schiene K, Redecker C, Hagemann G (2000) Functional differentiation of multiple perilesional zones after focal cerebral ischemia. J Cereb Blood Flow Metab 20:1149–1165PubMedCrossRefGoogle Scholar
  52. Wong PT, Feng H, Teo WL (1995) Interaction of the dopaminergic and serotonergic systems in the rat striatum: effects of selective antagonists and uptake inhibitors. Neurosci Res 23:115–119PubMedCrossRefGoogle Scholar
  53. Zifa E, Fillion G (1992) 5-Hydroxytryptamine receptors. Pharmacol Rev 44:401–458PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Anatomy and NeurobiologyCollege of Medicine, Hallym UniversityKangwon-DoRepublic of Korea
  2. 2.Department of AnatomyCollege of Medicine, Soonchunhyang UniversityChungcheongnam-DoRepublic of Korea

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