Marti Matteo, Mela Flora, Ulazzi Linda, Hanau Stefania, Stocchi Sara, Paganini Francesca, Beani Lorenzo, Bianchi Clementina, Morari Michele
Department of Experimental and Clinical Medicine, Section of Pharmacology, via Fossato di Mortara 17-19, 44100 Ferrara, Italy.
Eur J Neurosci. 2003 Aug;18(4):759-67. doi: 10.1046/j.1460-9568.2003.02806.x.
Rat striatal synaptosomes and slices were used to investigate the responsiveness of different populations of nerve terminals to 3-nitropropionic acid (3-NP), a suicide inhibitor of the mitochondrial enzyme succinate dehydrogenase, and to elucidate the ionic mechanisms involved. 3-NP (0.3-3 mm) stimulated spontaneous gamma-aminobutyric acid (GABA), glutamate and [3H]-dopamine efflux but left unchanged acetylcholine efflux from synaptosomes. This effect was associated with a >70% inhibition of succinate dehydrogenase, as measured in the whole synaptosomal population. The facilitation was not dependent on extracellular Ca2+ but relied on voltage-dependent Na+ channel opening, because it was prevented by tetrodotoxin and riluzole. 3-NP also elevated spontaneous glutamate efflux from slices but in a tetrodotoxin-insensitive way. To investigate whether energy depletion could change the responsiveness of nerve endings to a depolarizing stimulus, synaptosomes were pretreated with 3-NP and challenged with pulses of KCl evoking 'quasi-physiological' neurotransmitter release. 3-NP potentiated the K+-evoked GABA, glutamate and [3H]-dopamine release but inhibited the K+-evoked acetylcholine release. The 3-NP induced potentiation of GABA release was Ca2+-dependent and prevented by tetrodotoxin and riluzole whereas the 3-NP-induced inhibition of acetylcholine release was tetrodotoxin- and riluzole-insensitive but reversed by glipizide, an ATP-dependent K+ channel inhibitor. We conclude that the responsiveness of striatal nerve endings to 3-NP relies on activation of different ionic conductances, and suggest that the selective survival of striatal cholinergic interneurons following chronic 3-NP treatment (as in models of Huntington's disease) may rely on the opening of ATP-dependent K+ channels, which counteracts the fall in membrane potential as a result of mitochondrial impairment.
大鼠纹状体突触体和切片被用于研究不同神经末梢群体对线粒体酶琥珀酸脱氢酶的自杀性抑制剂3-硝基丙酸（3-NP）的反应性，并阐明其中涉及的离子机制。3-NP（0.3-3 mM）刺激突触体中γ-氨基丁酸（GABA）、谷氨酸和[3H]-多巴胺的自发性外流，但对乙酰胆碱的外流没有影响。在整个突触体群体中测量，这种效应与琥珀酸脱氢酶>70%的抑制有关。这种促进作用不依赖于细胞外Ca2+，而是依赖于电压依赖性Na+通道的开放，因为它被河豚毒素和利鲁唑所阻断。3-NP还以河豚毒素不敏感的方式提高了切片中谷氨酸的自发性外流。为了研究能量耗竭是否会改变神经末梢对去极化刺激的反应性，突触体先用3-NP预处理，然后用诱发“准生理性”神经递质释放的KCl脉冲进行刺激。3-NP增强了K+诱发的GABA、谷氨酸和[3H]-多巴胺释放，但抑制了K+诱发的乙酰胆碱释放。3-NP诱导的GABA释放增强是Ca2+依赖性的，并被河豚毒素和利鲁唑所阻断，而3-NP诱导的乙酰胆碱释放抑制对河豚毒素和利鲁唑不敏感，但被ATP依赖性K+通道抑制剂格列吡嗪所逆转。我们得出结论，纹状体神经末梢对3-NP的反应性依赖于不同离子电导的激活，并表明慢性3-NP治疗后（如在亨廷顿病模型中）纹状体胆碱能中间神经元的选择性存活可能依赖于ATP依赖性K+通道的开放，这抵消了线粒体损伤导致的膜电位下降。
