Role of Serotonin2A (5-HT2A) Receptors in Epilepsy

  • Vincenzo Crunelli
  • Marcello Venzi
  • Philippe De Deurwaerdère
  • Giuseppe Di Giovanni
Part of the The Receptors book series (REC, volume 32)


5-Hydroxytryptamine 2A receptors (5-HT2ARs), have been implicated in various psychiatric and neurological disorders, including epilepsy. Interestingly, epileptic patients commonly present comorbid psychiatric symptoms, and a bidirectional link between depression and epilepsy has been suggested. Therefore, the alteration of 5-HT2A signalling might represent a common anatomical and neurobiological substrate of both pathologies.

After a brief presentation of the role of 5-HT in epilepsy, this chapter illustrates how 5-HT2A receptors may directly or indirectly control neuronal excitability in networks involved in different types of epilepsy. It also synthetizes the preclinical and clinical evidence, demonstrating the role of these receptors in antiepileptic responses.


5-HT 5-HT2A receptor Antidepressants Antipsychotics Depression Epilepsy 



5-hydroxytryptamine or serotonin


Serotonin 2A receptors


After discharge




Dentate gyrus




Dorsal raphe nucleus


Extrasynaptic GABAA


Genetic absence epilepsy in rats from Strasbourg


G protein coupled receptors


Locus coeruleus


Maximal dentate activation


Medial prefrontal cortex


Medial raphe nucleus




Nucleus reticulari thalami


Periaqueductal grey


Serotonin transporter


Selective serotonin reuptake inhibitor


Sudden unexpected death in epilepsy


Spike and wave discharges


Ventrobasal thalamus


Ventral tegmental area



Our work in this area was supported by the ERUK (grant P1202 to VC and GDG), the Malta Council of Science and Technology (grant R&I-2013-14 to GDG and VC) and EU COST Action CM1103 (GDG and PDD).


  1. 1.
    Barnes NM, Sharp T (1999) A review of central 5-HT receptors and their function. Neuropharmacology 38:1083–1152PubMedCrossRefGoogle Scholar
  2. 2.
    D’Adamo MC, Servettini I, Guglielmi L, Di Matteo V, Di Maio R, Di Giovanni G et al (2013) 5-HT2 receptors-mediated modulation of voltage-gated K+ channels and neurophysiopathological correlates. Exp Brain Res 230:453–462Google Scholar
  3. 3.
    Bagdy G, Kecskemeti V, Riba P, Jakus R (2007) Serotonin and epilepsy. J Neurochem 100:857–873PubMedCrossRefGoogle Scholar
  4. 4.
    Ghanbari R, El Mansari M, Blier P (2012) Electrophysiological impact of trazodone on the dopamine and norepinephrine systems in the rat brain. Eur Neuropsychopharmacol 22:518–526PubMedCrossRefGoogle Scholar
  5. 5.
    Jakus R, Bagdy G (2011a) The role of 5-HT2C receptor in epilepsy. In: Di Giovanni G et al (eds) 5-HT2C receptors in the pathophysiology of CNS disease, vol 22. Humana Press, Totowa, pp 429–444CrossRefGoogle Scholar
  6. 6.
    Di Giovanni G, Di Matteo V, Pierucci M, Benigno A, Esposito E (2006) Central serotonin2C receptor: from physiology to pathology. Curr Top Med Chem 6:1909–1925PubMedCrossRefGoogle Scholar
  7. 7.
    Millan MJ, Marin P, Bockaert J, Mannoury la Cour C (2008) Signaling at G-protein-coupled serotonin receptors: recent advances and future research directions. Trends Pharmacol Sci 29:454–464PubMedCrossRefGoogle Scholar
  8. 8.
    Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W et al (2010) Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia 51:676–685PubMedCrossRefGoogle Scholar
  9. 9.
    Manning JP, Richards DA, Bowery NG (2003) Pharmacology of absence epilepsy. Trends Pharmacol Sci 24:542–549PubMedCrossRefGoogle Scholar
  10. 10.
    Cope DW, Di Giovanni G, Fyson SJ, Orban G, Errington AC, Lorincz ML et al (2009) Enhanced tonic GABAA inhibition in typical absence epilepsy. Nat Med 15:1392–1398PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Errington AC, Di Giovanni G, Crunelli V (eds) (2014) Extrasynapitic GABAA receptors. Springer, New YorkGoogle Scholar
  12. 12.
    Errington AC, Gibson KM, Crunelli V, Cope DW (2011) Aberrant GABA(A) receptor-mediated inhibition in cortico-thalamic networks of succinic semialdehyde dehydrogenase deficient mice. PLoS One 6:e19021PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Bernhardt BC, Hong S, Bernasconi A, Bernasconi N (2013) Imaging structural and functional brain networks in temporal lobe epilepsy. Front Hum Neurosci 7:624PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Crunelli V, Leresche N (2002) Childhood absence epilepsy: genes, channels, neurons and networks. Nat Rev Neurosci 3:371–382PubMedCrossRefGoogle Scholar
  15. 15.
    Bonnycastle DD, Giarman NJ, Paasonen MK (1957) Anticonvulsant compounds and 5-hydroxytryptamine in rat brain. Br J Pharmacol Chemother 12:228–231PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Bombardi C (2012) Neuronal localization of 5-HT2A receptor immunoreactivity in the rat hippocampal region. Brain Res Bull 87:259–273PubMedCrossRefGoogle Scholar
  17. 17.
    Bombardi C, Di Giovanni G (2013) Functional anatomy of 5-HT2A receptors in the amygdala and hippocampal complex: relevance to memory functions. Exp Brain Res 230:427–439PubMedCrossRefGoogle Scholar
  18. 18.
    Li QH, Nakadate K, Tanaka-Nakadate S, Nakatsuka D, Cui YL, Watanabe Y (2004) Unique expression patterns of 5-HT2A and 5-HT2C receptors in the rat brain during postnatal development: western blot and immunohistochemical analyses. J Comp Neurol 469:128–140PubMedCrossRefGoogle Scholar
  19. 19.
    Cornea-Hebert V, Riad M, Wu C, Singh SK, Descarries L (1999) Cellular and subcellular distribution of the serotonin 5-HT2A receptor in the central nervous system of adult rat. J Comp Neurol 409:187–209PubMedCrossRefGoogle Scholar
  20. 20.
    Doherty MD, Pickel VM (2000) Ultrastructural localization of the serotonin 2A receptor in dopaminergic neurons in the ventral tegmental area. Brain Res 864:176–185PubMedCrossRefGoogle Scholar
  21. 21.
    Nocjar C, Roth BL, Pehek EA (2002) Localization of 5-HT(2A) receptors on dopamine cells in subnuclei of the midbrain A10 cell group. Neuroscience 111:163–176PubMedCrossRefGoogle Scholar
  22. 22.
    Di Giovanni G (2013) Serotonin in the pathophysiology and treatment of CNS disorders. Exp Brain Res 230:371–373PubMedCrossRefGoogle Scholar
  23. 23.
    Prendiville S, Gale K (1993) Anticonvulsant effect of fluoxetine on focally evoked limbic motor seizures in rats. Epilepsia 34:381–384PubMedCrossRefGoogle Scholar
  24. 24.
    Yan QS, Jobe PC, Dailey JW (1994) Evidence that a serotonergic mechanism is involved in the anticonvulsant effect of fluoxetine in genetically epilepsy-prone rats. Eur J Pharmacol 252:105–112PubMedCrossRefGoogle Scholar
  25. 25.
    Statnick MA, Maring-Smith ML, Clough RW, Wang C, Dailey JW, Jobe PC et al (1996) Effect of 5,7-dihydroxytryptamine on audiogenic seizures in genetically epilepsy-prone rats. Life Sci 59:1763–1771PubMedCrossRefGoogle Scholar
  26. 26.
    Tripathi PP, Di Giovannantonio LG, Viegi A, Wurst W, Simeone A, Bozzi Y (2008) Serotonin hyperinnervation abolishes seizure susceptibility in Otx2 conditional mutant mice. J Neurosci 28:9271–9276PubMedCrossRefGoogle Scholar
  27. 27.
    Parsons LH, Kerr TM, Tecott LH (2001) 5-HT(1A) receptor mutant mice exhibit enhanced tonic, stress-induced and fluoxetine-induced serotonergic neurotransmission. J Neurochem 77:607–617PubMedCrossRefGoogle Scholar
  28. 28.
    Sarnyai Z, Sibille EL, Pavlides C, Fenster RJ, McEwen BS, Toth M (2000) Impaired hippocampal-dependent learning and functional abnormalities in the hippocampus in mice lacking serotonin(1A) receptors. Proc Natl Acad Sci U S A 97:14731–14736PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Applegate CD, Tecott LH (1998) Global increases in seizure susceptibility in mice lacking 5-HT2C receptors: a behavioral analysis. Exp Neurol 154:522–530PubMedCrossRefGoogle Scholar
  30. 30.
    Compan V, Zhou M, Grailhe R, Gazzara RA, Martin R, Gingrich J et al (2004) Attenuated response to stress and novelty and hypersensitivity to seizures in 5-HT4 receptor knock-out mice. J Neurosci 24:412–419PubMedCrossRefGoogle Scholar
  31. 31.
    Witkin JM, Baez M, Yu J, Barton ME, Shannon HE (2007) Constitutive deletion of the serotonin-7 (5-HT(7)) receptor decreases electrical and chemical seizure thresholds. Epilepsy Res 75:39–45PubMedCrossRefGoogle Scholar
  32. 32.
    Van Oekelen D, Megens A, Meert T, Luyten WH, Leysen JE (2003) Functional study of rat 5-HT2A receptors using antisense oligonucleotides. J Neurochem 85:1087–1100PubMedCrossRefGoogle Scholar
  33. 33.
    Tecott LH, Sun LM, Akana SF, Strack AM, Lowenstein DH, Dallman MF et al (1995) Eating disorder and epilepsy in mice lacking 5-HT2c serotonin receptors. Nature 374:542–546PubMedCrossRefGoogle Scholar
  34. 34.
    Gharedaghi MH, Seyedabadi M, Ghia JE, Dehpour AR, Rahimian R (2014) The role of different serotonin receptor subtypes in seizure susceptibility. Exp Brain Res 232:347–367PubMedCrossRefGoogle Scholar
  35. 35.
    Buchanan GF, Murray NM, Hajek MA, Richerson GB (2014) Serotonin neurones have anti-convulsant effects and reduce seizure-induced mortality. J Physiol 592:4395–4410PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Przegalinski E, Baran L, Siwanowicz J (1994) Role of 5-hydroxytryptamine receptor subtypes in the 1-[3- (trifluoromethyl)phenyl] piperazine-induced increase in threshold for maximal electroconvulsions in mice. Epilepsia 35:889–894PubMedCrossRefGoogle Scholar
  37. 37.
    Watanabe K, Ashby CR Jr, Katsumori H, Minabe Y (2000) The effect of the acute administration of various selective 5-HT receptor antagonists on focal hippocampal seizures in freely-moving rats. Eur J Pharmacol 398:239–246PubMedCrossRefGoogle Scholar
  38. 38.
    Orban G, Bombardi C, Marino Gammazza A, Colangeli R, Pierucci M, Pomara C et al (2014) Role(s) of the 5-HT2C receptor in the development of maximal dentate activation in the hippocampus of anesthetized rats. CNS Neurosci Ther 20:651–661PubMedCrossRefGoogle Scholar
  39. 39.
    Wada Y, Nakamura M, Hasegawa H, Yamaguchi N (1992) Role of serotonin receptor subtype in seizures kindled from the feline hippocampus. Neurosci Lett 141:21–24PubMedCrossRefGoogle Scholar
  40. 40.
    Velisek L, Bohacenkova L, Capkova M, Mares P (1994) Clonidine, but not ritanserin, suppresses kainic acid-induced automatisms in developing rats. Physiol Behav 55:879–884PubMedCrossRefGoogle Scholar
  41. 41.
    Ritz MC, George FR (1997) Cocaine-induced convulsions: pharmacological antagonism at serotonergic, muscarinic and sigma receptors. Psychopharmacology 129:299–310PubMedCrossRefGoogle Scholar
  42. 42.
    Wada Y, Shiraishi J, Nakamura M, Koshino Y (1997) Role of serotonin receptor subtypes in the development of amygdaloid kindling in rats. Brain Res 747:338–342PubMedCrossRefGoogle Scholar
  43. 43.
    Pericic D, Lazic J, Jazvinscak Jembrek M, Svob Strac D (2005) Stimulation of 5-HT 1A receptors increases the seizure threshold for picrotoxin in mice. Eur J Pharmacol 527:105–110PubMedCrossRefGoogle Scholar
  44. 44.
    Grant KA, Hellevuo K, Tabakoff B (1994) The 5-HT3 antagonist MDL-72222 exacerbates ethanol withdrawal seizures in mice. Alcohol Clin Exp Res 18:410–414PubMedCrossRefGoogle Scholar
  45. 45.
    Lazarova M, Petkova B, Petkov VD (1995) Effect of dotarizine on electroconvulsive shock or pentylenetetrazol-induced amnesia and on seizure reactivity in rats. Methods Find Exp Clin Pharmacol 17:53–58PubMedGoogle Scholar
  46. 46.
    Shorvon S, Tomson T (2011) Sudden unexpected death in epilepsy. Lancet 378:2028–2038PubMedCrossRefGoogle Scholar
  47. 47.
    Fletcher A, Higgins GA (2011) Serotonin and reward-related behaviour: focus on 5-HT2C receptors. In: Di Giovanni G et al (eds) 5-HT2C receptors in the pathophysiology of CNS disease. Springer, New York, pp 293–324CrossRefGoogle Scholar
  48. 48.
    Higgins GA, Silenieks LB, Lau W, de Lannoy IA, Lee DK, Izhakova J et al (2013) Evaluation of chemically diverse 5-HT(2)c receptor agonists on behaviours motivated by food and nicotine and on side effect profiles. Psychopharmacology 226:475–490PubMedCrossRefGoogle Scholar
  49. 49.
    Orban G, Pierucci M, Benigno A, Pessia M, Galati S, Valentino M et al (2013) High dose of 8-OH-DPAT decreases maximal dentate gyrus activation and facilitates granular cell plasticity in vivo. Exp Brain Res 230:441–451PubMedCrossRefGoogle Scholar
  50. 50.
    Stringer JL, Williamson JM, Lothman EW (1989) Induction of paroxysmal discharges in the dentate gyrus: frequency dependence and relationship to afterdischarge production. J Neurophysiol 62:126–135PubMedCrossRefGoogle Scholar
  51. 51.
    Di Matteo V, Di Giovanni G, Esposito E (2000) SB 242084: a selective 5-HT2C receptor antagonist. CNS Drug Rev 6:195–205CrossRefGoogle Scholar
  52. 52.
    Kennett GA, Wood MD, Bright F, Trail B, Riley G, Holland V et al (1997) SB 242084, a selective and brain penetrant 5-HT2C receptor antagonist. Neuropharmacology 36:609–620PubMedCrossRefGoogle Scholar
  53. 53.
    McLean TH, Parrish JC, Braden MR, Marona-Lewicka D, Gallardo-Godoy A, Nichols DE (2006) 1-Aminomethylbenzocycloalkanes: conformationally restricted hallucinogenic phenethylamine analogues as functionally selective 5-HT2A receptor agonists. J Med Chem 49:5794–5803PubMedCrossRefGoogle Scholar
  54. 54.
    Watanabe K, Minabe Y, Ashby CR Jr, Katsumori H (1998) Effect of acute administration of various 5-HT receptor agonists on focal hippocampal seizures in freely moving rats. Eur J Pharmacol 350:181–188PubMedCrossRefGoogle Scholar
  55. 55.
    Sorensen SM, Kehne JH, Fadayel GM, Humphreys TM, Ketteler HJ, Sullivan CK et al (1993) Characterization of the 5-Ht(2) receptor antagonist Mdl 100907 as a putative atypical antipsychotic—behavioral, electrophysiological and neurochemical studies. J Pharmacol Exp Ther 266:684–691PubMedGoogle Scholar
  56. 56.
    Montiel C, Herrero CJ, Garcia-Palomero E, Renart J, Garcia AG, Lomax RB (1997) Serotonergic effects of dotarizine in coronary artery and in oocytes expressing 5-HT2 receptors. Eur J Pharmacol 332:183–193PubMedCrossRefGoogle Scholar
  57. 57.
    Coenen AM, Drinkenburg WH, Inoue M, van Luijtelaar EL (1992) Genetic models of absence epilepsy, with emphasis on the WAG/Rij strain of rats. Epilepsy Res 12:75–86PubMedCrossRefGoogle Scholar
  58. 58.
    Graf M, Jakus R, Kantor S, Levay G, Bagdy G (2004) Selective 5-HT1A and 5-HT7 antagonists decrease epileptic activity in the WAG/Rij rat model of absence epilepsy. Neurosci Lett 359:45–48PubMedCrossRefGoogle Scholar
  59. 59.
    Jakus R, Graf M, Juhasz G, Gerber K, Levay G, Halasz P et al (2003) 5-HT2C receptors inhibit and 5-HT1A receptors activate the generation of spike-wave discharges in a genetic rat model of absence epilepsy. Exp Neurol 184:964–972PubMedCrossRefGoogle Scholar
  60. 60.
    Jakus R, Bagdy G (2011b) The role of 5-HT2C receptor in epilepsy. In: Di Giovanni G et al (eds) 5-HT2C receptors in the pathophysiology of CNS disease. Springer-Verlag, Wien, pp 429–444CrossRefGoogle Scholar
  61. 61.
    Tokuda S, Kuramoto T, Tanaka K, Kaneko S, Takeuchi IK, Sasa M et al (2007) The ataxic groggy rat has a missense mutation in the P/Q-type voltage-gated Ca2+ channel alpha1A subunit gene and exhibits absence seizures. Brain Res 1133:168–177PubMedCrossRefGoogle Scholar
  62. 62.
    Ohno Y, Sofue N, Imaoku T, Morishita E, Kumafuji K, Sasa M et al (2010) Serotonergic modulation of absence-like seizures in groggy rats: a novel rat model of absence epilepsy. J Pharmacol Sci 114:99–105PubMedCrossRefGoogle Scholar
  63. 63.
    Cortez MA, McKerlie C, Snead OC 3rd (2001) A model of atypical absence seizures: EEG, pharmacology, and developmental characterization. Neurology 56:341–349PubMedCrossRefGoogle Scholar
  64. 64.
    Velazquez JL, Huo JZ, Dominguez LG, Leshchenko Y, Snead OC 3rd (2007) Typical versus atypical absence seizures: network mechanisms of the spread of paroxysms. Epilepsia 48:1585–1593PubMedCrossRefGoogle Scholar
  65. 65.
    Cortez MA, Perez Velazquez JL, Snead OC 3rd (2006) Animal models of epilepsy and progressive effects of seizures. Adv Neurol 97:293–304PubMedGoogle Scholar
  66. 66.
    Bercovici E, Cortez MA, Snead OC 3rd (2007) 5-HT2 modulation of AY-9944 induced atypical absence seizures. Neurosci Lett 418:13–17PubMedCrossRefGoogle Scholar
  67. 67.
    Danober L, Deransart C, Depaulis A, Vergnes M, Marescaux C (1998) Pathophysiological mechanisms of genetic absence epilepsy in the rat. Prog Neurobiol 55:27–57PubMedCrossRefGoogle Scholar
  68. 68.
    Depaulis A, David O, Charpier S (2015) The genetic absence epilepsy rat from Strasbourg as a model to decipher the neuronal and network mechanisms of generalized idiopathic epilepsies. J Neurosci MethodsGoogle Scholar
  69. 69.
    Venzi M, David F, Bellet J, Bombardi C, Cavaccini A, Di Giovanni G (2016) Role of serotonin2A (5-HT2A) and 2C (5-HT2C) receptors in experimental absence seizures: an electrophysiological and immunohistochemical study in GAERS and NEC rats. Neuropharmacology 108:292–304PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Bedard P, Pycock CJ (1977) “Wet-dog” shake behaviour in the rat: a possible quantitative model of central 5-hydroxytryptamine activity. Neuropharmacology 16:663–670PubMedCrossRefGoogle Scholar
  71. 71.
    Corne SJ, Pickering RW (1967) A possible correlation between drug-induced hallucinations in man and a behavioural response in mice. Psychopharmacologia 11:65–78PubMedCrossRefGoogle Scholar
  72. 72.
    Coulon P, Kanyshkova T, Broicher T, Munsch T, Wettschureck N, Seidenbecher T et al (2010) Activity modes in thalamocortical relay neurons are modulated by G(q)/G(11) family G-proteins—serotonergic and glutamatergic signaling. Front Cell Neurosci 4:132PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Munsch T, Freichel M, Flockerzi V, Pape HC (2003) Contribution of transient receptor potential channels to the control of GABA release from dendrites. Proc Natl Acad Sci U S A 100:16065–16070PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Di Giovanni G, Cope DW, Crunelli V (2008a) Cholinergic and monoaminergic modulation of tonic GABAA inhibition in the rat dorsal lateral geniculate nucleus. In: Annual meeting of Neuroscience Society, San Diego, USA, p 531.532/D533Google Scholar
  75. 75.
    Cavaccini A, Yagüe JG, Errington AC, Crunelli V, Di Giovanni G (2012) Opposite effects of thalamic 5-HT2A and 5-HT2C receptor activation on tonic GABA-A inhibition: implications for absence epilepsy. In: Annual meeting of Neuroscience Society, New Orleans, USA, p 138.103/B157Google Scholar
  76. 76.
    Barbaresi P, Spreafico R, Frassoni C, Rustioni A (1986) GABAergic neurons are present in the dorsal column nuclei but not in the ventroposterior complex of rats. Brain Res 382:305–326PubMedCrossRefGoogle Scholar
  77. 77.
    Yague JG, Cavaccini A, Errington AC, Crunelli V, Di Giovanni G (2013) Dopaminergic modulation of tonic but not phasic GABA(A)-receptor-mediated current in the ventrobasal thalamus of Wistar and GAERS rats. Exp Neurol 247:1–7PubMedCrossRefGoogle Scholar
  78. 78.
    Crunelli V, Di Giovanni G (2014) Monoamine modulation of tonic GABAA inhibition. Rev Neurosci 25(2):1–12CrossRefGoogle Scholar
  79. 79.
    Connelly WM, Errington AC, Di Giovanni G, Crunelli V (2013) Metabotropic regulation of extrasynaptic GABA(A) receptors. Front Neural Circuits 7:171PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Connelly WM, Errington AC, Yague JG, Cavaccini A, Crunelli V, Di Giovanni G (2014) GPCR modulation of extrasynapitic GABAA receptors. In: Errington AC et al (eds) Extrasynaptic GABAA receptors, vol 27. Springer, New York, pp 125–153Google Scholar
  81. 81.
    Steriade M (2005) Sleep, epilepsy and thalamic reticular inhibitory neurons. Trends Neurosci 28:317–324PubMedCrossRefGoogle Scholar
  82. 82.
    Pinault D, Leresche N, Charpier S, Deniau JM, Marescaux C, Vergnes M et al (1998) Intracellular recordings in thalamic neurones during spontaneous spike and wave discharges in rats with absence epilepsy. J Physiol 509(Pt 2):449–456PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    McCormick DA, Wang Z (1991) Serotonin and noradrenaline excite GABAergic neurones of the guinea-pig and cat nucleus reticularis thalami. J Physiol 442:235–255PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Polack PO, Guillemain I, Hu E, Deransart C, Depaulis A, Charpier S (2007) Deep layer somatosensory cortical neurons initiate spike-and-wave discharges in a genetic model of absence seizures. J Neurosci 27:6590–6599PubMedCrossRefGoogle Scholar
  85. 85.
    Warter JM, Vergnes M, Depaulis A, Tranchant C, Rumbach L, Micheletti G et al (1988) Effects of drugs affecting dopaminergic neurotransmission in rats with spontaneous petit mal-like seizures. Neuropharmacology 27:269–274PubMedCrossRefGoogle Scholar
  86. 86.
    Di Giovanni G, Di Matteo V, Esposito E (eds) (2008b) Serotonin–dopamine interaction: experimental evidence and therapeutic relevance. Elsevier, AmsterdamGoogle Scholar
  87. 87.
    Di Giovanni G, Esposito E, Di Matteo V (2010) Role of serotonin in central dopamine dysfunction. CNS Neurosci Ther 16:179–194PubMedCrossRefGoogle Scholar
  88. 88.
    McCormick DA (1992) Neurotransmitter actions in the thalamus and cerebral cortex and their role in neuromodulation of thalamocortical activity. Prog Neurobiol 39:337–388PubMedCrossRefGoogle Scholar
  89. 89.
    Meuth SG, Aller MI, Munsch T, Schuhmacher T, Seidenbecher T, Meuth P et al (2006) The contribution of TWIK-related acid-sensitive K+−containing channels to the function of dorsal lateral geniculate thalamocortical relay neurons. Mol Pharmacol 69:1468–1476PubMedCrossRefGoogle Scholar
  90. 90.
    Chapin EM, Andrade R (2001) A 5-HT(7) receptor-mediated depolarization in the anterodorsal thalamus. II. Involvement of the hyperpolarization-activated current I(h). J Pharmacol Exp Ther 297:403–409PubMedGoogle Scholar
  91. 91.
    Pape HC, McCormick DA (1989) Noradrenaline and serotonin selectively modulate thalamic burst firing by enhancing a hyperpolarization-activated cation current. Nature 340:715–718PubMedCrossRefGoogle Scholar
  92. 92.
    McCormick DA, Pape HC (1990) Properties of a hyperpolarization-activated cation current and its role in rhythmic oscillation in thalamic relay neurones. J Physiol 431:291–318PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Popa D, Lena C, Fabre V, Prenat C, Gingrich J, Escourrou P et al (2005) Contribution of 5-HT2 receptor subtypes to sleep-wakefulness and respiratory control, and functional adaptations in knock-out mice lacking 5-HT2A receptors. J Neurosci 25:11231–11238PubMedCrossRefGoogle Scholar
  94. 94.
    Dekeyne A, Brocco M, Loiseau F, Gobert A, Rivet JM, Di Cara B et al (2012) S32212, a novel serotonin type 2C receptor inverse agonist/alpha2-adrenoceptor antagonist and potential antidepressant: II. A behavioral, neurochemical, and electrophysiological characterization. J Pharmacol Exp Ther 340:765–780PubMedCrossRefGoogle Scholar
  95. 95.
    Bowden CL, Calabrese JR, Sachs G, Yatham LN, Asghar SA, Hompland M, Montgomery P, Earl N, Smoot TM, Deveaugh-Geiss J, Lamictal 606 Study, G (2003) A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. Arch Gen Psychiatry 60:392–400PubMedCrossRefGoogle Scholar
  96. 96.
    Huang HY, Lee HW, Chen SD, Shaw FZ (2012) Lamotrigine ameliorates seizures and psychiatric comorbidity in a rat model of spontaneous absence epilepsy. Epilepsia 53:2005–2014PubMedCrossRefGoogle Scholar
  97. 97.
    Glauser TA, Cnaan A, Shinnar S, Hirtz DG, Dlugos D, Masur D et al (2013) Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy: initial monotherapy outcomes at 12 months. Epilepsia 54:141–155PubMedCrossRefGoogle Scholar
  98. 98.
    Iyer A, Marson A (2014) Pharmacotherapy of focal epilepsy. Expert Opin Pharmacother 15:1543–1551PubMedCrossRefGoogle Scholar
  99. 99.
    Than M, Kocsis P, Tihanyi K, Fodor L, Farkas B, Kovacs G, Kis-Varga A, Szombathelyi Z, Tarnawa I (2007) Concerted action of antiepileptic and antidepressant agents to depress spinal neurotransmission: Possible use in the therapy of spasticity and chronic pain. Neurochem Int 50:642–652PubMedCrossRefGoogle Scholar
  100. 100.
    Loscher W (2002) Basic pharmacology of valproate: a review after 35 years of clinical use for the treatment of epilepsy. CNS Drugs 16:669–694PubMedCrossRefGoogle Scholar
  101. 101.
    Green AR, Johnson P, Mountford JA, Nimgaonkar VL (1985) Some anticonvulsant drugs alter monoamine-mediated behaviour in mice in ways similar to electroconvulsive shock; implications for antidepressant therapy. Br J Pharmacol 84:337–346PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Sullivan NR, Burke T, Siafaka-Kapadai A, Javors M, Hensler JG (2004) Effect of valproic acid on serotonin-2A receptor signaling in C6 glioma cells. J Neurochem 90:1269–1275PubMedCrossRefGoogle Scholar
  103. 103.
    Yatham LN, Liddle PF, Lam RW, Adam MJ, Solomons K, Chinnapalli M et al (2005) A positron emission tomography study of the effects of treatment with valproate on brain 5-HT2A receptors in acute mania. Bipolar Disord 7(Suppl 5):53–57PubMedCrossRefGoogle Scholar
  104. 104.
    Brown KM, Tracy DK (2013) Lithium: the pharmacodynamic actions of the amazing ion. Ther Adv Psychopharmacol 3:163–176PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Kanner AM (2003) Depression in epilepsy: prevalence, clinical semiology, pathogenic mechanisms, and treatment. Biol Psychiatry 54:388–398PubMedCrossRefGoogle Scholar
  106. 106.
    Kanner AM, Balabanov A (2002) Depression and epilepsy: how closely related are they? Neurology 58:S27–S39PubMedCrossRefGoogle Scholar
  107. 107.
    Stafford-Clark D (1954) Epilepsy and depression: implications of empirical therapy. Guys Hosp Rep 103:306–316PubMedGoogle Scholar
  108. 108.
    Kanner AM, Schachter SC, Barry JJ, Hersdorffer DC, Mula M, Trimble M et al (2012) Depression and epilepsy: epidemiologic and neurobiologic perspectives that may explain their high comorbid occurrence. Epilepsy Behav 24:156–168PubMedCrossRefGoogle Scholar
  109. 109.
    Vega C, Guo J, Killory B, Danielson N, Vestal M, Berman R et al (2011) Symptoms of anxiety and depression in childhood absence epilepsy. Epilepsia 52:e70–e74PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Harden CL (2002) The co-morbidity of depression and epilepsy: epidemiology, etiology, and treatment. Neurology 59:S48–S55PubMedCrossRefGoogle Scholar
  111. 111.
    Epps SA, Tabb KD, Lin SJ, Kahn AB, Javors MA, Boss-Williams KA et al (2012) Seizure susceptibility and epileptogenesis in a rat model of epilepsy and depression co-morbidity. Neuropsychopharmacology 37:2756–2763PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Sarkisova K, van Luijtelaar G (2012) The WAG/Rij strain: a genetic animal model of absence epilepsy with comorbidity of depression [corrected]. Prog Neuro-Psychopharmacol Biol Psychiatry 35:854–876CrossRefGoogle Scholar
  113. 113.
    Hesdorffer DC, Allen Hauser W, Olafsson E, Ludvigsson P, Kjartansson O (2006) Depression and suicide attempt as risk factors for incident unprovoked seizures. Ann Neurol 59:35–41PubMedCrossRefGoogle Scholar
  114. 114.
    Epps SA, Weinshenker D (2013) Rhythm and blues: animal models of epilepsy and depression comorbidity. Biochem Pharmacol 85:135–146PubMedCrossRefGoogle Scholar
  115. 115.
    Esposito E, Di Matteo V, Di Giovanni G (2008) Serotonin-dopamine interaction: an overview. Prog Brain Res 172:3–6PubMedCrossRefGoogle Scholar
  116. 116.
    Russo E, Citraro R, Davoli A, Gallelli L, Donato Di Paola E, De Sarro G (2013) Ameliorating effects of aripiprazole on cognitive functions and depressive-like behavior in a genetic rat model of absence epilepsy and mild-depression comorbidity. Neuropharmacology 64:371–379PubMedCrossRefGoogle Scholar
  117. 117.
    Hedges D, Jeppson K, Whitehead P (2003) Antipsychotic medication and seizures: a review. Drugs Today (Barc) 39:551–557CrossRefGoogle Scholar
  118. 118.
    Specchio LM, Iudice A, Specchio N, La Neve A, Spinelli A, Galli R et al (2004) Citalopram as treatment of depression in patients with epilepsy. Clin Neuropharmacol 27:133–136PubMedCrossRefGoogle Scholar
  119. 119.
    Hidaka N, Suemaru K, Araki H (2010) Serotonin-dopamine antagonism ameliorates impairments of spontaneous alternation and locomotor hyperactivity induced by repeated electroconvulsive seizures in rats. Epilepsy Res 90:221–227PubMedCrossRefGoogle Scholar
  120. 120.
    Genkova-Papazova M, Lazarova-Bakarova M, Petkov VD (1994) The 5-HT2 receptor antagonist ketanserine prevents electroconvulsive shock- and clonidine-induced amnesia. Pharmacol Biochem Behav 49:849–852PubMedCrossRefGoogle Scholar
  121. 121.
    Graybiel AM (2004) Network-level neuroplasticity in cortico-basal ganglia pathways. Parkinsonism Relat Disord 10:293–296PubMedCrossRefGoogle Scholar
  122. 122.
    Krebs-Thomson K, Paulus MP, Geyer MA (1998) Effects of hallucinogens on locomotor and investigatory activity and patterns: influence of 5-HT2A and 5-HT2C receptors. Neuropsychopharmacology 18:339–351PubMedCrossRefGoogle Scholar
  123. 123.
    Deransart C, Riban V, Le B, Marescaux C, Depaulis A (2000) Dopamine in the striatum modulates seizures in a genetic model of absence epilepsy in the rat. Neuroscience 100:335–344PubMedCrossRefGoogle Scholar
  124. 124.
    Marescaux C, Vergnes M, Depaulis A (1992) Genetic absence epilepsy in rats from Strasbourg - A review. J Neural Transm 35:37–69Google Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Neuroscience DivisionSchool of Bioscience, Cardiff UniversityCardiffUK
  2. 2.Department of Physiology and BiochemistryUniversity of MaltaMsidaMalta
  3. 3.AstraZeneca Translational Science Centre at Karolinska InstitutetStockholmSweden
  4. 4.Université de BordeauxBordeauxFrance
  5. 5.Centre National de la Recherche ScientifiqueUMR 5287BordeauxFrance

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