Sex differences in methamphetamine toxicity in mice: Effect on brain dopamine signaling pathways
Sex differences in methamphetamine toxicity in mice: Effect on brain dopamine signaling pathways
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DOI：
10.1016/j.psyneuen.2010.12.007
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发表时间：
2011-08-01
影响因子：
3.7
通讯作者：
Di Paolo, Therese
中科院分区：
文献类型：
--
作者：
Bourque, Melanie;Liu, Bin;Di Paolo, Therese
据报道，雄性小鼠比雌性小鼠表现出更大的甲基苯丙胺诱导的神经毒性。本研究评估了磷脂酰肌醇-3激酶(PI3K)/Akt和细胞外信号调节激酶（ERK1/2）通路在性别依赖性甲基苯丙胺毒性中的作用。给雌性和雄性小鼠注射甲基苯丙胺（20或40 mg/kg），一周后对其实施安乐死。侧纹状体多巴胺转运蛋白（DAT）和水疱单胺转运蛋白2 （VMAT2）放射自显像显示，与雌性小鼠相比，20 mg/kg甲基苯丙胺处理的雄性小鼠对侧纹状体的敏感性更高。纹状体多巴胺浓度和DAT放射自显像显示，与雌性小鼠相比，给予40 mg/kg甲基苯丙胺的雄性小鼠纹状体多巴胺的消耗更广泛。给药40 mg/kg的小鼠纹状体VMAT2放射自显像无性别差异。在黑质中，40 mg/kg甲基苯丙胺只降低了雄性小鼠的DAT特异性结合，并且在雌性和雄性小鼠中，甲基苯丙胺处理的DAT mRNA水平降低。甲基苯丙胺处理的雄性小鼠呈现剂量依赖性的VMAT2 mRNA水平下降。两种剂量的甲基苯丙胺均降低了雌性小鼠的胰岛素样生长因子1受体水平，而仅在雄性小鼠中升高了G蛋白偶联雌激素受体1 （GPER1）。磷酸化Akt水平仅在服用40 mg/kg甲基苯丙胺的雄性小鼠中降低。在雄性小鼠和雌性小鼠中，甲基苯丙胺剂量均降低了糖原合成酶激酶30的水平。雄性小鼠经甲基苯丙胺处理后，Bcl-2水平升高，而ERK1/2和BAD水平不变。这些结果暗示了一些与甲基苯丙胺诱导毒性的性别差异有关的信号通路。(C) 2011 Elsevier Ltd.版权所有。
Mate mice were reported to display greater methamphetamine-induced neurotoxicity than females. The present study evaluated the involvement of phosphatidylinositol-3 kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK1/2) pathways in this sex-dependent methamphetamine toxicity. Intact female and male mice were administered methamphetamine (20 or 40 mg/kg) and euthanized a week later. Dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) autoradiography in the lateral striatum showed a greater sensitivity in male mice treated with 20 mg/kg methamphetamine compared to female mice. Striatal dopamine concentration and DAT autoradiography showed a more extensive depletion in male mice given 40 mg/kg methamphetamine compared to female mice. Mice administered 40 mg/kg methamphetamine showed no sex difference in striatal VMAT2 autoradiography. In the substantia nigra, DAT specific binding was decreased only in male mice treated with 40 mg/kg methamphetamine and DAT mRNA levels decreased in methamphetamine-treated female and male mice. Methamphetamine-treated male mice presented a dose-dependent decrease of VMAT2 mRNA levels. Methamphetamine reduced insulin-like growth factor 1 receptor levels in females at both methamphetamine doses tested whereas it elevated G protein-coupled estrogen receptor 1 (GPER1) only in male mice. Phosphorylated Akt levels decreased only in male mice treated with 40 mg/kg methamphetamine. Glycogen synthase kinase 30 levels were reduced in male mice at both methamphetamine doses tested and in females receiving 40 mg/kg. Bcl-2 Levels were increased in male mice treated with methamphetamine, whereas ERK1/2 and BAD levels were unchanged. These results implicate some of the signaling pathways associated with the sex differences in methamphetamine-induced toxicity. (C) 2011 Elsevier Ltd. All rights reserved.