Different actions for acute and chronic administration of mirtazapine on serotonergic transmission associated with raphe nuclei and their innervation cortical regions
Research highlights
► Acute mirtazapine does not affect extracellular serotonin level in raphe nuclei. ► Chronic mirtazapine increased extracellular serotonin level in raphe nuclei. ► Chronic mirtazapine reduced the somatodendritic 5-HT1A receptor in raphe nuclei. ► Chronic mirtazapine enhanced postsynaptic 5-HT1A receptor in cortex. ► Chronic mirtazapine educed the expression of serotonin transporter and 5-HT1A receptor.
Introduction
The atypical antidepressant, mirtazapine (1,2,3,4,10,14b-hexa-hydro-2-methylpyrazino [2,1-a] pyrido[2,3-c]benzazepin) is a tetracyclic compound with antidepressant activity despite no monoamine transporter affinities (Croom et al., 2009, de Boer, 1995, de Boer, 1996). A recent meta-analysis study of multiple treatments has demonstrated that in terms of clinical response, mirtazapine is more efficacious than duloxetine, fluoxetine, fluvoxamine, paroxetine and reboxetine (Cipriani et al., 2009). Mirtazapine has attracted attention since its binding profile indicates an antagonistic action to α2 adrenoceptor, serotonin 5-HT2A, 5-HT2C and 5-HT3 receptors without affecting monoamine transporters (Millan et al., 2000, Tatsumi et al., 1997, Van der Mey et al., 2006). Therefore, mirtazapine has a unique binding profile different from that of the typical tricyclic antidepressants and selective serotonin reuptake inhibitor (SSRI), and could be described as a noradrenergic and specific serotonergic antidepressant, abbreviated as NaSSA (Croom et al., 2009, de Boer, 1995, de Boer, 1996). Furthermore, the inhibitory effects of mirtazapine on 5-HT2A/2C and 5-HT3 receptors reduce the likelihood of some serotonergic adverse effects associated with hyperactivated serotonin receptors induced by serotonin transporter inhibitors (e.g., restlessness, nausea and sexual dysfunction), and this appears to be supported by tolerability data from clinical trials (Croom et al., 2009).
With regard to the antidepressant mechanisms of mirtazapine, previous studies indicated that mirtazapine increases the extracellular norepinephrine level in raphe nuclei through inhibition of α2 adrenoceptor on the pre-synaptic terminal from locus coeruleus noradrenergic projection and indirectly enhances serotonergic transmission via activation of α1 adrenoceptor on the postsynaptic membrane of raphe nuclei (NaSSA hypothesis) (Croom et al., 2009, de Boer, 1995, de Boer, 1996). Systemic administration of mirtazapine increased extracellular levels of norepinephrine and dopamine in various brain regions, e.g., frontal cortex (FC), dorsal and ventral hippocampus (de Boer, 1996, de Boer et al., 1996, Devoto et al., 2004, Millan et al., 2000). Contrary to norepinephrine, the effects of mirtazapine on the extracellular serotonin level remain controversial, since a report demonstrated that systemic administration of mirtazapine increased extracellular serotonin level in ventral hippocampus (de Boer et al., 1996), whereas several other studies could not detect the stimulatory effects on extracellular serotonin level in FC, striatum, dorsal and ventral hippocampus (Bengtsson et al., 2000, Millan et al., 2000, Nakayama et al., 2004).
Both the median (MRN) and dorsal (DRN) raphe nuclei receive noradrenergic projections from the locus coeruleus (Adell et al., 2002), as well as serotonergic projections from each other raphe nuclei (Adell et al., 2002, Imai et al., 1986). The serotonergic neurons in DRN project to FC, ventral hippocampus and striatum, whereas the serotonergic neurons in MRN project to the entorhinal cortex (EC), dorsal hippocampus and nucleus accumbens (Adell et al., 2002, Imai et al., 1986). Based on the serotonergic networks, the present study was designed to determine the effects of mirtazapine on serotonergic transmission associated with raphe nuclei. For this purpose, the acute and chronic effects of mirtazapine on extracellular serotonin levels in raphe nuclei and their innervated cortical regions were analyzed in rats using multiple-probes microdialysis. Furthermore, the present study determined the expression of protein and mRNA of serotonin transporter (Slc6a4) and 5-HT1A receptor (Htr1a) in the same regions.
Section snippets
Experimental animals
All experiments described in this report were approved by the Ethics Review Committee for Animal Experimentation of Mie University. Male Sprague–Dawley rats (SLC, Shizuoka, Japan), were housed in air-conditioned rooms (temperature, 22 ± 2 °C) set at 12-h light–dark cycle.
Chemical agents
The following drugs were used in this study: mirtazapine (Sigma, St. Louis, MO), 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, Sigma), 5-HT1A receptor antagonist, WAY100635 (Sigma) and 5-HT2A/2C antagonist,
Results
The basal extracellular serotonin levels in the DRN and MRN were 83.6 ± 6.9 fmol/sample (40 μL) (2.1 nM; n = 84) and 64.5 ± 5.8 fmol/sample (40 μL) (1.6 nM; n = 84), respectively. The basal extracellular serotonin levels in the FC and EC were 4.6 ± 0.5 fmol/sample (40 μL) (0.12 nM; n = 84) and 3.4 ± 0.4 fmol/sample (40 μL) (0.09 nM; n = 84), respectively. The basal extracellular serotonin levels in DRN, MRN, FC and EC were tetrodotoxin-sensitive, Ca2+-dependent, and K+-sensitive (data not
Discussion
Taken together with the binding profiles of mirtazapine, the potential antidepressant mechanism of mirtazapine is as follows: blockade of α2 adrenoceptor enhances noradrenergic transmission and secondarily activates serotonergic transmission via activation of α1 adrenoceptor-mediated noradrenergic facilitation (Croom et al., 2009, de Boer, 1996). Therefore, the antidepressant activity of mirtazapine is considered to be due to enhancement of the noradrenergic and serotonergic effects (NaSSA
Conclusion
The present study demonstrated the mechanism of action of mirtazapine on serotonergic transmission associated with raphe nuclei. Acute administration of mirtazapine did not alter the extracellular serotonin level in raphe nuclei or their innervation cortical regions (FC and EC). However, mirtazapine probably enhanced the serotonergic transmission in raphe nuclei, based on the following results. First, under 5-HT1A receptor blockade, acute administration of mirtazapine increased the
Acknowledgments
This study was supported by a grant-in-aid for Scientific Research from the Japanese Ministry of Education, Science and Culture (18390316 and 18659330), 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. The authors state no conflict of interest.
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These authors contributed equally to this work.