Modulation of L-DOPA's antiparkinsonian and dyskinetic effects by α2-noradrenergic receptors within the locus coeruleus.
Modulation of L-DOPA's antiparkinsonian and dyskinetic effects by α2-noradrenergic receptors within the locus coeruleus.
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DOI：
10.1016/j.neuropharm.2015.03.008
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发表时间：
2015-08
影响因子：
4.7
通讯作者：
Bishop C
中科院分区：
文献类型：
--
作者：
Ostock CY;Hallmark J;Palumbo N;Bhide N;Conti M;George JA;Bishop C
长期使用左旋多巴治疗帕金森氏病（PD）经常会出现一种称为左旋多巴诱导的运动障碍（LID）的衰弱性运动副作用。越来越多的证据表明去甲肾上腺素（NE）系统参与了LID的发病机制。本研究采用单侧6-羟多巴胺大鼠PD模型，探讨α2-肾上腺素受体（α2R）在左旋多巴的治疗和有害运动诱导作用中的作用。首先，我们利用啮齿类动物异常不自主运动量表，研究了用可口定刺激或用阿替帕唑阻断全身α2R对LID的影响，并利用前爪调节步骤测试和运动活动室，研究了左旋多巴的治疗效果。通过在给药前直接给药可乐定或阿替帕唑，研究了LID中α2R的解剖作用位点。结果显示，全身可乐定治疗降低了LID和运动活动，但不干扰左旋多巴的抗帕金森益处。相反，系统性阿替帕唑预处理延长了LID和运动活动，但没有调节左旋多巴的抗帕金森益处。lc内注射可乐定和阿替帕唑反映了全身效应，可乐定减少，阿替帕唑增加。综上所述，这些结果表明α2R在左旋多巴介导的行为中起着重要的调节作用，作为潜在的治疗靶点应进一步研究。
Long-term L-DOPA use for Parkinson’s disease (PD) is frequently complicated by the emergence of a debilitating motor side effect known as L-DOPA-induced dyskinesia (LID). Accumulating evidence has implicated the norepinephrine (NE) system in the pathogenesis of LID. Here we used the unilateral 6-hydroxydopamine rat model of PD to determine the role of the α2-adrenoceptors (α2R) in L-DOPA’s therapeutic and detrimental motor-inducing effects. First, we characterized the effects of systemic α2R stimulation with clonidine, or blockade with atipamezole, on LID using the rodent abnormal involuntary movements scale, and L-DOPA’s therapeutic effects using the forepaw adjusting steps test and locomotor activity chambers. The anatomical locus of action of α2R in LID was investigated by directly infusing clonidine or atipamezole into the locus coeruleus prior to systemic L-DOPA administration. Results showed systemic clonidine treatment reduced LID and locomotor activity but did not interfere with L-DOPA’s antiparkinsonian benefits. Conversely, systemic atipamezole pretreatment prolonged LID and locomotor activity but did not modulate L-DOPA’s antiparkinsonian benefits. Intra-LC infusions of clonidine and atipamezole mirrored systemic effects where clonidine reduced, and atipamezole increased, LID. Collectively, these results demonstrate that α2R play an important modulatory role in L-DOPA-mediated behaviors and should be further investigated as a potential therapeutic target.
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影响因子：
4.7
作者：
Dupre KB;Eskow KL;Barnum CJ;Bishop C
通讯作者：
Bishop C
影响因子：
2.5
作者：
ELLIOTT, PJ;WALSH, DM;CLOSE, SP
通讯作者：
CLOSE, SP
DOI：
10.1073/pnas.68.3.662
发表时间：
1971-01-01
影响因子：
11.1
作者：
CHALMERS, JP;BALDESSARINI, RJ;WURTMAN, RJ
通讯作者：
WURTMAN, RJ
影响因子：
5.3
作者：
Carta, Anna R.;Frau, Lucia;Morelli, Micaela
通讯作者：
Morelli, Micaela
影响因子：
4.7
作者：
BARABAN, JM;AGHAJANIAN, GK
通讯作者：
AGHAJANIAN, GK