Mirtazapine increases dopamine release in prefrontal cortex by 5-HT1A receptor activation
Introduction
Mirtazapine {1,2,3,4,10,14b-hexa-hydro-2-meth-ylpyrazino[2,1-a]pyrido[2,3-c]benzazepin} is a tetracyclic compound with antidepressant activity in human 6., 14.. Mirtazapine has a unique mechanism of action, different from that of the classical tricyclic antidepressants, the serotonin selective reuptake inhibitors and monoamine oxidase inhibitors, and could be described as a noradrenergic and specific serotonergic antidepressant, abbreviated as NaSSA [10]. The pharmacological profile of mirtazapine is characterized by potent presynaptic α2-adrenergic antagonistic activity, 5-HT1 agonistic activity, and potent 5-HT2 and 5-HT3 antagonistic activities, as well as by a potent H1 antagonistic activity [11]. The blockade of presynaptic α2-adrenergic receptors is considered as a possible mechanism for antidepressant activity of mirtazapine. The interactions of mirtazapine with 5-HT receptors were studied in vivo in experiments measuring selective 5-HT receptor subtype-mediated behaviors [4]. Mirtazapine was found to induce lower lip retraction mediated by 5-HT1A receptors in rats [3]. Moreover, the taste aversion induced by mirtazapine was also prevented by pretreatment with the 5-HT1A agonist, 8-hydroxy-2-(di-N-propylamino)tetralin (8-OH-DPAT), indicating similar stimulus properties of mirtazapine and 8-OH-DPAT [3]. This indicates that mirtazapine exerts in vivo effects mediated by 5-HT1A receptor without high affinity for 5-HT1A receptors. There is to date no clear evidence that mirtazapine enhances 5-HT1A neurotransmission. The frontal cortex has been repeatedly proposed as an area involved in depression, since positron emission tomography studies revealed that depressed patients show functional changes in the frontal cortex 2., 5., 9.. It has been suggested that the property of stimulating dopamine transmission in the prefrontal cortex has a role in the antidepressant action 23., 24..
In light of these observations, the aims of the study reported here were to assess the effects of mirtazapine on dialysate levels of dopamine and 5-HT in the medial prefrontal cortex (mPFC) of freely moving rats and to determine whether this drug could modulate 5-HT1A neurotransmission.
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Animals
Male Wistar rats (Clea Japan Inc., Tokyo) weighing 220–300 g were used. Rats were housed in groups of five and maintained at a temperature 25±2 °C on a 12-h-light/12-h-dark cycle with lights on between 7 am and 7 pm. Rats were fed a standard laboratory food and tap water ad libitum. The experimental procedures for animals were conducted in accordance with the guidelines of the Guiding Principles for the Care and Use of Laboratory Animals approved by The Japanese Pharmacological Society.
Surgery
Rats were
Results
The basal extracellular levels of dopamine in the dialysates of the medial prefrontal cortex, without considering probe recovery, were 0.42±0.04 pg/sample. As shown in Fig. 1, the administration of mirtazapine at doses of 8 and 16 mg/kg, i.p. elicited a dose-dependent increase in extracellular levels of dopamine in dialysates of the medial prefrontal cortex, whereas its 2 and 4 mg/kg doses were ineffective. Forty minutes after administration of mirtazapine at a dose of 16 mg/kg, i.p., a significant
Discussion
The present results show that mirtazapine elicits increase in extracellular dopamine levels in the medial prefrontal cortex of freely moving rats. Neurochemical studies in vitro have shown that the affinity of mirtazapine for dopamine, 5-HT and noradrenaline uptake sites was negligible [19]. It has also been shown that mirtazapine manifests high affinity for in vitro study with recombinant human α1A-adrenergic, α2A-adrenergic, 5-HT2A, 5-HT2B, and 5-HT2C receptors. Antagonist action of
References (26)
- et al.
The 5-HT1A receptor selective ligands, (R)-8-OH-DPAT and (S)-UH-301, differentially affect the activity of midbrain dopamine neurons
Naunyn-Schmiedebergs Arch. Pharmacol.
(1993) - et al.
Reduction of prefrontal cortex glucose metabolism common to three types of depression
Arch. Gen Psychiat.
(1989) - et al.
Indirect in vivo 5-HT1A-agonistic effects of the new antidepressant mirtazapine
Psychopharmacology
(1997) - et al.
Down regulation of 5-HT2A receptors after chronic treatment with remeron
Eur. Neuropsychopharmacol.
(1995) - et al.
Frontal cortex and basal ganglia metabolic rates assessed by positron emission tomography with [18F]2-deoxyglucose in affective illness
J. Affect. Disord.
(1986) - et al.
A double-blind Placebo-controlled study of antidepressant augmentation with mirtazapine
Biol. Psychiatry
(2002) - et al.
Projections from the rat prefrontal cortex to the ventral tegmental area: target specificity in the synaptic associations with mesoaccumbens and mesocortical neurons
J. Neurosci.
(2000) - et al.
Serotonin 5-HT1A receptors might control the output of cortical glutamatergic neurons in rat cingulate cortex
Brain Res.
(2003) - et al.
Inhibition of stress- or anxiogenic-drug-induced increases in dopamine release in the rat prefrontal cortex by long-term treatment with antidepressant drugs
J. Neurochem.
(2001) The effects of mirtazapine on central noradrenergic and serotonergic neurotransmission
International Clinical Psychopharmacology
(1996)
The pharmacologic profile of mirtazapine
J. Clin. Psychiatry
Targeting of serotonin 1A receptors to dopaminergic neurons within the parabrachial subdivision of the ventral tegmental area in rat brain
J. Comp. Neurol.
Regulation of dopamine release by impulse flow and by autoreceptors as studied by in vivo voltammetry in the rat striatum
Neuroscience
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