Dual effects of L-DOPA on nigral dopaminergic neurons
Dual effects of L-DOPA on nigral dopaminergic neurons
复制标题
DOI：
10.1016/j.expneurol.2013.02.009
复制
发表时间：
2013-09-01
影响因子：
5.3
通讯作者：
Lipski, Janusz
中科院分区：
文献类型：
--
作者：
Guatteo, Ezia;Yee, Andrew;Lipski, Janusz
左旋多巴（左旋多巴）仍然是治疗帕金森病（PD）运动症状的金标准，尽管有迹象表明该药物可能对细胞培养产生不利影响。很经典。L-DOPA增加黑质多巴胺能神经元多巴胺（DA）的产生，同时矛盾地抑制这些神经元的放电，由于激活D2自身受体的细胞外释放DA。使用电生理学和钙显微荧光测定法在脑切片的组合，我们已经确定了一种新的影响L-DOPA多巴胺能神经元时，D2受体被阻断。在这些条件下，L-DOPA（0.03-3 mM）诱发了由两种成分组成的兴奋效应。在应用药物期间和之后立即观察到的“早期”成分与增加的放电、膜去极化和内向电流有关。CNQX（10 μ M）强烈减弱了这种兴奋性反应，表明涉及TOPA醌，TOPA醌是L-DOPA的自氧化产物，是AMPA/红藻氨酸受体的有效激活剂。短暂应用L-DOPA后，兴奋的“晚期”相持续>30分钟，并且不受离子型谷氨酸受体介导，也不受D1、α 1-肾上腺素能、mGluR 1或GABA（B）受体介导。它被消除卡比多巴，表明其依赖于转换的L-DOPA DA。外源性DA（50 μ M）也引起了谷氨酸受体独立的增加时，D2受体被阻断的射击和内向电流。在电压钳位神经元中，L-DOPA和DA均产生[Ca 2 +]（i）的长期增加，其不受亲离子型谷氨酸受体阻断的影响。这些结果表明，左旋多巴具有双重，抑制和兴奋，对黑质多巴胺能神经元的影响，并建议，兴奋和钙的上升可能有长期的后果，这些神经元的活性和生存时，D2受体的表达或功能受损。(C)2013 Elsevier Inc. All rights reserved.
L-DOPA (Levodopa) remains the gold standard for the treatment of motor symptoms of Parkinson's disease (PD), despite indications that the drug may have detrimental effects in cell culture. Classically. L-DOPA increases the production of dopamine (DA) in nigral dopaminergic neurons, while paradoxically inhibiting the firing of these neurons due to activation of D2 autoreceptors by extracellularly released DA. Using a combination of electrophysiology and calcium microfluorometry in brain slices, we have identified a novel effect of L-DOPA on dopaminergic neurons when D2 receptors were blocked. Under these conditions, L-DOPA (0.03-3 mM) evoked an excitatory effect consisting of two components. The 'early' component observed during and immediately after application of the drug, was associated with increased firing, membrane depolarization and inward current This excitatory response was strongly attenuated by CNQX (10 mu M), pointing to the involvement of TOPA quinone, an auto-oxidation product of L-DOPA and a potent activator of AMPA/kainate receptors. The 'late' phase of excitation persisted >30 min after brief L-DOPA application and was not mediated by ionotropic glutamate receptors, nor by D1, alpha 1-adrenergic, mGluR1 or GABA(B) receptors. It was eliminated by carbidopa, demonstrating its dependence on conversion of L-DOPA to DA. Exogenous DA (50 mu M) also evoked a glutamate-receptor independent increase in firing and an inward current when D2 receptors were blocked. In voltage-clamped neurons, both L-DOPA and DA produced a long-lasting increase in [Ca2+](i) which was unaffected by block of ionotropic glutamate receptors. These results demonstrate that L-DOPA has dual, inhibitory and excitatory, effects on nigral dopaminergic neurons, and suggest that the excitation and calcium rise may have long-lasting consequences for the activity and survival of these neurons when the expression or function of D2 receptors is impaired. (C) 2013 Elsevier Inc. All rights reserved.