Psychopharmacology

, Volume 229, Issue 4, pp 617–626 | Cite as

Differential mechanisms underlie the regulation of serotonergic transmission in the dorsal and median raphe nuclei by mirtazapine: a dual probe microdialysis study

  • Kouji Fukuyama
  • Shunske Tanahashi
  • Tatsuya Hamaguchi
  • Masanori Nakagawa
  • Takashi Shiroyama
  • Eishi Motomura
  • Motohiro Okada
Original Investigation

Abstract

Rationale

Blockade of α2 adrenoceptors and histamine H1 receptors plays important roles in the antidepressant and hypnotic effects of mirtazapine.

Objectives

However, it remains unclear how mirtazapine’s actions at these receptors interact to affect serotonergic transmission in the dorsal (DRN) and median (MRN) raphe nuclei.

Method

Using dual-probe microdialysis, we determined the roles of α2 and H1 receptors in the effects of mirtazapine on serotonergic transmission in the DRN and MRN and their respective projection regions, the frontal (FC) and entorhinal (EC) cortices.

Results

Mirtazapine (<30 μM) failed to alter extracellular serotonin levels when perfused alone into the raphe nuclei, but when co-perfused with a 5-HT1A receptor antagonist, mirtazapine increased serotonin levels in the DRN, MRN, FC, and EC. Serotonin levels in the DRN and FC were decreased by blockade and increased by activation of H1 receptors in the DRN. Serotonin levels in the MRN and EC were not affected by H1 agonists/antagonists perfused in the MRN. The increase in serotonin levels in the DRN and FC induced by DRN H1 receptor activation was attenuated by co-perfusion with mirtazapine. Furthermore, the increase in serotonin levels (DRN/FC) induced by DRN α2 adrenoceptor blockade was attenuated by concurrent DRN H1 blockade, whereas the increase in serotonin levels (MRN/EC) induced by MRN α2 adrenoceptor inhibition was unaffected by concurrent MRN H1 receptor blockade.

Conclusion

These results suggest that enhanced serotonergic transmission resulting from α2 adrenoceptor blockade is offset by subsequent activation of 5-HT1A receptors and, in the DRN but not MRN, H1 receptor inhibition. These pharmacological actions of mirtazapine may explain its antidepressant and hypnotic actions.

Keywords

Mirtazapine Microdialysis Serotonin Raphe nuclei Cortex Histamine 

Notes

Acknowledgments

This study was supported by a grant-in-aid for Scientific Research from the Japanese Ministry of Education, Science and Culture (22390224 and 23659564) and a grant from the Japan Epilepsy Research Foundation. We thank A/Prof. F.G. Issa (http://www.word-medex.com.au) for the careful reading and editing of the manuscript.

Conflict of interest

The authors declare no conflict of interest.

References

  1. Adell A, Celada P, Abellan MT, Artigas F (2002) Origin and functional role of the extracellular serotonin in the midbrain raphe nuclei. Brain Res Brain Res Rev 39:154–180PubMedCrossRefGoogle Scholar
  2. Alexander SP, Mathie A, Peters JA (2011) Guide to receptors and channels (GRAC), 5th edition. Br J Pharmacol 164(Suppl 1):S1–S324PubMedCrossRefGoogle Scholar
  3. Bengtsson HJ, Kele J, Johansson J, Hjorth S (2000) Interaction of the antidepressant mirtazapine with alpha2-adrenoceptors modulating the release of 5-HT in different rat brain regions in vivo. Naunyn Schmiedebergs Arch Pharmacol 362:406–412PubMedCrossRefGoogle Scholar
  4. Benmansour S, Owens WA, Cecchi M, Morilak DA, Frazer A (2002) Serotonin clearance in vivo is altered to a greater extent by antidepressant-induced downregulation of the serotonin transporter than by acute blockade of this transporter. J Neurosci 22:6766–6772PubMedGoogle Scholar
  5. Cipriani A, Furukawa TA, Salanti G, Geddes JR, Higgins JP, Churchill R, Watanabe N, Nakagawa A, Omori IM, McGuire H, Tansella M, Barbui C (2009) Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet 373:746–758PubMedCrossRefGoogle Scholar
  6. Cohrs S, Meier A, Neumann AC, Jordan W, Ruther E, Rodenbeck A (2005) Improved sleep continuity and increased slow wave sleep and REM latency during ziprasidone treatment: a randomized, controlled, crossover trial of 12 healthy male subjects. J Clin Psychiatry 66:989–996PubMedCrossRefGoogle Scholar
  7. Cohrs S, Rodenbeck A, Guan Z, Pohlmann K, Jordan W, Meier A, Ruther E (2004) Sleep-promoting properties of quetiapine in healthy subjects. Psychopharmacology (Berl) 174:421–429Google Scholar
  8. Croom KF, Perry CM, Plosker GL (2009) Mirtazapine: a review of its use in major depression and other psychiatric disorders. CNS Drugs 23:427–452PubMedCrossRefGoogle Scholar
  9. de Boer T (1995) The effects of mirtazapine on central noradrenergic and serotonergic neurotransmission. Int Clin Psychopharmacol 10(Suppl 4):19–23PubMedCrossRefGoogle Scholar
  10. de Boer T (1996) The pharmacologic profile of mirtazapine. J Clin Psychiatry 57(Suppl 4):19–25PubMedGoogle Scholar
  11. Fava M (2004) Daytime sleepiness and insomnia as correlates of depression. J Clin Psychiatry 65(Suppl 16):27–32PubMedGoogle Scholar
  12. Haas HL, Sergeeva OA, Selbach O (2008) Histamine in the nervous system. Physiol Rev 88:1183–1241PubMedCrossRefGoogle Scholar
  13. Imai H, Steindler DA, Kitai ST (1986) The organization of divergent axonal projections from the midbrain raphe nuclei in the rat. J Comp Neurol 243:363–380PubMedCrossRefGoogle Scholar
  14. Ishida T, Obara Y, Kamei C (2009) Effects of some antipsychotics and a benzodiazepine hypnotic on the sleep-wake pattern in an animal model of schizophrenia. J Pharmacol Sci 111:44–52PubMedCrossRefGoogle Scholar
  15. Komossa K, Depping AM, Gaudchau A, Kissling W, Leucht S (2010) Second-generation antipsychotics for major depressive disorder and dysthymia. Cochrane Database Syst Rev (12):CD008121.Google Scholar
  16. Meltzer HY, Li Z, Kaneda Y, Ichikawa J (2003) Serotonin receptors: their key role in drugs to treat schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 27:1159–1172PubMedCrossRefGoogle Scholar
  17. Millan MJ, Gobert A, Rivet JM, Adhumeau-Auclair A, Cussac D, Newman-Tancredi A, Dekeyne A, Nicolas JP, Lejeune F (2000) Mirtazapine enhances frontocortical dopaminergic and corticolimbic adrenergic, but not serotonergic, transmission by blockade of alpha2-adrenergic and serotonin2C receptors: a comparison with citalopram. Eur J Neurosci 12:1079–1095PubMedCrossRefGoogle Scholar
  18. Monti JM (2011) Serotonin control of sleep-wake behavior. Sleep Med Rev 15:269–281PubMedCrossRefGoogle Scholar
  19. Nakayama K, Sakurai T, Katsu H (2004) Mirtazapine increases dopamine release in prefrontal cortex by 5-HT1A receptor activation. Brain Res Bull 63:237–241PubMedCrossRefGoogle Scholar
  20. Ohoyama K, Yamamura S, Hamaguchi T, Nakagawa M, Motomura E, Shiroyama T, Tanii H, Okada M (2011) Effects of novel atypical antipsychotic, blonanserin, on extracellular neurotransmitter level in rat prefrontal cortex. Eur J Pharmacol 653(1–3):47–57PubMedCrossRefGoogle Scholar
  21. Paxinos G, Watson C (1998) The rat brain in stereotoxic coordinates, 4th edn. Academic, San DiegGoogle Scholar
  22. Petty F, Davis LL, Kabel D, Kramer GL (1996) Serotonin dysfunction disorders: a behavioral neurochemistry perspective. J Clin Psychiatry 57(Suppl 8):11–16PubMedGoogle Scholar
  23. Raap DK, Evans S, Garcia F, Li Q, Muma NA, Wolf WA, Battaglia G, Van De Kar LD (1999) Daily injections of fluoxetine induce dose-dependent desensitization of hypothalamic 5-HT1A receptors: reductions in neuroendocrine responses to 8-OH-DPAT and in levels of Gz and Gi proteins. J Pharmacol Exp Ther 288:98–106PubMedGoogle Scholar
  24. Richelson E, Souder T (2000) Binding of antipsychotic drugs to human brain receptors focus on newer generation compounds. Life Sci 68:29–39PubMedCrossRefGoogle Scholar
  25. Sakai K, Crochet S (2000) Serotonergic dorsal raphe neurons cease firing by disfacilitation during paradoxical sleep. Neuroreport 11:3237–3241PubMedCrossRefGoogle Scholar
  26. Schatzberg AF, Kremer C, Rodrigues HE, Murphy GM Jr (2002) Double-blind, randomized comparison of mirtazapine and paroxetine in elderly depressed patients. Am J Geriatr Psychiatry 10:541–550PubMedGoogle Scholar
  27. Shen J, Chung SA, Kayumov L, Moller H, Hossain N, Wang X, Deb P, Sun F, Huang X, Novak M, Appleton D, Shapiro CM (2006) Polysomnographic and symptomatological analyses of major depressive disorder patients treated with mirtazapine. Can J Psychiatry 51:27–34PubMedGoogle Scholar
  28. Takekita Y, Kato M, Wakeno M, Sakai S, Suwa A, Nishida K, Okugawa G, Kinoshita T (2012) A 12-week randomized, open-label study of perospirone versus aripiprazole in the treatment of Japanese schizophrenia patients. Prog Neuropsychopharmacol Biol Psychiatry 40:110–114PubMedCrossRefGoogle Scholar
  29. Tanahashi S, Ueda Y, Nakajima A, Yamamura S, Nagase H, Okada M (2012a) Novel delta1-receptor agonist KNT-127 increases the release of dopamine and l-glutamate in the striatum, nucleus accumbens and median pre-frontal cortex. Neuropharmacology 62:2057–2067PubMedCrossRefGoogle Scholar
  30. Tanahashi S, Yamamura S, Nakagawa M, Motomura E, Okada M (2011a) Clozapine, but not haloperidol, enhances glial d-serine and l-glutamate release in rat frontal cortex and primary cultured astrocytes. Br J Pharmacol 165(5):1543–1555CrossRefGoogle Scholar
  31. Tanahashi S, Yamamura S, Nakagawa M, Motomura E, Okada M (2011b) Effect of lamotrigine and carbamazepine on corticotropin-releasing factor-associated serotonergic transmission in rat dorsal raphe nucleus. Psychopharmacology (Berl) 220(3):599–610PubMedCrossRefGoogle Scholar
  32. Tanahashi S, Yamamura S, Nakagawa M, Motomura E, Okada M (2012b) Dopamine D2 and serotonin 5-HT1A receptors mediate the actions of aripiprazole in mesocortical and mesoaccumbens transmission. Neuropharmacology 62:765–774PubMedCrossRefGoogle Scholar
  33. Tatsumi M, Groshan K, Blakely RD, Richelson E (1997) Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol 340:249–258PubMedCrossRefGoogle Scholar
  34. Thase ME (1999) Antidepressant treatment of the depressed patient with insomnia. J Clin Psychiatry 60(Suppl 17):28–31, discussion 46–8PubMedGoogle Scholar
  35. Tsuno N, Besset A, Ritchie K (2005) Sleep and depression. J Clin Psychiatry 66:1254–1269PubMedCrossRefGoogle Scholar
  36. Van der Mey M, Windhorst AD, Klok RP, Herscheid JD, Kennis LE, Bischoff F, Bakker M, Langlois X, Heylen L, Jurzak M, Leysen JE (2006) Synthesis and biodistribution of [11C]R107474, a new radiolabeled alpha2-adrenoceptor antagonist. Bioorg Med Chem 14:4526–4534PubMedCrossRefGoogle Scholar
  37. Watanabe N, Omori IM, Nakagawa A, Cipriani A, Barbui C, Churchill R, Furukawa TA (2011) Mirtazapine versus other antidepressive agents for depression. Cochrane Database Syst Rev (12):CD006528.Google Scholar
  38. Westenberg HG (1999) Pharmacology of antidepressants: selectivity or multiplicity? J Clin Psychiatry 60(Suppl 17):4–8, discussion 46–8PubMedGoogle Scholar
  39. Wilson S, Argyropoulos S (2005) Antidepressants and sleep: a qualitative review of the literature. Drugs 65:927–947PubMedCrossRefGoogle Scholar
  40. Winokur A, DeMartinis NA 3rd, McNally DP, Gary EM, Cormier JL, Gary KA (2003) Comparative effects of mirtazapine and fluoxetine on sleep physiology measures in patients with major depression and insomnia. J Clin Psychiatry 64:1224–1229PubMedCrossRefGoogle Scholar
  41. Yamamura S, Abe M, Nakagawa M, Ochi S, Ueno S, Okada M (2011) Different actions for acute and chronic administration of mirtazapine on serotonergic transmission associated with raphe nuclei and their innervation cortical regions. Neuropharmacology 60:550–560PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Kouji Fukuyama
    • 1
    • 2
  • Shunske Tanahashi
    • 1
    • 2
  • Tatsuya Hamaguchi
    • 1
    • 2
  • Masanori Nakagawa
    • 1
    • 2
  • Takashi Shiroyama
    • 1
    • 2
  • Eishi Motomura
    • 1
    • 2
  • Motohiro Okada
    • 1
    • 2
  1. 1.Department of Neuropsychiatry, Division of NeuroscienceMie University Graduate School of MedicineTsuJapan
  2. 2.Pharmacological Unit, Brain Science and Animal Model Research Centre (BSAM)Mie UniversityTsuJapan

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