Experimental studies on the role of dopamine and glutamate in methamphetamine psycosis

本研究通过一系列实验研究了谷氨酸在甲基苯丙胺（MA）行为和神经毒性效应中的作用。按递增剂量（2.5、5、7.5和10.0 mg/kg，sc，每天2次，分别于第1、3、5和7天）给药的大鼠表现出行为敏化。预处理与非竞争性（MK-801，0.5 mg/kg，ip）或竞争药物（D-CPP-ene，20 mg/kg，ip）NMDA拮抗剂在MA给药前阻止了行为敏化的发展。（5.0或7.5毫克/公斤，sc，2小时间隔）造成显着下降（40-60%的控制值）的DA在纹状体和5-HT在不同的脑区的水平。MK-801或D-CPP-ene预处理可防止DA和5-HT的这些降低。微透析研究表明，中毒剂量的MA显著增加纹状体谷氨酸的水平。一氧化氮（NO）合成酶抑制对MA诱导的行为和行为敏化的影响也进行了检查。一氧化氮合酶抑制剂N-硝基-L-精氨酸甲酯可显著降低小鼠的运动和刻板行为。此外，该抑制剂还能降低MA对类固醇刺激效应的致敏程度。这些结果表明，多巴胺能系统在MA诱导的行为致敏和神经毒性中起重要作用。

A series of experiments was conducted to examine the role of glutamate in the behavioral and neurotoxic effects of methamphetamine (MA). Rats treated with MA accoding to an escalating dose schedule (2.5,5,7.5 and 10.0 mg/kg, sc, twice a day on days 1,3,5 and 7, respectively) indicated behavioral sensitization. Pretreatment with either a noncompetitive (MK-801,0.5 mg/kg, ip) or a competitive (D-CPP-ene, 20 mg/kg, ip) NMDA antagonist prior to MA administration prevented the development of behavioral sensitization.On the other hand, rats treated with four injections of MA (5.0 or 7.5 mg/kg, sc, at 2 hr intervals) caused significant decrements (40-60% of control values) in levels of DA in the striatum and 5-HT in various brain regions. These decreases in DA and 5-HT were prevented by pretreatment with MK-801 or D-CPP-ene. Microdialysis studies revealed that the toxic dose of MA significantly increased levels of glutamate in the striatum.Effects of Nitric Oxide (NO) syntase inhibition on MA-induced behavior and behavioral sensitization were also examined. Nw-nitro-L-arginine methyl ester, an inhibitor of NO synthase, significantly decreased the level of locomotion and stereotypy. In addition, the inhibitor reduced the degree of sensitization to sterotypy stimulating effect of MA.These results suggest that the glutamatergic system plays an important role for MA-induced behavioral sensitization and neurotoxicity.