Xu Wenjing, Zhu Judy P Q, Angulo Jesus A
Department of Biological Sciences, Hunter College of the City University of New York, New York, NY 10021, USA.
Synapse. 2005 Nov;58(2):110-21. doi: 10.1002/syn.20185.
Methamphetamine (METH) is a psychostimulant that induces excessive release of dopamine (DA) in the striatum. In this study we have assessed the role of DA D1 and D2 receptors (D1R and D2R) on striatal METH-induced apoptosis and depletion of DA-terminal markers. Male mice were given one i.p. injection of METH (30 mg/kg). Apoptosis was assessed at 24 h, and DA-terminal marker depletion 3 days, after METH. A single toxic dose of METH induced apoptosis in approximately 10-13% of striatal neurons. This was completely prevented by pretreatment (30 min before METH) with either the D1R antagonist SCH-23390 (0.1 mg/kg) or the D2R antagonist raclopride (1 mg/kg). The same dose of METH induced depletion of DA transporter sites up to 61, 56, 71, and 69% in dorsal-medial, ventral-medial, dorsal-lateral, and ventral-lateral striatum, respectively, relative to vehicle-injected controls. Similarly, METH induced depletion of TH protein levels up to 80, 72, 87, and 90% in those respective quadrants. METH induced the expression of glial fibrillary acidic protein throughout the striatum. All these neurochemical changes were significantly attenuated by pretreatment with SCH-23390 (0.1 mg/kg) or raclopride (1 mg/kg). However, pretreatment with either raclopride or SCH-23390 did not prevent METH-induced hyperthermia in mice. These data demonstrate that the induction by METH of both striatal apoptosis and DA-terminal damage requires the activity of the postsynaptic DA receptors in the mouse brain. Moreover, since blockade of either receptor subtype protected from METH, the activity of both DA receptor subtypes is required for the induction of toxicity by METH in the striatum.
甲基苯丙胺（METH）是一种精神兴奋剂，可诱导纹状体中多巴胺（DA）的过度释放。在本研究中，我们评估了DA D1和D2受体（D1R和D2R）在纹状体METH诱导的细胞凋亡和DA终末标志物耗竭中的作用。给雄性小鼠腹腔注射一次METH（30 mg/kg）。在METH注射后24小时评估细胞凋亡，3天后评估DA终末标志物耗竭情况。单次毒性剂量的METH可诱导约10 - 13%的纹状体神经元发生细胞凋亡。用D1R拮抗剂SCH - 23390（0.1 mg/kg）或D2R拮抗剂雷氯必利（1 mg/kg）预处理（在METH注射前30分钟）可完全预防这种情况。相对于注射溶剂的对照组，相同剂量的METH分别使背内侧、腹内侧、背外侧和腹外侧纹状体中的DA转运体位点耗竭高达61%、56%、71%和69%。同样，METH使这些相应象限中的TH蛋白水平耗竭高达80%、72%、87%和90%。METH诱导整个纹状体中胶质纤维酸性蛋白的表达。用SCH - 23390（0.1 mg/kg）或雷氯必利（1 mg/kg）预处理可显著减轻所有这些神经化学变化。然而，用雷氯必利或SCH - 23390预处理并不能预防METH诱导的小鼠体温过高。这些数据表明，METH诱导的纹状体细胞凋亡和DA终末损伤均需要小鼠脑中突触后DA受体的活性。此外，由于阻断任一受体亚型均可保护小鼠免受METH的毒性作用，因此两种DA受体亚型的活性对于METH在纹状体中诱导毒性均是必需的。
