Saulle Emilia, Centonze Diego, Martín Ana B, Moratalla Rosario, Bernardi Giorgio, Calabresi Paolo
Clinica Neurologica, Dipartimento di Neuroscienze, Università "Tor Vergata," and IRCCS Fondazione Santa Lucia, Rome, Italy.
Stroke. 2002 Dec;33(12):2978-84. doi: 10.1161/01.str.0000038093.42512.0f.
Several observations indicate that, during energy deprivation, endogenous dopamine may become neurotoxic. Accordingly, the nucleus striatum is a preferential site of silent infarcts in humans, and experimental ischemia caused by homolateral carotid occlusion selectively damages this dopamine-enriched brain area. In an attempt to clarify how dopamine takes part in ischemia-induced neuronal damage, we performed in vitro electrophysiological recordings from neurons of the nucleus striatum.
Intracellular recordings with sharp microelectrodes were performed from corticostriatal slices. Slices were obtained from both rats and wild-type and dopamine D1 receptor-lacking mice. In some experiments, the striatum was unilaterally denervated by injecting the dopamine-specific neurotoxin 6-hydroxydopamine in the homolateral substantia nigra. Dopamine agonists and antagonists, as well as drugs targeting the intracellular cascade coupled to dopamine receptor stimulation, were applied at known concentrations.
Manipulation of the dopamine system failed to affect the membrane depolarization of striatal neurons exposed to combined oxygen and glucose deprivation of short duration, but it reduced the amplitude of postischemic long-term potentiation (LTP) expressed at corticostriatal synapses. In particular, pharmacological blockade or genetic inactivation of D1/cAMP/protein kinase A pathway prevented the long-term increase of the excitatory postsynaptic potential (EPSP) amplitude caused by a transient ischemic episode, while it failed to prevent the increase of the EPSP half-decay coupled to ischemic LTP.
The present data suggest that endogenous dopamine, via D1 receptors, selectively facilitates the expression of ischemic LTP on the AMPA-mediated component of the EPSPs, while it does not alter the expression of this form of synaptic plasticity on the N-methyl-D-aspartate-mediated component of corticostriatal synaptic potentials. Understanding the cellular and molecular mechanisms of ischemia-triggered excitotoxicity offers hope for the development of specific treatments able to interfere with this pathological process.
多项观察结果表明，在能量剥夺期间，内源性多巴胺可能具有神经毒性。因此，纹状体核是人类无症状梗死的优先发生部位，并且同侧颈动脉闭塞引起的实验性缺血会选择性地损伤这个富含多巴胺的脑区。为了阐明多巴胺如何参与缺血诱导的神经元损伤，我们对纹状体核的神经元进行了体外电生理记录。
用尖锐微电极对皮质纹状体切片进行细胞内记录。切片取自大鼠、野生型小鼠和缺乏多巴胺D1受体的小鼠。在一些实验中，通过向同侧黑质注射多巴胺特异性神经毒素6-羟基多巴胺，对纹状体进行单侧去神经支配。以已知浓度应用多巴胺激动剂和拮抗剂，以及针对与多巴胺受体刺激偶联的细胞内级联反应的药物。
对多巴胺系统的操作未能影响暴露于短期联合氧和葡萄糖剥夺的纹状体神经元的膜去极化，但降低了皮质纹状体突触处缺血后长期增强（LTP）的幅度。特别是，D1/cAMP/蛋白激酶A途径的药理学阻断或基因失活可防止短暂缺血发作引起的兴奋性突触后电位（EPSP）幅度的长期增加，而未能阻止与缺血LTP偶联的EPSP半衰期的增加。
目前的数据表明，内源性多巴胺通过D1受体选择性地促进EPSP的AMPA介导成分上缺血LTP的表达，而不改变这种突触可塑性在皮质纹状体突触电位的N-甲基-D-天冬氨酸介导成分上的表达。了解缺血引发的兴奋性毒性的细胞和分子机制为开发能够干扰这一病理过程的特异性治疗方法带来了希望。
