Research reportAcute and long-term actions of the antidepressant drug mirtazapine on central 5-HT neurotransmission1
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
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These results have been reported in part in two publications (Haddjeri et al., 1996, Haddjeri et al., 1997).