Department of Basic Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV 26506, USA.
Neuropharmacology. 2011 Oct-Nov;61(5-6):992-1000. doi: 10.1016/j.neuropharm.2011.06.028. Epub 2011 Jul 7.
Methamphetamine (METH) is a highly addictive psychostimulant drug of abuse. Low and high dose administration of METH leads to locomotor stimulation, and dopaminergic and serotonergic neurotoxicity, respectively. The behavioral stimulant and neurotoxic effects of METH can contribute to addiction and other neuropsychiatric disorders, thus necessitating the identification of potential pharmacotherapeutics against these effects produced by METH. METH binds to σ receptors at physiologically relevant concentrations. Also, σ receptors are present on and can modulate dopaminergic and serotonergic neurons. Therefore, σ receptors provide a viable target for the development of pharmacotherapeutics against the adverse effects of METH. In the present study, CM156, a σ receptor ligand with high affinity and selectivity for σ receptors over 80 other non-σ binding sites, was evaluated against METH-induced stimulant, hyperthermic, and neurotoxic effects. Pretreatment of male, Swiss Webster mice with CM156 dose dependently attenuated the locomotor stimulation, hyperthermia, striatal dopamine and serotonin depletions, and striatal dopamine and serotonin transporter reductions produced by METH, without significant effects of CM156 on its own. These results demonstrate the ability of a highly selective σ ligand to mitigate the effects of METH.
甲基苯丙胺（METH）是一种高度成瘾的精神兴奋剂药物。低剂量和高剂量的 METH 给药分别导致运动刺激和多巴胺能和血清素能神经毒性。METH 的行为兴奋剂和神经毒性作用可导致成瘾和其他神经精神疾病，因此需要确定针对 METH 产生的这些作用的潜在药物治疗方法。METH 在生理相关浓度下与 σ 受体结合。此外，σ 受体存在于多巴胺能和血清素能神经元上，并可以调节它们。因此，σ 受体为开发针对 METH 不良反应的药物治疗方法提供了可行的靶标。在本研究中，CM156 是一种 σ 受体配体，对 σ 受体具有高亲和力和选择性，对 80 多种其他非 σ 结合位点的选择性超过 80 种，用于评估其对 METH 诱导的兴奋剂、发热和神经毒性作用的影响。CM156 预处理雄性瑞士 Webster 小鼠可剂量依赖性地减弱 METH 引起的运动刺激、体温升高、纹状体多巴胺和血清素耗竭以及纹状体多巴胺和血清素转运蛋白减少，而 CM156 本身没有显著影响。这些结果表明，一种高选择性的 σ 配体具有减轻 METH 作用的能力。
