German D C, Liang C L, Manaye K F, Lane K, Sonsalla P K
Department of Psychiatry, University of Texas Southwestern Medical School, Dallas, TX 75390-9070, USA.
Neuroscience. 2000;101(4):1063-9. doi: 10.1016/s0306-4522(00)00385-7.
The vesicular monoamine transporter in the brain can sequester the neurotoxin 1-methyl-4-phenylpyridinium into synaptic vesicles and protect catecholamine-containing neurons from degeneration. Mouse nigrostriatal dopaminergic neurons, and to a lesser extent locus coeruleus noradrenergic neurons, are vulnerable to toxicity produced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. The present study sought to determine whether pharmacological inactivation of the vesicular monoamine transporter in the brain would enhance the degeneration of substantia nigra dopaminergic neurons and locus coeruleus noradrenergic neurons in 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine-treated animals. Mice were treated subacutely with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine alone, or in combination with vesicular monoamine transporter inhibitors (tetrabenazine or Ro4-1284), and 10-24 days later striatal dopamine and cortical norepinephrine levels were measured using chromatographic methods. In the same animals, substantia nigra and locus coeruleus catecholaminergic neurons were counted using tyrosine hydroxylase immunohistochemical staining with computer imaging techniques. Mice in which pharmacological blockage of the vesicular monoamine transporter enhanced the effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity in the depletion of striatal dopamine concentrations also exhibited enhanced degeneration of substantia nigra dopaminergic neurons. In the same animals, however, vesicular monoamine transporter blockade did not enhance the effects of 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine in the locus coeruleus noradrenergic system. These data are consistent with the hypothesis that the vesicular monoamine transporter can protect catecholamine-containing neurons from 1-methyl-4-phenylpyridinium-induced degeneration by sequestration of the toxin within brain vesicular monoamine transporter-containing synaptic vesicles. Since the amount of vesicular monoamine transporter in locus coeruleus neurons is more than in substantia nigra neurons, and because 1-methyl-4-phenylpyridinium is sequestered within locus coeruleus neurons to a far greater extent than within substantia nigra neurons, it may be that a greater amount of vesicular monoamine transporter inhibition is required for 1-methyl-4-phenylpyridinium to be toxic to locus coeruleus neurons than to substantia nigra dopaminergic neurons.
大脑中的囊泡单胺转运体可将神经毒素1-甲基-4-苯基吡啶鎓隔离到突触小泡中，保护含儿茶酚胺的神经元免于退化。小鼠黑质纹状体多巴胺能神经元，以及程度较轻的蓝斑去甲肾上腺素能神经元，易受1-甲基-4-苯基-1,2,3,6-四氢吡啶产生的毒性影响。本研究旨在确定大脑中囊泡单胺转运体的药理学失活是否会增强1-甲基-4-苯基-1,2,3,6-四氢吡啶处理动物中黑质多巴胺能神经元和蓝斑去甲肾上腺素能神经元的退化。小鼠单独用1-甲基-4-苯基-1,2,3,6-四氢吡啶或与囊泡单胺转运体抑制剂（丁苯那嗪或Ro4-1284）联合进行亚急性处理，10 - 24天后使用色谱法测量纹状体多巴胺和皮质去甲肾上腺素水平。在同一批动物中，使用酪氨酸羟化酶免疫组织化学染色和计算机成像技术对黑质和蓝斑中的儿茶酚胺能神经元进行计数。药理学阻断囊泡单胺转运体增强了1-甲基-4-苯基-1,2,3,6-四氢吡啶毒性对纹状体多巴胺浓度消耗的影响的小鼠，其黑质多巴胺能神经元的退化也增强。然而，在同一批动物中，囊泡单胺转运体阻断并未增强1-甲基-4-苯基-1,2,3,6-四氢吡啶对蓝斑去甲肾上腺素能系统的影响。这些数据与以下假设一致：囊泡单胺转运体可通过将毒素隔离在大脑中含囊泡单胺转运体的突触小泡内，保护含儿茶酚胺的神经元免受1-甲基-4-苯基吡啶鎓诱导的退化。由于蓝斑神经元中囊泡单胺转运体的量多于黑质神经元，并且因为1-甲基-4-苯基吡啶鎓在蓝斑神经元中的隔离程度远大于在黑质神经元中的程度，所以可能需要更大程度地抑制囊泡单胺转运体，1-甲基-4-苯基吡啶鎓才会对蓝斑神经元产生毒性，而对黑质多巴胺能神经元则不然。
