Fast-scan cyclic voltammetry demonstrates that L-DOPA produces dose-dependent, regionally selective bimodal effects on striatal dopamine kinetics invivo
Fast-scan cyclic voltammetry demonstrates that L-DOPA produces dose-dependent, regionally selective bimodal effects on striatal dopamine kinetics invivo
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DOI：
10.1111/jnc.13444
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发表时间：
2016-03-01
影响因子：
4.7
通讯作者：
Wagner, Amy K.
中科院分区：
文献类型：
--
作者：
Harun, Rashed;Hare, Kristin M.;Wagner, Amy K.
帕金森病（PD）是一种由黑质致密部多巴胺能（DAergic）神经元的相对特异性变性引起的衰弱性疾病。40多年前，左旋多巴作为一种可行的帕金森病治疗方案被引入，并且仍然是帕金森病最常见和有效的治疗方法。虽然左旋多巴增加纹状体多巴生成的作用是众所周知的，但实际上对左旋多巴如何改变多巴神经传递动力学，从而导致其有益和有害的影响知之甚少。在这项研究中，我们使用快速扫描循环伏安法研究了左旋多巴（50mg/kg卡比多巴+ 0,100和250mg/kg左旋多巴）对麻醉大鼠区域电刺激DA反应动力学的影响。我们证明左旋多巴可以促进背纹状体（D-STR）和伏隔核（NAc）的DA释放，但令人惊讶的是，左旋多巴会延迟抑制D-STR的释放。在这两个区域，左旋多巴逐渐减弱再摄取动力学，主要是通过降低V-max。这些发现对了解左旋多巴的药效学具有重要意义，这可能有助于了解其治疗效果和常见的副作用，如左旋多巴诱导的运动障碍（LID）。
Parkinson's disease (PD) is a debilitating condition that is caused by a relatively specific degeneration of dopaminergic (DAergic) neurons of the substantia nigra pars compacta. L-DOPA was introduced as a viable treatment option for PD over 40years ago and still remains the most common and effective therapy for PD. Though the effects of L-DOPA to augment striatal DA production are well known, little is actually known about how L-DOPA alters the kinetics of DA neurotransmission that contribute to its beneficial and adverse effects. In this study, we examined the effects of L-DOPA administration (50mg/kg carbidopa+0, 100, and 250mg/kg L-DOPA) on regional electrically stimulated DA response kinetics using fast-scan cyclic voltammetry in anesthetized rats. We demonstrate that L-DOPA enhances DA release in both the dorsal striatum (D-STR) and nucleus accumbens (NAc), but surprisingly causes a delayed inhibition of release in the D-STR. In both regions, L-DOPA progressively attenuated reuptake kinetics, predominantly through a decrease in V-max. These findings have important implications on understanding the pharmacodynamics of L-DOPA, which may be informative for understanding its therapeutic effects and also common side effects like L-DOPA-induced dyskinesias (LID).