CNS Drugs

, Volume 4, Supplement 1, pp 29–38 | Cite as

The Selective α2-Adrenoceptor Antagonist Mirtazapine (Org 3770) Enhances Noradrenergic and 5-HT1A-Mediated Serotonergic Neurotransmission

  • Thijs de Boer
  • Gé S. F. Ruigt


Mirtazapine (Org 3770) is a selective antagonist at α2-adrenergic auto- and heteroreceptors, which are involved in regulation of neuronal noradrenaline (norepinephrine) and serotonin (5-hydroxytryptamine; 5-HT) release. It was identified as a potential antidepressant in rat sleep studies, showing characteristic REM sleep suppression, as well as activity in the bulbectomised rat and an operant behaviour model. However, mirtazapine does not inhibit monoamine reuptake and is inactive in classical tests predictive of antidepressant activity (antagonism of reserpine-induced hypothermia, Porsolt test, and muricidal behaviour). As an α2-antagonist, mirtazapine inhibits clonidine-induced mydriasis and resembles idazoxan in evoking conditioned taste aversion. In addition, mirtazapine induces lower lip retraction, a response characteristic of 5-HT1A receptor stimulation, and resembles the 5-HT1A agonist 8-hydroxy-dipropylaminotetraline (8-OH-DPAT) in producing conditioned taste aversion. Thus, mirtazapine may have indirect serotonin-enhancing effects, since its affinity for 5-HT1A receptors is low.

As a consequence of noradrenergic facilitation, mirtazapine increases the firing of serotonergic raphe neurons and antagonises the inhibitory effects of noradrenaline on serotonergic terminals. In combination, these effects offer a mechanistic basis for the drug’s observed stimulatory effect on hippocampal serotonin release. Because mirtazapine blocks 5-HT2 and 5-HT3 receptors, 5-HT1-mediated transmission is selectively enhanced, as reflected in its 5-HT1A-like behavioural effects.

In conclusion, noradrenergic activation via (α2-autoreceptor blockade and the consequent indirect enhancement of serotonergic transmission probably underlie the marked antidepressant activity of mirtazapine. Blockade of 5-HT2 and 5-HT3 receptors may account for the absence of those adverse effects associated with nonselective serotonergic activation and may also contribute to the anxiolytic and hypnotic properties of mirtazapine.


Mirtazapine Mianserin Conditioned Taste Aversion Idazoxan Serotonergic Neurotransmission 
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  1. 1.
    Richelson E, Nelson A. Antagonism by antidepressants of neurotransmitter receptor of normal human brain in vitro. J Pharmacol Exp Ther 1984; 230: 94–102PubMedGoogle Scholar
  2. 2.
    Baldessarini RJ. Current status of antidepressants: clinical pharmacology and therapy. J Clin Psychiatry 1989; 50: 117–26PubMedGoogle Scholar
  3. 3.
    Richelson E. Biological basis of depression and therapeutic relevance. J Clin Psychiatry 1991; 52Suppl.: 4–10PubMedGoogle Scholar
  4. 4.
    Potter WZ, Rudorfer MV, Manji H. The pharmacological treatment of depression. N Eng J Med 1991; 325: 633–42CrossRefGoogle Scholar
  5. 5.
    Stahl SM. Serotonergic mechanism and the new antidepressants. Psychol Med 1993; 23: 281–5PubMedCrossRefGoogle Scholar
  6. 6.
    Lejoyeux M, Adés J, Rouillon F. Serotonin syndrome: incidence, symptoms and treatment. CNS Drugs 1992; 2: 132–43CrossRefGoogle Scholar
  7. 7.
    Stokes PE. Fluoxetine: a five-year review. Clin Ther 1993; 15: 216–43PubMedGoogle Scholar
  8. 8.
    Williams R, Edwards RA, Newburn GM, et al. A double-blind comparision of moclobemide and fluoxetine in the treatment of depressive disorders. Int Clin Psychopharmacol 1993; 7: 155–8PubMedCrossRefGoogle Scholar
  9. 9.
    Moll E, Neumann N, Schmid-Burgk W, et al. Safety and efficacy during long-term treatment with moclobemide. Clin Neuropharmacol 1994; 17: S74–87PubMedCrossRefGoogle Scholar
  10. 10.
    Leonard BE. Comparative pharmacology of new antidepressants. J Clin Psychiat 1993; 54Suppl.: 3–15Google Scholar
  11. 11.
    Fontaine R. Novel serotonergic mechanisms and clinical experiences with nefazone. Clin Neuropharmacol 1993; 16Suppl. 3P: S45–50PubMedGoogle Scholar
  12. 12.
    Van Praag HM, Asnis GM, Kahn RS. Monoamines and abnormal behaviour: a multi-aminergic perspective. Br J Psychiatry 1990; 157: 723–34PubMedCrossRefGoogle Scholar
  13. 13.
    Delgado PL, Miller MML, Salomon M, et al. Monoamines and the mechanism of antidepressant action: effects of catecholamine depletion on mood of patients treated with antidepressants. Psychopharmacol Bull 1993; 29: 389–96PubMedGoogle Scholar
  14. 14.
    Cummings JL. The neuroanatomy of depression. J Clin Psychiatry 1993; 54Suppl.: 14–20PubMedGoogle Scholar
  15. 15.
    Ruigt GSF, Van Proosdij JN. Antidepressant characteristics of Org 3770, Org 4428 and Org 9768 on rat sleep. Eur J Pharmacol 1990; 183: 1467–8CrossRefGoogle Scholar
  16. 16.
    Ruigt GSF, Engelen S, Gerrits A, et al. Computer-based prediction of psychotropic drug classes based on a discriminant analysis of drug effects on rat sleep. Neuropsychobiology 1993; 28: 138–53PubMedCrossRefGoogle Scholar
  17. 17.
    Ruigt GSF, Kemp B, Groenhout CM, et al. Effect of the antidepressant Org 3770 on human sleep. Eur J Clin Pharmacol 1990; 38: 551–4PubMedCrossRefGoogle Scholar
  18. 18.
    Leonard BE, O’Connor WT. Effect of isomers of the 6-aza derivative of mianserin on behaviour and noradrenaline metabolism in bulbectomized rats. Br J Pharmacol 1984; 82: 246PGoogle Scholar
  19. 19.
    Andrews JS, Jansen JHM, Linders S, et al. Effects of imipramine and mirtazapine on operant performance in rats. Drug Dev Res 1994; 32: 58–66CrossRefGoogle Scholar
  20. 20.
    Van Riezen H, Delver A. The effect of a number of drugs with different pharmacological properties upon reserpine induced hypothermia in mice. Arzneimittelforschung 1971; 22: 1562–6Google Scholar
  21. 21.
    De Graaf JS, Berendsen HMG, Van Riezen H, et al. A set of behavioural tests predicting antidepressant activity. Drug Dev Res 1985; 5: 291–301CrossRefGoogle Scholar
  22. 22.
    De Boer Th, Maura G, Raiteri M, et al. Neurochemical and autonomic pharmacological profiles of the 6-aza-analogue of mianserin, Org 3770 and its enantiomers. Neuropharmacology 27; 1988: 399–408PubMedCrossRefGoogle Scholar
  23. 23.
    Gower AJ, Broekkamp CLE, Rijk HW, et al. Pharmacological evaluation of in vivo tests for α2-adrenoceptor blockade in the central nervous system and the effects of the enantiomers of mianserin and its aza-analogue Org 3770. Arch Int Pharmacodyn Ther 1988; 291: 185–201PubMedGoogle Scholar
  24. 24.
    De Beun R, Rijk HW, Broekkamp CLE. The cross-familiarization conditioned taste aversion procedure as a method to reveal stimulus resemblance between drugs: studies on the 5-HT1A-agonist 8-OH-DPAT. Psychopharmacology 112; 1993: 121–8PubMedCrossRefGoogle Scholar
  25. 25.
    Baraban JM, Aghajanian GK. Suppression of firing activity of 5-HT neurons in the dorsal raphe by alpha-adrenoceptor antagonists. Neuropharmacology 1980; 19: 355–63PubMedCrossRefGoogle Scholar
  26. 26.
    Smith DA, Gallager DW. Electrophysiological and biochemical characterization of the development of alpha-1 adrenergic and 5-HT1 receptors associated with dorsal raphé neurons. Dev Brain Res 1989; 46: 173–86CrossRefGoogle Scholar
  27. 27.
    Rouquier L, Claustre C, Benavides J. (α2-Adrenoceptor antagonists differentially control serotonin release in the hippocampus and striatum: a microdialysis study. Eur J Pharmacol 1994; 261: 59–64PubMedCrossRefGoogle Scholar
  28. 28.
    Clement HM, Geusa D, Wesemann W. The effect of adrenergic drugs on serotonin metabolism in the nucleus raphe dorsalis of the rat, studied by in vivo voltammetry. Eur J Pharmacol 1992; 217: 43–8PubMedCrossRefGoogle Scholar
  29. 29.
    De Boer Th, Nefkens F, Van Helvoirt A. The α2-antagonist Org 3770 enhances serotonin transmission in vivo. Eur J Pharmacol 1994; 253: R5–6PubMedCrossRefGoogle Scholar
  30. 30.
    Kooyman AR, Zwart R, Vanderheyden PML, et al. Interaction between enantiomers of mianserin and Org 3770 at 5-HT3 receptors in cultured mouse neuroblastoma cells. Neuropharmacology 1994; 33: 501–10PubMedCrossRefGoogle Scholar
  31. 31.
    Berendsen HHG, De Boer Th, van Delft AML. Down regulation of 5-HT2A receptors after chronic treatment with remeron. Eur Neuropsychopharmacol. In pressGoogle Scholar
  32. 32.
    Berendsen HHG, Jenck F, Broekkamp CLE. Selective activation of 5-HT1A receptors induces lower lip retraction in the rat. Pharmacol Biochem Behav 1989; 33: 821–7PubMedCrossRefGoogle Scholar
  33. 33.
    Berendsen HHG, Broekkamp CLE. Behavioural evidence for functional interactions between 5-HT-receptor subtypes in rats and mice. Br J Pharmacol 1990; 101: 667–73PubMedCrossRefGoogle Scholar
  34. 34.
    Haddjeri N, Blier P, De Montigny C. Effect of the (α2-adrenoceptor antagonist Remeron on rat 5-HT neurotransmission [abstract]. Soc Neurosci 1994; 20: 1553Google Scholar
  35. 35.
    Mongeau R, Blier P, De Montigny C. In vivo electrophysiological evidence for tonic activation by endogeneous noradrenaline on (α2-adrenergic heteroreceptors of 5-hydroxytryptamine terminals in the rat hippocampus. Naunyn Schmeidebergs Arch Pharmacol 1993; 347: 266–72CrossRefGoogle Scholar
  36. 36.
    Mongeau R, De Montigny C, Blier P. Electrophysiological evidence for desensitization of (α2-adrenoreceptors on serotonin terminals following long-term treatment with drugs increasing norepinephrine synaptic concentration. Neuropsychopharmacology 1994; 10: 41–51PubMedGoogle Scholar
  37. 37.
    Blier P, De Montigny C. Current advances and trends in the treatment of depression. Trends Pharmacol Sci 1994; 15: 220–6PubMedCrossRefGoogle Scholar
  38. 38.
    Dugovic C, Wauquier A, Leysen JE, et al. Functional role of 5-HT2 receptors in the regulation of sleep and wakefulness in the rat. Psychopharmacology 1989; 97: 436–42PubMedCrossRefGoogle Scholar
  39. 39.
    Dubfosky SL. Beyond the serotonin reuptake inhibitors: rationales for development of new serotonergic agents. J Clin Psychiatry 1994; 55Suppl.: 34–44Google Scholar
  40. 40.
    Matilla M, Mattila MJ, Vrijmoed-de Vries M, et al. Action and interaction of psychotropic drugs on human performance and mood: single doses of Org 3770, amitriptyline and diazepam. Pharmacol Toxicol 1989; 65: 81–8CrossRefGoogle Scholar
  41. 41.
    Dickinson SL. Alpha2-adrenoceptors antagonism and depression. Drug News Perspect 1991; 4: 197–202Google Scholar

Copyright information

© Adis International Limited 1995

Authors and Affiliations

  • Thijs de Boer
    • 1
  • Gé S. F. Ruigt
    • 1
  1. 1.Neuropharmacology DepartmentScientific Development Group, N.V. OrganonOssThe Netherlands

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