Elsevier

Journal of Affective Disorders

Volume 51, Issue 3, 1 December 1998, Pages 255-266
Journal of Affective Disorders

Research report
Acute and long-term actions of the antidepressant drug mirtazapine on central 5-HT neurotransmission1

https://doi.org/10.1016/S0165-0327(98)00223-7Get rights and content

Abstract

Mirtazapine (ORG 3770, Remeron®) is a new α2-adrenoceptor antagonist which has been shown to be an effective antidepressant drug. The aims of the studies were to assess, using an in vivo electrophysiological paradigm in the rat, the effects of acute and long-term treatment with mirtazapine on pre- and postsynaptic α2-adrenoceptors and to determine whether this drug could modulate serotonin (5-HT) neurotransmission. Acute administration of mirtazapine produced a transient increase of the firing activity of dorsal raphe 5-HT neurons. This effect was mediated via norepinephrine (NE) neurons because it was abolished in NE-lesioned rats. In fact, this increased firing rate of 5-HT neurons was due to their activation by the enhanced release of NE resulting from the blockade of α2-adrenergic autoreceptors of locus coeruleus neurons. Furthermore, acute mirtazapine injection transiently enhanced the firing activity of locus coeruleus NE neurons and attenuated the suppressant effect of the α2-adrenoceptor agonist clonidine on these NE neurons. Sustained administration of mirtazapine for 21 days (5 mg/kg/day, s.c., using minipumps) lead to a marked increase in the firing rate of 5-HT neurons (75%) but a more modest increase in the firing rate of NE neurons (30%), as well as to a desensitization of α2-adrenergic heteroreceptors on 5-HT terminals in the hippocampus. The desensitization of these heteroreceptors, resulting from an increased synaptic availability of NE induced by mirtazapine would free 5-HT terminals from the inhibitory influence of NE on 5-HT release. These modifications of 5-HT neurons lead to an increased tonic activation of postsynaptic 5-HT1A receptors. The latter conclusion was based on the capacity of the selective 5-HT1A receptor antagonist WAY 100635 to enhance the firing activity of dorsal hippocampus CA3 pyramidal neurons in mirtazapine-treated rats but not in controls. This enhanced 5-HT neurotransmission may underlie to the antidepressant effect of mirtazapine.

Introduction

Even though the physiopathology of the depressive illness is not fully understood, there is now ample preclinical and clinical evidence showing that the repeated administration of several classes of antidepressant treatments leads to an enhanced serotonin (5-HT) neurotransmission (Price et al., 1990, Blier and de Montigny, 1994). This would be mediated via different mechanisms such as postsynaptic sensitization to 5-HT, desensitization of the somatodendritic and/or terminal 5-HT autoreceptors or a desensitization of α2-adrenergic heteroreceptors located on 5-HT terminals (see, for a review, Blier and de Montigny, 1994). Among new antidepressants, mirtazapine, the 6-aza-analogue of the atypical antidepressant mianserin, 1,2,3,4,10,14b-hexa-hydro-2-methylpyrazino[2,1-a]pyrido[2,3-c]benzazepin (ORG 3770 or Remeron), is a tetracyclic compound with antidepressant activity in humans (Smith et al., 1990, van Moffaert et al., 1995, Claghorn and Lesem, 1995). Its pharmacological profile is characterized by potent presynaptic α2-adrenoceptor blockade, weak 5-HT1 and α1-adrenergic and potent 5-HT2 and 5-HT3 antagonistic activities, as well as by potent H1 antagonistic activity. It is devoid of anticholinergic activity and has no effect on reuptake of catecholamines or of indolamines (Nickolson et al., 1982, De Boer et al., 1988). The blockade of presynaptic α2-adrenoceptors is considered as a possible mechanism for antidepressant activity (see Pinder and Wieringa, 1993, for a review). Using microdialysis in freely moving rats, it has been shown that mirtazapine increases 5-HT release in the ventral hippocampus (De Boer et al., 1994, De Boer and Ruigt, 1995, De Boer et al., 1996). It has been suggested that both the indirect α1-adrenoceptor-mediated enhancement of 5-HT neuron firing activity and the direct blockade of inhibitory α2-adrenergic heteroreceptors located on 5-HT terminals are responsible for this increase in extracellular 5-HT. In order to distinguish in vivo the activations of α2-adrenergic auto- and heteroreceptors, previous studies in our laboratory, using the electrical stimulation of the ascending 5-HT pathway, have shown that low doses of clonidine enhance the effectiveness of the electrical stimulation of the ascending 5-HT pathway in suppressing the firing activity of dorsal hippocampus CA3 pyramidal neurons. In contrast, high doses of clonidine reduce the effectiveness of the stimulation. Both these incremental and decremental effects of clonidine were reversed by the intravenous injection of the α2-adrenoceptor antagonist yohimbine, indicating that these effects are mediated via α2-adrenoceptors. Furthermore, the enhancing effects of the low doses, but not those of the high doses, of clonidine were abolished in rats pretreated with the norepinephrine (NE) neurotoxin 6-hydroxydopamine (6-OHDA). This indicates that the enhancing effect of a low dose of clonidine results from the selective activation of the α2-adrenergic autoreceptors on NE terminals, thereby reducing the tonic activation by NE of α2-adrenergic heteroreceptors on 5-HT terminals. On the other hand, the reducing effect of high doses of clonidine could be due to a direct activation of the α2-adrenergic heteroreceptors on 5-HT terminals (Mongeau et al., 1993). The aims of the studies reported here were to assess, using an in vivo electrophysiological paradigm in the rat, the effects of acute and long-term treatment with mirtazapine on pre- and postsynaptic α2-adrenoceptors and to determine whether this drug could modulate 5-HT neurotransmission.

Section snippets

Methods

The experiments were carried out on male Sprague-Dawley rats weighing 250–300 g which were housed under standard laboratory conditions (12:12 light–dark cycle with free access to food and water). In the chronic study, they were treated for 21 days with 5 mg/kg per day of mirtazapine or vehicle, delivered by an osmotic minipump (ALZA, Palo Alto, CA) inserted subcutaneously. Experiments were carried out either with the minipump in place or after a 48 h washout (i.e. the minipumps were removed 48

Effects of acute administration of mirtazapine

Using microdialysis in freely moving rats, De Boer et al. (1996)have shown that mirtazapine increases extracellular 5-HT and DOPAC (considered to be an index of noradrenergic presynaptic activity) in the ventral hippocampus. The indirect α1-adrenoceptor-mediated enhancement of 5-HT neuron firing activity and direct blockade of inhibitory α2-adrenergic heteroreceptors located on 5-HT terminals may be responsible for this increase in extracellular 5-HT. In this study, mirtazapine (25 μg/kg, i.v.)

Discussion

We have characterized, in a first study, the acute effects of mirtazapine on pre- and postsynaptic α2-adrenoceptors. Mirtazapine (25 μg/kg, i.v.) enhanced the effectiveness of the stimulation of the ascending 5-HT pathway and prevented the effects of both a low and a high dose of clonidine, indicating a blockade of both α2-adrenergic auto- and heteroreceptors. At the postsynaptic level, mirtazapine (500 μg/kg, i.v.) blocked the suppressant effect of microiontophoretically applied NE on the

References (40)

  • T.H. Svensson et al.

    Inhibition of both NA and 5-HT neurons in brain by the α-adrenergic agonist clonidine

    Brain Res.

    (1975)
  • Aghajanian, G.K., 1978. Feedback regulation of central monoaminergic neurons: Evidence from single cell recording...
  • H.H.G. Berendsen et al.

    Indirect in vivo 5-HT1A-agonist effects of the new antidepressant mirtazapine

    Psychopharmacology

    (1997)
  • P. Blier et al.

    Frequency-dependence of serotonin autoreceptor but not α2-adrenoceptor inhibition of 3[H]-serotonin release in rat hypothalamic slices

    Naunyn-Schmiedeberg's Arch. Pharmacol.

    (1989)
  • Y. Chaput et al.

    In vivo electrophysiological evidence for the regulatory role of autoreceptors on serotoninergic terminals

    J. Neurosci.

    (1986)
  • J.L. Claghorn et al.

    A double-blind, placebo-controlled study of ORG 3770 in depressed outpatients

    J. Affect. Dis.

    (1995)
  • A.L. Curtis et al.

    Acute and chronic effect of the atypical antidepressant mianserin on brain noradrenergic neurons

    Psychopharmacology

    (1991)
  • R. Davis et al.

    Mirtazapine: A review of its pharmacology and therapeutic potential in the management of major depression

    CNS Drugs

    (1996)
  • T. De Boer et al.

    The selective α2-adrenoceptor antagonist mirtazapine (Org 3770) enhanced noradrenergic and 5-HT1A-mediated serotoninergic neurotransmission

    CNS Drugs

    (1995)
  • T. De Boer et al.

    Differences in modulation of noradrenergic and serotonergic transmission by the alpha-2 adrenoceptor antagonists, mirtazapine, mianserin and idazoxan

    J. Pharmacol. Exp. Ther.

    (1996)
  • Cited by (54)

    • Mirtazapine: Multitarget strategies for treating substance use disorder and depression

      2021, The Neuroscience of Depression: Features, Diagnosis, and Treatment
    • Role of central serotonin and noradrenaline interactions in the antidepressants’ action: Electrophysiological and neurochemical evidence

      2021, Progress in Brain Research
      Citation Excerpt :

      Pei and Zetterstrom (1996) have shown that ECS administration increases, only in the dentate gyrus and not in other subregions of hippocampus, mRNA levels of the rat voltage-dependent K+ channel (subunit Kv4.2). However, it has been shown that ECS can reduce the 5-HT1A receptor-mediated inhibition of forskolin activated adenylate cyclase (Newman and Lerer, 1988; Varrault et al., 1991) but enhance the tonic activation of postsynaptic 5-HT1A receptors located on dHC CA3 pyramidal neurons, suggesting an increase of the 5-HT neurotransmission (Haddjeri et al., 1998a,b,c). In addition, Burnet et al. (1999) showed a decrease mRNA level of 5-HT1A receptor, as well as a decrease 5-HT1A receptor binding, in a specific region of the hippocampus (CA4), but an increase mRNA level/binding in the dentate gyrus.

    • A heuristic model for working memory deficit in schizophrenia

      2016, Biochimica et Biophysica Acta - General Subjects
    • Asenapine alters the activity of monoaminergic systems following its subacute and long-term administration: An in vivo electrophysiological characterization

      2015, European Neuropsychopharmacology
      Citation Excerpt :

      In contrast, acute asenapine reversed the inhibitory effect of clonidine on NE neurons (ED50=85 µg/kg), demonstrating potent in vivo antagonistic properties at α2-adrenergic autoreceptors (Ghanbari et al., 2009). Notably, mirtazapine had a similar dynamic effect on α2-autoreceptors; it reversed clonidine-induced inhibition on NE neurons acutely (Haddjeri et al., 1996), whereas after 21 days of administration the dose–response effect of clonidine to inhibit NE neurons did not differ from controls (Haddjeri et al., 1998a). Thus, both tetracyclic medications blocked α2-adrenergic autoreceptors on LC neurons acutely, whereas the function of these receptors was restored after their long-term administration.

    View all citing articles on Scopus
    1

    These results have been reported in part in two publications (Haddjeri et al., 1996, Haddjeri et al., 1997).

    View full text