Itzhak Y, Gandia C, Huang P L, Ali S F
Department of Biochemistry and Molecular Biology, University of Miami School of Medicine, Florida, USA.
J Pharmacol Exp Ther. 1998 Mar;284(3):1040-7.
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.
甲基苯丙胺（METH）是一种强效精神兴奋剂，会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、酪氨酸羟化酶活性及多巴胺转运体（DAT）结合位点减少。我们最近报告称，7-硝基吲唑对神经元型一氧化氮合酶（nNOS）亚型的阻断可保护瑞士韦伯斯特小鼠免受METH诱导的神经毒性。本研究旨在调查神经毒性剂量的METH对缺乏nNOS基因的突变小鼠[nNOS(-/-)]和野生型对照小鼠的影响。此外，我们试图研究暴露于神经毒性剂量的METH后的行为结果。给纯合子nNOS(-/-)、杂合子nNOS(+/-)和野生型动物注射生理盐水或METH（5mg/kg×3）。在最后一次注射METH 72小时后，测定纹状体组织中的多巴胺、3,4-二羟基苯乙酸（DOPAC）和高香草酸（HVA）水平以及DAT结合位点水平。给予nNOS(-/-)小鼠的这种METH给药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(+/-)小鼠纹状体中多巴胺水平（35%）和DAT结合位点（32%）有适度降低，但野生型动物中多巴胺能标志物的耗竭更为严重（高达68%）。除nNOS(-/-)小鼠外，在所有检测的动物品系中均观察到METH诱导的体温过高。对给予神经毒性剂量的METH（5mg/kg×3）前后动物的自发运动活性进行调查，未发现差异。给未接触过药物的动物（nNOS(-/-)和野生型）注射低剂量的METH（1.0mg/kg）会产生相似强度的运动刺激。然而，在暴露于高剂量METH给药方案68至72小时后，野生型小鼠对METH激发注射出现明显的敏感反应，而nNOS(-/-)小鼠则未出现。综上所述，这些结果表明nNOS(-/-)小鼠可免受METH诱导的多巴胺能神经毒性和运动敏感化。似乎野生型动物中多巴胺能传递的部分缺陷并不能阻止对METH敏感化的发展，而nNOS的缺陷可能会减弱这一过程。
