Kihara T, Ikeda M
Kanzakigawa Laboratory, Shionogi Research Laboratories, Shionogi & Co. Ltd., Osaka, Japan.
J Pharmacol Exp Ther. 1995 Jan;272(1):177-83.
The effects of duloxetine (LY248686), a new inhibitor of serotonin (5-hydroxytryptamine; 5-HT) and norepinephrine (NE) uptake on extracellular levels of NE, 5-HT and dopamine (DA), were studied in the rat frontal cortex and nucleus accumbens, using in vivo microdialysis. The oral administration of duloxetine (3.125-12.5 mg/kg) produced a dose-dependent increase in the output of both NE and 5-HT from the frontal cortex, this increase being maintained throughout the 4-hr observation period. Chronic administration of duloxetine (6.25 mg/kg, p.o.) for 14 days failed to alter basal NE and 5-HT levels in the frontal cortex, but augmented the duloxetine-induced increase in output of NE and 5-HT. Amitriptyline and maprotiline, administered p.o. at doses of 6.25 to 25 mg/kg, increased NE output, but the effect was weaker than that of duloxetine, and neither amitriptyline nor maprotiline changed 5-HT output from the frontal cortex. Duloxetine, amitriptyline, and maprotiline brought about increases in DA levels in the rat frontal cortex, the increase in DA levels induced by duloxetine being approximately two or three times more potent than that induced by amitriptyline and maprotiline. In the nucleus accumbens, duloxetine also produced a dose-dependent increase in DA output more potent than that produced by amitriptyline and maprotiline. These results show that duloxetine causes a potent and sustained increase in the output of both NE and 5-HT in the rat frontal cortex, related to its inhibition of NE and 5-HT uptake; these results also show that duloxetine increases DA output in the frontal cortex.
使用体内微透析技术，研究了新型5-羟色胺（5-HT）和去甲肾上腺素（NE）摄取抑制剂度洛西汀（LY248686）对大鼠额叶皮质和伏隔核细胞外NE、5-HT及多巴胺（DA）水平的影响。口服度洛西汀（3.125 - 12.5mg/kg）可使额叶皮质中NE和5-HT的释放量呈剂量依赖性增加，且在4小时的观察期内持续保持升高。连续14天口服度洛西汀（6.25mg/kg，经口给药）未能改变额叶皮质中NE和5-HT的基础水平，但增强了度洛西汀诱导的NE和5-HT释放增加。口服剂量为6.25至25mg/kg的阿米替林和马普替林可增加NE的释放，但效果弱于度洛西汀，且二者均未改变额叶皮质中5-HT的释放。度洛西汀、阿米替林和马普替林均可使大鼠额叶皮质中的DA水平升高，度洛西汀诱导的DA水平升高比阿米替林和马普替林诱导的约强两至三倍。在伏隔核中，度洛西汀也可使DA释放产生剂量依赖性增加，且比阿米替林和马普替林更有效。这些结果表明度洛西汀可使大鼠额叶皮质中NE和5-HT的释放产生强效且持续的增加，这与其对NE和5-HT摄取的抑制作用有关；这些结果还表明度洛西汀可增加额叶皮质中DA的释放。
