SEROTONIN AND ROLE IN EPILEPSY

Yıl 2019, , 182 - 187, 30.12.2019

Mehmet Taşkıran

https://doi.org/10.34108/eujhs.517293

Öz

Serotonin (5-HT), has important roles in epilepsy as
well as its many physiological roles in the central and
peripheral nervous systems. By now, seven serotonin
receptor types, 5-HT1-5-HT7, and their subtypes have
been identified. In addition to these receptors, there are
serotonin reuptake transporter proteins, involved in
serotonergic neurotransmission and responsible for
serotonin reuptake from nerve endings.
In general, chemical agents such as serotonin precursors, 5-hydroxytryptophan, and serotonin reuptake
inhibitors that increase extracellular serotonin levels
and serotonin receptor agonists suppress both focal and
generalized seizures. On the other hand, depletion of 5-
HT or receptor antagonists reduces the threshold of
seizures in audio genic, chemical and electrical induced
epilepsy models.
Studies have especially focused on the 5-HT1A, 5-HT2C, 5
-HT3, 5-HT4 and 5-HT7 receptors and serotonin reuptake inhibitors. The results showed that these receptors
have important roles in both epileptogenesis and epileptiform activity.

Anahtar Kelimeler

Serotonin, experimental epilepsy models, 5-HT receptors

SEROTONİN ve EPİLEPSİDE ROLÜ

Öz

Serotonin (5-HT), merkezi ve periferik sinir sistemindeki birçok fizyolojik rolünün yanı sıra epilepsi üzerinde
de önemli rollere sahiptir. Şimdiye kadar 5-HT1-5-HT7
olmak üzere serotonine ait yedi reseptör tipi ve bunların alt tipleri tanımlanmıştır. Bu reseptörlere ilave olarak serotonerjik nörotransmisyonda görev alan ve sinir
sonlanmalarından serotoninin geri alınımından sorumlu
olan serotonin geri alım taşıyıcı proteinleri de bulunmaktadır.
Genel olarak, serotonin öncülü 5-hidroksitriptofan ve
serotonin geri alım inhibitörleri gibi hücre dışı
serotonin seviyelerini yükselten ajanlar ile serotonin
reseptör agonistleri hem fokal hem de jeneralize nöbetleri baskılamaktadır. Aksine beyinde 5-HT’nin uzaklaştırılması veya reseptör antagonistlerinin uygulanması ise
odyojenik, kimyasal ve elektrikle uyarılan epilepsi modellerinde nöbet eşik değerini düşürdüğü bilinmektedir.
Yapılan çalışmalarda, özellikle 5-HT1A, 5-HT2C, 5-HT3, 5-
HT4 ve 5-HT7 reseptörleri ve serotonin geri alım inhibitörleri üzerine odaklanılmıştır. Elde edilen bulgular bu
reseptörlerin hem epileptogenezde hem de epileptiform
aktivitenin sürdürülmesinde önemli rollere sahip olduğunu ortaya koymuştur. 

Anahtar Kelimeler

Serotonin, deneysel epilepsi modelleri, 5-HT reseptörleri

Kaynakça

• 1. Davis KL, Charney D, Coyle JT, and Nemeroff C. Neuropsychopharmacology - The fifth generation of progress. 2002, New York: Lippincott, Williams & Wilkins. 2010.
• 2. Mohammad-Zadeh LF, Moses L, and Gwaltney-Brant SM. Serotonin: a review. J Vet Pharmacol Ther 2008. 31(3): p. 187-99.
• 3. Rapport MM, Green AA, and Page IH. Serum vasoconstrictor, serotonin; isolation and characterization. J Biol Chem 1948c. 176(3): p. 1243-51.
• 4. Zucker MB. A Study Of The Substances In Blood Serum And Platelets Which Stimulate Smooth Muscle. Am J Physiol 1944. 142(1): p. 12-26.
• 5. Brodie BB and Shore PA. A concept for a role of serotonin and norepinephrine as chemical mediators in the brain. Ann. N. Y. Acad. Sci. 1957. 66(3): p. 631-42.
• 6. Dahlstroem A and Fuxe K. Evidence for the existence of monoamine-containing neurons in the central nervous system. I. Demonstration of monoamines in the cell bodies of brain stem neurons. Acta Physiol Scand 1964. Suppl 232:: p. 1-55.
• 7. Twarog BM and Page IH. Serotonin content of some mammalian tissues and urine and a method for its determination. Am J Physiol 1953. 175(1): p. 157-61.
• 8. Cardinali DP, Hyyppä MT, and Wurtman RJ. Fate of Intracisternally Injected Melatonin in the Rat Brain. Neuroendocrinology 1973. 12(1): p. 30-40.
• 9. Muller CP and Jacobs B. Handbook of the Behavioral Neurobiology of Serotonin. 2009, United States of America: Elsevier Science. 836.
• 10. Hamon M, Bourgoin S, Mestikawy S, and Goetz C, Central Serotonin Receptors, in Handbook of Neurochemistry, A Lajtha, Editor. 1984, Springer US: New York. p. 107-143.
• 11. Hoyer D, Clarke DE, Fozard JR, et al. International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin). Pharmacol Rev 1994. 46(2): p. 157-203.
• 12. Algül A, Alpay MA, Semiz ÜB, and Çetin M, Reseptörler, in Temel Psikofarmakoloji, N Yüksel, Editor. 2010, Türkiye Psikiyatri Derneği: Ankara. p. 66-71.
• 13. Aghajanian GK and Marek GJ. Serotonin induces excitatory postsynaptic potentials in apical dendrites of neocortical pyramidal cells. Neuropharmacology 1997. 36(4-5): p. 589-99.
• 14. Bruinvels AT, Palacios JM, and Hoyer D. Autoradiographic characterisation and localisation of 5-HT1D compared to 5-HT1B binding sites in rat brain. Naunyn Schmiedebergs Arch Pharmacol 1993. 347(6): p. 569-82.
• 15. Sari Y. Serotonin1B receptors: from protein to physiological function and behavior. Neurosci Biobehav Rev 2004. 28(6): p. 565-82.
• 16. Aghajanian GK, Electrophysiology of serotonin receptor subtypes and signal transduction pathways, in Psychopharmacology: The Fourth Generation of Progress, FR Bloom and DJ Kupfer, Editors. 1995, Raven Press: New York. p. 1451-1459.
• 17. Choi DS and Maroteaux L. Immunohistochemical localisation of the serotonin 5-HT2B receptor in mouse gut, cardiovascular system, and brain. FEBS Lett 1996. 391(1-2): p. 45-51.
• 18. Kursar JD, Nelson DL, Wainscott DB, and Baez M. Molecular cloning, functional expression, and mRNA tissue distribution of the human 5-hydroxytryptamine2B receptor. Mol Pharmacol 1994. 46(2): p. 227-34.
• 19. Brunton L, Chabner BA, and Knollman B. Goodman and Gilman's The Pharmacological Basis of Therapeutics, Twelfth Edition. 2011: McGraw-Hill Education.
• 20. Koek W, Jackson A, and Colpaert FC. Behavioral pharmacology of antagonists at 5-HT2/5-HT1C receptors. Neurosci Biobehav Rev 1992. 16(1): p. 95-105.
• 21. Ortells MO and Lunt GG. Evolutionary history of the ligand-gated ion-channel superfamily of receptors. Trends Neurosci 1995. 18(3): p. 121-7.
• 22. Mikics E, Vas J, Aliczki M, et al. Interactions between the anxiogenic effects of CB1 gene disruption and 5-HT3 neurotransmission. Behav Pharmacol 2009. 20(3): p. 265-72.
• 23. Patel S, Roberts J, Moorman J, and Reavill C. Localization of serotonin-4 receptors in the striatonigral pathway in rat brain. Neuroscience 1995. 69(4): p. 1159-67.
• 24. Roychowdhury S, Haas H, and Anderson EG. 5-HT1A and 5-HT4 receptor colocalization on hippocampal pyramidal cells. Neuropharmacology 1994. 33(3-4): p. 551-7.
• 25. Ge J and Barnes NM. 5-HT4 receptor-mediated modulation of 5-HT release in the rat hippocampus in vivo. Br J Pharmacol 1996. 117(7): p. 1475-80.
• 26. Bockaert J, Claeysen S, Compan V, and Dumuis A. 5-HT4 Receptors. CNS Neurol Disord Drug Targets 2004. 3(1): p. 39-51.
• 27. Grailhe R, Amlaiky AN, Ghavami A, et al. Human and mouse 5-HT5A and 5-HT5B receptors: Cloning and functional expression. J Neurosci Res 1994. 20 (1-2) p. 1160.
• 28. Francken BJ, Jurzak M, Vanhauwe JF, et al. The human 5-ht5A receptor couples to Gi/Go proteins and inhibits adenylate cyclase in HEK 293 cells. Eur J Pharmacol 1998. 361(2-3): p. 299-309.
• 29. Kohen R, Metcalf MA, Khan N, et al. Cloning, characterization, and chromosomal localization of a human 5-HT6 serotonin receptor. J Neurochem 1996. 66(1): p. 47-56.
• 30. Ferrero H, Solas M, Francis PT, and Ramirez MJ. Serotonin 5-HT6 Receptor Antagonists in Alzheimer's Disease: Therapeutic Rationale and Current Development Status. CNS Drugs 2017. 31(1): p. 19-32.
• 31. Dean B, Pavey G, Thomas D, and Scarr E. Cortical serotonin 7, 1D and 1F receptors: effects of schizophrenia, suicide and antipsychotic drug treatment. Schizophr Res 2006. 88(1-3): p. 265-74.
• 32. Abbas AI, Hedlund PB, Huang XP, et al. Amisulpride is a potent 5-HT7 antagonist: relevance for antidepressant actions in vivo. Psychopharmacology 2009. 205(1): p. 119-28.
• 33. Bonnycastle DD, Giarman NJ, and Paasonen MK. Anticonvulsant compounds and 5-hydroxytryptamine in rat brain. Br J Pharmacol Chemother 1957. 12(2): p. 228-31.
• 34. Prendiville S and Gale K. Anticonvulsant effect of fluoxetine on focally evoked limbic motor seizures in rats. Epilepsia 1993. 34(2): p. 381-384.
• 35. Statnick MA, Maring-Smith ML, Clough RW, et al. Effect of 5,7-dihydroxytryptamine on audiogenic seizures in genetically epilepsy-prone rats. Life Sci 1996. 59(21): p. 1763-1771.
• 36. Pasini A, Tortorella A, and Gale K. The anticonvulsant action of fluoxetine in substantia nigra is dependent upon endogenous serotonin. Brain Res 1996. 724(1): p. 84-88.
• 37. Wada Y, Shiraishi J, Nakamura M, and Hasegawa H. Prolonged but not acute fluoxetine administration produces its inhibitory effect on hippocampal seizures in rats. Psychopharmacology 1995. 118(3): p. 305-9.
• 38. Dailey JW, Yan QS, Mishra PK, et al. Effects of fluoxetine on convulsions and on brain serotonin as detected by microdialysis in genetically epilepsy-prone rats. J Pharmacol Exp Ther 1992. 260(2): p. 533-40.
• 39. Gharedaghi MH, Seyedabadi M, Ghia JE, et al. The role of different serotonin receptor subtypes in seizure susceptibility. Exp Brain Res 2014. 232(2): p. 347-367.
• 40. Bagdy G, Kecskemeti V, Riba P, and Jakus R. Serotonin and epilepsy. J Neurochem 2007. 100(4): p. 857-73.
• 41. Graf M, Jakus R, Kantor S, et al. Selective 5-HT1A and 5-HT7 antagonists decrease epileptic activity in the WAG/Rij rat model of absence epilepsy. Neurosci Lett 2004. 359(1-2): p. 45-8.
• 42. Barnes NM and Neumaier JF. Neuronal 5-HT Receptors and SERT. Tocris Review 2011. 34: p. 1-13.
• 43. Clarke WP, Yocca FD, and Maayani S. Lack of 5-hydroxytryptamine1A-mediated inhibition of adenylyl cyclase in dorsal raphe of male and female rats. J Pharmacol Exp Ther 1996. 277(3): p. 1259-1266.
• 44. Beck SG and Choi KC. 5-Hydroxytryptamine hyperpolarizes CA3 hippocampal pyramidal cells through an increase in potassium conductance. Neurosci Lett 1991. 133(1): p. 93-6.
• 45. Behr J and Heinemann U. Effects of serotonin on different patterns of low Mg(2+)-induced epileptiform activity in the subiculum of rats studied in vitro. Brain Res 1996. 737(1-2): p. 331-4.
• 46. Arbabi Jahan A, Rad A, Ghanbarabadi M, et al. The role of serotonin and its receptors on the anticonvulsant effect of curcumin in pentylenetetrazol-induced seizures. Life Sci 2018. 211: p. 252-260.
• 47. Moreau JL, Griebel G, Jenck F, et al. Behavioral profile of the 5HT1A receptor antagonist (S)-UH-301 in rodents and monkeys. Brain Res Bull 1992. 29(6): p. 901-904.
• 48. Lopez-Meraz ML, Gonzalez-Trujano ME, Neri-Bazan L, et al. 5-HT1A receptor agonists modify epileptic seizures in three experimental models in rats. Neuropharmacology 2005. 49(3): p. 367-75.
• 49. Parsons LH, Kerr TM, and Tecott LH. 5-HT(1A) receptor mutant mice exhibit enhanced tonic, stress-induced and fluoxetine-induced serotonergic neurotransmission. J Neurochem 2001. 77(2): p. 607-17.
• 50. Theodore WH. Does Serotonin Play a Role in Epilepsy? Epilepsy Curr 2003. 3(5): p. 173-177.
• 51. Ohno Y, Sofue N, Imaoku T, et al. Serotonergic modulation of absence-like seizures in groggy rats: a novel rat model of absence epilepsy. J Pharmacol Sci 2010. 114(1): p. 99-105.
• 52. Applegate CD and Tecott LH. Global increases in seizure susceptibility in mice lacking 5-HT2C receptors: a behavioral analysis. Exp Neurol 1998. 154(2): p. 522-30.
• 53. Tecott LH, Sun LM, Akana SF, et al. Eating disorder and epilepsy in mice lacking 5-HT2c serotonin receptors. Nature 1995. 374(6522): p. 542-6.
• 54. Taskiran M, Tasdemir A, Ayyildiz N, et al. The effect of serotonin on penicillin-induced epileptiform activity. Int J Neurosci 2018: p. 1-11.
• 55. Gobert A, Rivet JM, Lejeune F, et al. Serotonin(2C) receptors tonically suppress the activity of mesocortical dopaminergic and adrenergic, but not serotonergic, pathways: a combined dialysis and electrophysiological analysis in the rat. Synapse 2000. 36(3): p. 205-21.
• 56. Mirski MA, Ziai WC, Chiang J, et al. Anticonvulsant serotonergic and deep brain stimulation in anterior thalamus. Seizure 2009. 18(1): p. 64-70.
• 57. Jakus R and Bagdy G, The Role of 5-HT2C Receptor in Epilepsy. 2010. p. 429-444.
• 58. Gholipour T, Ghasemi M, Riazi K, et al. Seizure susceptibility alteration through 5-HT3 receptor: Modulation by nitric oxide. Seizure 2010. 19(1): p. 17-22.
• 59. Blandina P, Goldfarb J, Walcott J, and Green JP. Serotonergic modulation of the release of endogenous norepinephrine from rat hypothalamic slices. J Pharmacol Exp Ther 1991. 256(1): p. 341-347.
• 60. Hiramatsu M, Ogawa K, Kabuto H, and Mori A. Reduced uptake and release of 5-hydroxytryptamine and taurine in the cerebral cortex of epileptic El mice. Epilepsy Res 1987. 1(1): p. 40-5.
• 61. Zhao H, Lin Y, Chen S, et al. 5-HT3 Receptors: A Potential Therapeutic Target for Epilepsy. Curr Neuropharmacol 2018. 16(1): p. 29-36.
• 62. Mishra A and Goel RK. Chronic 5-HT3 receptor antagonism ameliorates seizures and associated memory deficit in pentylenetetrazole-kindled mice. Neuroscience 2016. 339: p. 319-328.
• 63. Li B, Wang L, Sun Z, et al. The Anticonvulsant Effects of SR 57227 on Pentylenetetrazole-Induced Seizure in Mice. PLOS ONE 2014. 9(4): p. e93158.
• 64. Maricq AV, Peterson AS, Brake AJ, et al. Primary structure and functional expression of the 5HT3 receptor, a serotonin-gated ion channel. Science 1991. 254(5030): p. 432-437.
• 65. Yang Z, Liu X, Yin Y, et al. Involvement of 5-HT(7) receptors in the pathogenesis of temporal lobe epilepsy. Eur J Pharmacol 2012. 685(1-3): p. 52-8.
• 66. Witkin JM, Baez M, Yu J, et al. Constitutive deletion of the serotonin-7 (5-HT7) receptor decreases electrical and chemical seizure thresholds. Epilepsy Res 2007. 75(1): p. 39-45.
• 67. Matthys A, Haegeman G, Van Craenenbroeck K, and Vanhoenacker P. Role of the 5-HT7 receptor in the central nervous system: From current status to future perspectives. Mol Neurobiol 2011. 43(3): p. 228-253.