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首页> 外文期刊>Journal of Behavioral and Brain Science >Dopamine and GABA Interaction in Basal Ganglia: GABA-A or GABA-B Receptor Stimulation Attenuates L-DOPA-Induced Striatal and Nigral ERK1/2 Signaling in a Rat Model of Parkinson’s Disease
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Dopamine and GABA Interaction in Basal Ganglia: GABA-A or GABA-B Receptor Stimulation Attenuates L-DOPA-Induced Striatal and Nigral ERK1/2 Signaling in a Rat Model of Parkinson’s Disease

机译：多巴胺和GABA在基底节的相互作用：GABA-A或GABA-B受体刺激减弱帕金森氏病大鼠模型中L-DOPA诱导的纹状体和黑质ERK1 / 2信号传导

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Parkinson’s disease (PD) is characterized by degeneration of nigrostriatal dopamine (DA) neurons. The primary drug used to treat PD symptoms is L-DOPA, but side effects such as dyskinesias limit its use. Previous findings show that L-DOPA treatment induces extracellular signal-regulated kinase (ERK1/2), a MAP-kinase protein. γ-aminobutyric acid (GABA) is intimately involved in basal ganglia function. Our previous study using a unilaterally lesioned rat model of PD indicated that elevating GABA levels by GABA transaminase inhibitor, aminooxyacetic acid significantly attenuated L-DOPA-induced ERK phosphorylation in the striatum and substantia nigra (SN). The aim of the present study was to assess the role of GABA-A and GABA-B receptor by using a selective agonists, muscimol and baclofen respectively, on L-DOPA-induced ERK phosphorylation in the striatum and SN. Unilaterally 6-OHDA-lesioned rats were prescreened by apomorphine induced rotation test for the extent of DA loss. Lesioned rats were treated with L-DOPA alone or after muscimol or baclofen pretreatment. Appropriate control groups were used. Phospho-ERK levels, tyrosine hydroxylase (to ascertain DA loss) and substance P (an indirect marker for DA loss) levels were assessed by immunohistochemistry using coronal slices at the level of striatum and SN. L-DOPA administration induced a robust increase (>300%) in phospho-ERK1/2 levels in the striatum and SN. Muscimol as well as baclofen pretreatment attenuated the L-DOPA-induced increase in phospho-ERK1/2 levels by >60% in the striatum and SN. Muscimol and baclofen pretreatment also greatly reduced the number of L-DOPA induced phospho-ERK1/2 stained cells in the striatum as well as the contralateral rotational behavior. The present data taken together with our previous study indicate that the L-DOPA induced increase in ERK1/2 is attenuated by GABA via a GABA-A and GABA-B receptor linked mechanism. The study provides further insight into a dopamine-GABA-ERK interaction in the therapeutic and/or side effects of L-DOPA in the basal ganglia.
机译：帕金森氏病（PD）的特征是黑质纹状体多巴胺（DA）神经元的变性。用于治疗PD症状的主要药物是L-DOPA，但诸如运动障碍等副作用限制了其使用。先前的发现表明，L-DOPA处理可诱导细胞外信号调节激酶（ERK1 / 2），一种MAP激酶蛋白。 γ-氨基丁酸（GABA）与基底神经节功能密切相关。我们先前使用PD的单侧病变大鼠模型进行的研究表明，通过GABA转氨酶抑制剂，氨基氧乙酸升高GABA水平，可显着减弱纹状体和黑质（SN）中L-DOPA诱导的ERK磷酸化。本研究的目的是通过分别使用选择性激动剂muscimol和巴氯芬来评估GABA-A和GABA-B受体对L-DOPA诱导的纹状体和SN中ERK磷酸化的作用。通过阿扑吗啡诱导的旋转试验对单侧6-OHDA损伤的大鼠进行了DA丢失程度的预筛选。损伤的大鼠单独或在麝香酚或巴氯芬预处理后用L-DOPA治疗。使用适当的对照组。使用纹状体和SN水平的冠状切片，通过免疫组织化学评估了磷酸化ERK水平，酪氨酸羟化酶（以确定DA损失）和P物质（DA损失的间接标记）水平。 L-DOPA给药导致纹状体和SN的磷酸化ERK1 / 2水平显着增加（> 300％）。 Muscimol以及巴氯芬预处理可使纹状体和SN中L-DOPA诱导的磷酸化ERK1 / 2水平增加> 60％。麝香酚和巴氯芬预处理也大大减少了纹状体中L-DOPA诱导的磷酸化ERK1 / 2染色细胞的数量以及对侧旋转行为。目前的数据与我们以前的研究一起表明，L-DOPA诱导的ERK1 / 2的增加被GABA通过GABA-A和GABA-B受体连接的机制所减弱。该研究提供了对L-DOPA在基底神经节的治疗和/或副作用中多巴胺-GABA-ERK相互作用的进一步了解。

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