Attenuation of methamphetamine-induced effects through the antagonism of sigma (σ) receptors: Evidence from in vivo and in vitro studies
Attenuation of methamphetamine-induced effects through the antagonism of sigma (σ) receptors: Evidence from in vivo and in vitro studies
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DOI：
10.1016/j.euroneuro.2008.07.006
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发表时间：
2008-12-01
影响因子：
5.6
通讯作者：
Coop, Andrew
中科院分区：
文献类型：
--
作者：
Matsumoto, Rae R.;Shaikh, Jamaluddin;Coop, Andrew
甲基苯丙胺（METH）和许多其他滥用物质与σ受体相互作用。在多巴胺能神经元上发现σ受体，并可调节多巴胺能神经传递。σ受体的反义敲除也减轻了MET诱导的刺激作用，表明这些蛋白质是治疗精神兴奋剂滥用的可行药物开发靶点。在本研究中，评估了σ受体拮抗剂AC 927在体内和体外减弱METH诱导作用的能力。放射性配体结合研究表明，与29种其他受体、转运蛋白和离子通道相比，AC 927对σ受体具有优先亲和力。用AC 927预处理mate、Swiss韦伯斯特小鼠显著减弱了MET诱导的运动刺激、纹状体多巴胺耗竭、纹状体多巴胺转运蛋白减少和体温过高。当METH的神经毒性在温度控制条件下在体外进一步检查时，与AC927共孵育减轻了METH诱导的细胞毒性。总之，结果表明，AC927可以防止METH诱导的效应，并提出了治疗精神兴奋剂滥用的新策略。(C)2008 Elsevier B.V.和ECNP。All rights reserved.
Methamphetamine (METH) and many other abused substances interact with sigma receptors. sigma receptors are found on dopaminergic neurons and can modulate dopaminergic neurotransmission. Antisense knockdown of sigma receptors also mitigates METH-induced stimulant effects, suggesting that these proteins are viable medication development targets for treating psychostimulant abuse. In the present study, AC927, a sigma receptor antagonist, was evaluated for its ability to attenuate METH-induced effects in vivo and in vitro. Radioligand binding studies showed that AC927 had preferential affinity for sigma receptors compared to 29 other receptors, transporters and ion channels, Pretreatment of mate, Swiss Webster mice with AC927 significantly attenuated METH-induced locomotor stimulation, striatal dopamine depletions, striatal dopamine transporter reductions, and hyperthermia. When the neurotoxicity of METH was further examined in vitro under temperature-controlled conditions, co-incubation with AC927 mitigated METH-induced cytotoxicity. Together, the results demonstrate that AC927 protects against METH-induced effects, and suggests a new strategy for treating psychostimulant abuse. (C) 2008 Elsevier B.V. and ECNP. All rights reserved.