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Psychopharmacology

, Volume 207, Issue 4, pp 661–669 | Cite as

Effect of acute and chronic treatment with milnacipran potentiates the anticonvulsant activity of conventional antiepileptic drugs in the maximal electroshock-induced seizures in mice

  • Kinga K. BorowiczEmail author
  • Kamila Furmanek-Karwowska
  • Marta Morawska
  • Jarogniew J. Luszczki
  • Stanislaw J. Czuczwar
Original Investigation

Abstract

Rationale

Depression often coexists with epilepsy. Simultaneous therapy of the two diseases may be associated with pharmacodynamic and/or pharmacokinetic interactions between antiepileptic and antidepressant drugs.

Objectives

The aim of this study was to investigate the influence of acute and chronic treatment with intraperitoneal milnacipran (MLN), a selective serotonin/noradrenaline reuptake inhibitor, on the protective activity of valproate, carbamazepine (CBZ), phenytoin, or phenobarbital (PB) in the maximal electroshock (MES) test in mice.

Materials and methods

Electroconvulsions were produced by an alternating current (50 Hz, 25 mA) delivered via ear-clip electrodes. Motor coordination and long-term memory were evaluated in the chimney test and passive-avoidance task, respectively. Brain concentrations of antiepileptic drugs (AEDs) were assessed by immunofluorescence.

Results

Given acutely, MLN at 10 mg/kg increased the convulsive threshold. Acute MLN applied at the subprotective dose of 5 mg/kg enhanced the anticonvulsant effects of CBZ and PB. Chronic treatment with MLN (5–30 mg/kg once daily for 2 weeks) did not affect either the electroconvulsive threshold or the anticonvulsant action of all studied conventional antiepileptic drugs. Since the antidepressant did not affect brain concentrations of antiepileptics used in the study, the revealed interactions seem to be of pharmacodynamic nature. Moreover, acute and chronic MLN, AEDs, and their combinations did not produce significant motor and long-term memory impairment.

Conclusions

Acute, but not chronic, treatment with MLN can increase the effectiveness of some AEDs against MES-induced seizures in mice. It seems that MLN may also be considered as a candidate drug for clinical trials in patients with epilepsy and depressive disorders.

Keywords

Milnacipran Antiepileptic drugs Maximal electroshock Pharmacokinetic interaction 

Notes

Acknowledgments

This study was supported by a grant from Medical University of Lublin.

References

  1. Assie MB, Charveron M, Palmier C, Puozzo C, Moret C, Briley M (1992) Effects of prolonged administration of milnacipran, a new antidepressant, on receptors and monoamine uptake in the brain. Neuropharmacology 31:149–155CrossRefPubMedGoogle Scholar
  2. Bagdy G, Kecskemeti V, Riba P, Jakus R (2007) Serotonin and epilepsy. J Neurochem 100(4):857–873CrossRefPubMedGoogle Scholar
  3. Boissier JR, Tardy J, Diverres JC (1960) Une nouvelle methode simple pour explorer l’action tranquilisante: le test de la cheminee. Med Exp (Basel) 3:81–84CrossRefGoogle Scholar
  4. Borowicz KK, Stepien K, Czuczwar SJ (2006) Fluoxetine enhances the anticonvulsant effects of conventional antiepileptic drugs in maximal electroshock seizures in mice. Pharmacol Rep 58:83–90PubMedGoogle Scholar
  5. Borowicz KK, Banach M, Zarczuk R, Lukasik D, Luszczki JJ, Czuczwar SJ (2007a) Acute and chronic treatment with mianserin differentially affects the anticonvulsant activity of conventional antiepileptics drugs in the mouse maximal electroshock model. Psychopharmacology 195:167–174CrossRefGoogle Scholar
  6. Borowicz KK, Furmanek-Karwowska K, Sawicka K, Luszczki JJ, Czuczwar SJ (2007b) Chronically administered fluoxetine enhances the anticonvulsant activity of conventional antiepileptics drugs in the mouse maximal electroshock model. Eur J Pharmacol 567:77–82CrossRefGoogle Scholar
  7. Bourin M (1999) Psychopharmacological profile of venlafaxine. Encephale 25 Spec No 2:21–25Google Scholar
  8. Bourin M, Masse F, Daily E, Hascoet M (2005) Anxiolytic-like effect of milnacipran in the four-plate test in mice: mechanism of action. Pharmacol Biochem Behav 81:645–656CrossRefPubMedGoogle Scholar
  9. Briley M, Prost JF, Moret C (1996) Preclinical pharmacology of milnacipran. Int Clin Psychopharmacol 11 Suppl 4:9–14CrossRefGoogle Scholar
  10. Ceron-Litvoc D, Soares BG, Geddes J, Litvoc J, de Lima MS (2009) Comparison of carbamazepine and lithium in treatment of bipolar disorder: a systematic review of randomized controlled trials. Hum Psychopharmacol 24:19–28CrossRefPubMedGoogle Scholar
  11. Ceyhan M, Kayir H, Uzbay IT (2005) Investigation of the effects of tianeptine and fluoxetine on pentylenetetrazole-induced seizures in rats. J Psychiatr Res 39:191–196CrossRefPubMedGoogle Scholar
  12. Chen Z, Yang J, Tobak A (2008) Designing new treatments for depression and anxiety. I Drugs 11:189–197PubMedGoogle Scholar
  13. Clinckers R, Smolders I, Meurs A, Ebinger G, Michotte Y (2004) Anticonvulsant action of hippocampal dopamine and serotonin is independently mediated by D and 5HT receptors. J Neurochem 89:834–843CrossRefPubMedGoogle Scholar
  14. Dailey JW, Naritoku DK (1996) Antidepressants and seizures: clinical anecdotes overshadow neuroscience. Biochem Pharmacol 52:1323–1329CrossRefPubMedGoogle Scholar
  15. Deak F, Lasztoczi B, Pacher P, Petheo GL, Kecskemeti V, Spat A (2000) Inhibition of voltage-gated calcium channels by fluoxetine in rat hippocampal pyramidal cells. Neuropharmacology 39:1029–1036CrossRefPubMedGoogle Scholar
  16. Favale E, Rubino V, Mainardi P, Lunardi G, Albano C (1995) Anticonvulsant effect of fluoxetine in humans. Neurology 45:1926–1927PubMedGoogle Scholar
  17. Haddad PM, Das A, Ashfaq M, Wieck A (2009) A review of valproate in psychiatric practice. Expert Opin Drug Metab Toxicol 5:539–551CrossRefPubMedGoogle Scholar
  18. Harden CL, Goldstein MA (2002) Mood disorders in patients with epilepsy: epidemiology and management. CNS Drugs 16:291–302CrossRefPubMedGoogle Scholar
  19. Holmes GL (2007) Animal model studies application to human patients. Neurology 69(Suppl 3):S28–S32CrossRefPubMedGoogle Scholar
  20. Ivanez V, Ojeda J (2006) Exacerbation of seizures in medial temporal lobe epilepsy due to an alpha1-adrenergic antagonist. Epilepsia 47:1741–1742CrossRefPubMedGoogle Scholar
  21. Ivkovic M, Damjanovic A, Jovanovic A, Cvetic T, Jasovic-Gasic M (2009) Lamotrigine versus lithium augmentation of antidepressant therapy in treatment-resistant depression: efficacy and tolerability. Psychiatr Danub 21:187–193PubMedGoogle Scholar
  22. Jobe PC (2003) Common pathogenic mechanisms between depression and epilepsy: an experimental perspective. Epilepsy Behav 4:S14–S24CrossRefPubMedGoogle Scholar
  23. Jobe CJ, Browning RA (2005) The serotonergic and noradrenergic effects of antidepressant drugs are anticonvulsant, not proconvulsant. Epilepsy Behav 7:602–619CrossRefPubMedGoogle Scholar
  24. Jobe PC, Dailey JW, Wernicke JF (1999) A noradrenergic and serotonergic hypothesis of the linkage between epilepsy and affective disorders. Crit Rev Neurobiol 13:317–356PubMedGoogle Scholar
  25. Juruena MF, Ottoni GL, Machado-Vieira R, Carneiro RM, Weingarthner N, Marquardt AR, Fleig SS, Broilo L, Busnello EA (2009) Bipolar I and II disorder residual symptoms: oxcarbazepine and carbamazepine as add-on treatment to lithium in a double-blind, randomized trial. Prog Neuropsychopharmacol Biol Psychiatry 33:94–99CrossRefPubMedGoogle Scholar
  26. Kleinrok Z, Gustaw J, Czuczwar SJ (1991) Influence of antidepressant drugs on seizure susceptibility and the anticonvulsant activity of valproate in mice. J Neural Transm (Suppl.) 34:85–90Google Scholar
  27. Litchfield JT, Wilcoxon F (1949) A simplified method of evaluating dose-effect experiments. J Pharmacol Exp Ther 96:99–113PubMedGoogle Scholar
  28. Luszczki JJ, Czuczwar SJ (2005) How significant is the difference between drug doses influencing the threshold for electroconvulsions? Pharmacol Rep 57:782–786PubMedGoogle Scholar
  29. Meurs A, Clinckers R, Ebinger G, Michotte Y, Smolders I (2008) Seizure activity and changes in hippocampal extracellular glutamate, GABA, dopamine and serotonin. Epilepsy Res 78:50–59CrossRefPubMedGoogle Scholar
  30. Moojen VK, Martins MR, Reinke A, Feier G, Agostinho FR, Cechin EM, Quevedo J (2006) Effects of milnacipran in animal models of anxiety and memory. Neurochem Res 31:571–577CrossRefPubMedGoogle Scholar
  31. Morishita S (2009) Clonazepam as a therapeutic adjunct to improve the management of depression: a brief review. Hum Psychopharmacol 24:191–198CrossRefPubMedGoogle Scholar
  32. Pae CU (2009) Pregabalin augmentation to antidepressants in patients with major depressive disorder. Prog Neuro-Psychopharmacol Biol Psychiatry 33:577–578CrossRefGoogle Scholar
  33. Pericic D, Svob Strac D (2007) The role of 5-HT(7) receptors in the control of seizures. Brain Res 1141:48–55CrossRefPubMedGoogle Scholar
  34. Poirier MF, Galinowski A, Amado I, Longevialle R, Bourdel MC, Tournoux A, Serre C, Loo H (2004) Double-blind comparative study of the action of repeated administration of milnacipran versus placebo on cognitive functions in healthy volunteers. Hum Psychopharmacol 19:1–7CrossRefPubMedGoogle Scholar
  35. Porecca F, Jiang Q, Tallarida RJ (1990) Modulation of morphine antinociception by peripheral [Leu5]enkephalin: a synergistic interaction. Eur J Pharmacol 179:463–468CrossRefGoogle Scholar
  36. Puozzo C, Panconi E, Deprez D (2002) Pharmacology and pharmacokinetics of milnacipran. Int Clin Psychopharmacol 17(1):S25–S35PubMedGoogle Scholar
  37. Rosenstein DL, Nelson JC, Jacobs SC (1993) Seizures associated with antidepressants: a review. J Clin Psychiatry 54:289–299PubMedGoogle Scholar
  38. Salzberg MR, Vajda FJE (2001) Epilepsy, depression and antidepressant drugs. J Clin Neurosci 8:209–215CrossRefPubMedGoogle Scholar
  39. Seethalakshmi R, Krishnamoorthy ES (2007) Depression in epilepsy: phenomenology, diagnosis and management. Epileptic Disord 9:1–10PubMedGoogle Scholar
  40. Sillis MA, Loo PS (1989) Tricyclic antidepressant and dextromethorphan bind with higher affinity to the phencyclidine receptor in the absence of magnesium and L-glutamate. Mol Pharmacol 36:160–165Google Scholar
  41. Smolders I, Clinckers R, Meurs A, De Bundel D, Portelli J, Ebinger G, Michotte Y (2008) Direct enhancement of hippocampal dopamine or serotonin levels as a pharmacodynamic measure of combined antidepressant–anticonvulsant action. Neuropharmacology 54:1017–1028CrossRefPubMedGoogle Scholar
  42. Statnick MA, Maring-Smith ML, Clough RW, Wang C, Dailey JW, Jobe PC, Browning RA (1996) Effect of 5, 7-dihydroxytryptamine on audiogenic seizures in genetically epilepsy-prone rats. Life Sci 69:1763–1771CrossRefGoogle Scholar
  43. Tran PV, Bymaster FP, McNamara RK, Potter WZ (2003) Dual monoamine modulation for improved treatment of major depressive disorder. J Clin Psychopharmacol 23:78–86CrossRefPubMedGoogle Scholar
  44. Treiman DM (2001) GABAergic mechanism in epilepsy. Epilepsia 42(Suppl. 3):8–12CrossRefPubMedGoogle Scholar
  45. Trimble MR, Meldrum BS, Anlezark G (1977) Effect of nomifensine on brain amines and epilepsy in photosensitive baboons. Br J Clin Pharmacol 4(Suppl 2):101S–107SPubMedGoogle Scholar
  46. Tutka P, Mróz T, Klucha K, Piekarczyk M, Wielosz M (2005) Bupropion-induced convulsions: preclinical evaluation of antiepileptic drugs. Epilepsy Res 64:13–22CrossRefPubMedGoogle Scholar
  47. Ugale RR, Mittal N, Hirani K, Chopde CT (2004) Essentiality of central GABAergic neuroactive steroid allopregnanolone for anticonvulsant action of fluoxetine against pentylenetetrazole-induced seizures in mice. Brain Res 1023:102–111CrossRefPubMedGoogle Scholar
  48. Uzbay IT (2008) Serotonergic anti-depressants and ethanol withdrawal syndrome: a review. Alcohol Alcohol 43:15–25PubMedGoogle Scholar
  49. Venault P, Chapouthier G, De Carvalho LP, Simiand J, Morre M, Dodd RH, Rossier J (1986) Benzodiazepines impair and beta-carbolines enhance performance in learning and memory tasks. Nature 321:864–866CrossRefPubMedGoogle Scholar
  50. Vigo DV, Baldessarini RJ (2009) Anticonvulsants in the treatment of major depressive disorder: an overview. Harv Rev Psychiatry 17:231–241CrossRefPubMedGoogle Scholar
  51. Wang C, Mishra PK, Dailey JW, Jobe PC, Browning RA (1994) Noradrenergic terminal fields as determinants of seizure predisposition in GEPR-3s: a neuroanatomic assessment with intracerebral microinjections of 6-hydroxydopamine. Epilepsy Res 18:1–9CrossRefPubMedGoogle Scholar
  52. Wegener G, Volke V, Harvey BH, Rosenberg R (2003) Local, but not systemic, administration of serotonergic antidepressants decreases hippocampal nitric oxide synthase activity. Brain Res 959(1):128–134CrossRefPubMedGoogle Scholar
  53. Weinshenker D, Szot P, Miller NS, Palmiter RD (2001) Alpha(1) and beta(2) adrenoreceptor agonists inhibit pentylenetetrazole-induced seizures in mice lacking norepinephrine. J Pharmacol Exp Ther 298:1042–1048PubMedGoogle Scholar
  54. Weiss M, Blier P, de Montigny C (2007) Effect of long-term administration of the antidepressant drug milnacipran on serotonergic and noradrenergic projections. Exp Neurol 108:136–140CrossRefGoogle Scholar
  55. Wesolowska A, Nikiforuk A, Chojnacka-Wójcik E (2006) Anticonvulsant effect of the selective 5-HT1B receptor agonist CP 94253 in mice. Eur J Pharmacol 541:57–63CrossRefPubMedGoogle Scholar
  56. 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 75:39–45CrossRefPubMedGoogle Scholar
  57. Yilmaz I, Sezer Z, Kayir H, Uzbay TI (2007) Mirtazapine does not affect pentylenetetrazole- and maximal electroconvulsive shock-induced seizures in mice. Epilepsy Beh 11:1–5CrossRefGoogle Scholar
  58. Zemlan FP, Garver DL (1990) Depression and antidepressant therapy: receptor dynamics. Prog Neuropsychopharmacol Biol Psychiatry 14:503–523CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Kinga K. Borowicz
    • 1
    Email author
  • Kamila Furmanek-Karwowska
    • 1
  • Marta Morawska
    • 1
  • Jarogniew J. Luszczki
    • 1
  • Stanislaw J. Czuczwar
    • 1
  1. 1.Experimental Neuropathophysiology Unit, Department of PathophysiologyLublin Medical UniversityLublinPoland

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