Mirtazapine-induced corelease of dopamine and noradrenaline from noradrenergic neurons in the medial prefrontal and occipital cortex.
The novel antidepressant mirtazapine has been shown to increase extracellular noradrenaline and dopamine in the medial prefrontal cortex. Our previous studies indicate that extracellular dopamine in the cerebral cortex originates largely from noradrenergic terminals, such release being controlled by alpha(2)-adrenoceptors. Because mirtazapine inhibits alpha(2)-adrenoceptors, the possibility that it might corelease dopamine and noradrenaline was investigated. By means of microdialysis, the effect of mirtazapine on extracellular dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and noradrenaline in the medial prefrontal cortex, densely innervated by dopaminergic and noradrenergic neurons, and in the occipital cortex, receiving equal noradrenergic but scarce dopaminergic projections, was compared. Basal extracellular concentration of noradrenaline was similar in both cortices, while dopamine in the occipital cortex was only about 50% lower than in the medial prefrontal cortex, reflecting noradrenergic rather than dopaminergic projections. The intraperitoneal (i.p.) administration of mirtazapine (5 and 10 mg/kg) increased extracellular dopamine, DOPAC and noradrenaline to approximately the same extent in both cortices, an effect totally suppressed by the alpha(2)-adrenoceptors agonist clonidine (0.15 mg/kg, i.p.). To exclude the possibility that mirtazapine-induced increase in dopamine might result from reduced dopamine removal from extracellular space, noradrenaline and dopamine uptake mechanisms were blocked by perfusing 100 microM desipramine into either cortex. The combined i.p. administration of mirtazapine (5 mg/kg) and the local perfusion of desipramine produced an additional increase in extracellular dopamine, DOPAC and noradrenaline in the medial prefrontal cortex and occipital cortex compared with the increase produced by either drug given alone. The results suggest that mirtazapine by inhibiting alpha(2)-adrenoceptors produces a corelease of noradrenaline and dopamine from noradrenergic terminals in the cerebral cortex.
Devoto
Paola
P
B.B. Brodie Department of Neuroscience, University of Cagliari, SS 554 km 4,5, 09042 Monserrato (CA), Italy. pdevoto@unica.it
Flore
Giovanna
G
Pira
Luigi
L
Longu
Giorgio
G
Gessa
Gian Luigi
GL
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D003000:Clonidine / Q000494:pharmacology; D003891:Desipramine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D007274:Injections, Intraperitoneal; D008297:Male; D008803:Mianserin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D017551:Microdialysis; D000078785:Mirtazapine; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism*; D009778:Occipital Lobe / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013564:Sympathetic Nervous System / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
D018759:Adrenergic Uptake Inhibitors; D000316:Adrenergic alpha-Agonists; D000928:Antidepressive Agents; D008803:Mianserin; D000078785:Mirtazapine; D003000:Clonidine; D003891:Desipramine; D004298:Dopamine; D009638:Norepinephrine