Resistance of neuronal nitric oxide synthase-deficient mice to methamphetamine-induced dopaminergic neurotoxicity.
Resistance of neuronal nitric oxide synthase-deficient mice to methamphetamine-induced dopaminergic neurotoxicity.
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发表时间：
1998-03
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通讯作者：
Y. Itzhak;Carlos Gandia;Paul L. Huang;SYED F. Ali
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作者：
Y. Itzhak;Carlos Gandia;Paul L. Huang;SYED F. Ali
甲基苯丙胺(METH)是一种强大的精神刺激剂，它能产生多巴胺能神经毒性，表现为黑质纹状体系统中多巴胺水平、酪氨酸羟基酶活性和多巴胺转运体(DAT)结合部位的减少。我们最近报道，用7-硝基吲唑阻断神经元型一氧化氮合酶(NNOS)亚型可保护瑞士韦氏小鼠免受冰毒所致的神经毒性。本研究旨在研究神经毒性剂量的冰毒对nNOS基因缺失突变小鼠[nNOS(-/-)]和野生型对照小鼠的影响。此外，我们试图调查暴露在神经毒性剂量的冰毒下的行为结果。纯合子nNOS(-/-)、杂合子nNOS(+/-)和野生型动物分别给予生理盐水或冰毒(5 mg/kg×3)。最后一次注射冰毒72 h后，测定纹状体组织中多巴胺、DOPAC和HVA水平以及DAT结合位点水平。这种给nNOS(-/-)小鼠服用冰毒的方案既不影响多巴胺及其代谢物的组织含量，也不影响DAT结合位点的数量。虽然杂合子nNOS(+/-)小鼠纹状体中的多巴胺水平(35%)和DAT结合位点(32%)水平适度降低，但在野生型动物中观察到更严重的多巴胺能标记物的缺失(高达68%)。除nNOS(-/-)小鼠外，所有动物品系均可观察到冰毒诱导的体温升高。神经毒性剂量冰毒(5 mg/kg×3)给药前后动物自发活动无明显差异。给幼稚动物(nNOS(-/-)和野生型)注射低剂量冰毒(1.0 mg/kg)，可产生类似强度的运动刺激。然而，在暴露于大剂量冰毒方案后68~72小时，野生型小鼠对攻击冰毒注射有明显的致敏反应，而nNOS(-/-)小鼠则没有。综上所述，这些结果表明，nNOS(-/-)小鼠受到保护，免受冰毒诱导的多巴胺能神经毒性和运动敏化。野生型动物多巴胺能传递的部分缺陷似乎也不能阻止对冰毒的敏感性的发展，而nNOS的缺陷可能会减弱这一过程。
Methamphetamine (METH) is a powerful psychostimulant that produces dopaminergic neurotoxicity manifested by a decrease in the levels of dopamine, tyrosine hydroxylase activity and dopamine transporter (DAT) binding sites in the nigrostriatal system. We have recently reported that blockade of the neuronal nitric oxide synthase (nNOS) isoform by 7-nitroindazole provides protection against METH-induced neurotoxicity in Swiss Webster mice. The present study was undertaken to investigate the effect of a neurotoxic dose of METH on mutant mice lacking the nNOS gene [nNOS(-/-)] and wild-type controls. In addition, we sought to investigate the behavioral outcome of exposure to a neurotoxic dose of METH. Homozygote nNOS(-/-), heterozygote nNOS(+/-) and wild-type animals were administered either saline or METH (5 mg/kg x 3). Dopamine, DOPAC and HVA levels, as well as DAT binding site levels, were determined in striatal tissue derived 72 h after the last METH injection. This regimen of METH given to nNOS(-/-) mice affected neither the tissue content of dopamine and its metabolites nor the number of DAT binding sites. Although a moderate reduction in the levels of dopamine (35%) and DAT binding sites (32%) occurred in striatum of heterozygote nNOS(+/-) mice, a more profound depletion of the dopaminergic markers (up to 68%) was observed in the wild-type animals. METH-induced hyperthermia was observed in all animal strains examined except the nNOS(-/-) mice. Investigation of the animals' spontaneous locomotor activity before and after administration of the neurotoxic dose of METH (5 mg/kg x 3) revealed no differences. A low dose of METH (1.0 mg/kg) administered to naive animals (nNOS(-/-) and wild-type) resulted in a similar intensity of locomotor stimulation. However, 68 to 72 h after exposure to the high-dose METH regimen, a marked sensitized responses to a challenge METH injection was observed in the wild-type mice but not in the nNOS(-/-) mice. Taken together, these results indicate that nNOS(-/-) mice are protected against METH-induced dopaminergic neurotoxicity and locomotor sensitization. It also appears that a partial deficit of dopaminergic transmission in wild-type animals does not prevent the development of sensitization to METH, whereas a deficit in nNOS may attenuate this process.