Devoto Paola, Flore Giovanna, Pira Luigi, Longu Giorgio, Gessa Gian Luigi
B.B. Brodie Department of Neuroscience, University of Cagliari, SS 554 km 4,5, 09042 Monserrato (CA), Italy.
Eur J Pharmacol. 2004 Mar 8;487(1-3):105-11. doi: 10.1016/j.ejphar.2004.01.018.
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.
新型抗抑郁药米氮平已被证明可增加内侧前额叶皮质中的细胞外去甲肾上腺素和多巴胺。我们之前的研究表明，大脑皮质中的细胞外多巴胺主要源自去甲肾上腺素能终末，这种释放受α₂ - 肾上腺素能受体控制。由于米氮平抑制α₂ - 肾上腺素能受体，因此对其是否可能共同释放多巴胺和去甲肾上腺素进行了研究。通过微透析法，比较了米氮平对内侧前额叶皮质（由多巴胺能和去甲肾上腺素能神经元密集支配）以及枕叶皮质（接受等量去甲肾上腺素能但多巴胺能投射稀少）中细胞外多巴胺、3,4 - 二羟基苯乙酸（DOPAC）和去甲肾上腺素的影响。两种皮质中去甲肾上腺素的基础细胞外浓度相似，而枕叶皮质中的多巴胺仅比内侧前额叶皮质低约50%，这反映了去甲肾上腺素能而非多巴胺能投射。腹腔注射米氮平（5和10 mg/kg）使两种皮质中的细胞外多巴胺、DOPAC和去甲肾上腺素增加到大致相同的程度，α₂ - 肾上腺素能受体激动剂可乐定（0.15 mg/kg，腹腔注射）可完全抑制这种作用。为排除米氮平诱导的多巴胺增加可能是由于细胞外空间多巴胺清除减少所致的可能性，通过向任一皮质灌注100 μM地昔帕明来阻断去甲肾上腺素和多巴胺摄取机制。与单独给予任一药物相比，腹腔注射米氮平（5 mg/kg）并局部灌注地昔帕明可使内侧前额叶皮质和枕叶皮质中的细胞外多巴胺、DOPAC和去甲肾上腺素进一步增加。结果表明，米氮平通过抑制α₂ - 肾上腺素能受体，从大脑皮质的去甲肾上腺素能终末共同释放去甲肾上腺素和多巴胺。
