Behavioral and Cellular Modulation of L-DOPA-Induced Dyskinesia by β-Adrenoceptor Blockade in the 6-Hydroxydopamine-Lesioned Rat
Behavioral and Cellular Modulation of L-DOPA-Induced Dyskinesia by β-Adrenoceptor Blockade in the 6-Hydroxydopamine-Lesioned Rat
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DOI：
10.1124/jpet.111.179416
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发表时间：
2011-06-01
影响因子：
3.5
通讯作者：
Bishop, Christopher
中科院分区：
文献类型：
--
作者：
Lindenbach, David;Ostock, Corinne Y.;Bishop, Christopher
帕金森病（PD）的慢性多巴胺替代疗法导致称为左旋多巴诱导的运动障碍（LID）的有害运动后遗症。没有已知的治疗方法可以消除LID，但初步证据表明，dl-1-异丙基氨基-3-（1-萘氧基）-2-丙醇[（+/-）普萘洛尔]（一种非选择性β-肾上腺素能受体（β AR）拮抗剂）可能会减少LID。本研究使用大鼠单侧6-羟基多巴胺PD模型来表征和定位（+/-）普萘洛尔作为L-DOPA治疗辅助治疗的疗效。我们首先确定（+/-）普萘洛尔是否能够减少LID的发展和表达，而不损害运动性能ON和OFF L-DOPA。与此同时，我们使用逆转录聚合酶链反应技术来分析慢性（+/-）普萘洛尔对已知参与LID的纹状体活动标记物的影响。为了确定（+/-）普萘洛尔是否通过β AR阻断降低LID，我们随后分别检查了每种对映体，因为只有（-）对映体具有显著的β AR亲和力。接下来，我们通过在全身注射L-DOPA之前对该区域进行插管并微量输注（+/-）普萘洛尔来研究局部纹状体β AR阻断对LID的影响。结果表明，（+/-）普萘洛尔的剂量范围减少LID，而不会有害地影响运动活动。药理学上，只有（+/-）普萘洛尔具有抗LID特性，表明β AR特异性作用。与LID相关的异常纹状体信号传导通过（+/-）普萘洛尔联合治疗而正常化，并且纹状体内（+/-）普萘洛尔能够急性降低LID。这项研究证实了以前的工作表明，（+/-）普萘洛尔通过β AR拮抗作用降低LID，并提出了新的证据，表明潜在的纹状体部位的药理作用。
Chronic dopamine replacement therapy in Parkinson's disease (PD) leads to deleterious motor sequelae known as L-DOPA-induced dyskinesia (LID). No known therapeutic can eliminate LID, but preliminary evidence suggests that dl-1-isopropylamino-3-(1-naphthyloxy)-2-propanol [(+/-)propranolol], a nonselective beta-adrenergic receptor (beta AR) antagonist, may reduce LID. The present study used the rat unilateral 6-hydroxydopamine model of PD to characterize and localize the efficacy of (+/-)propranolol as an adjunct to therapy with L-DOPA. We first determined whether (+/-)propranolol was capable of reducing the development and expression of LID without impairing motor performance ON and OFF L-DOPA. Coincident to this investigation, we used reverse-transcription polymerase chain reaction techniques to analyze the effects of chronic (+/-)propranolol on markers of striatal activity known to be involved in LID. To determine whether (+/-)propranolol reduces LID through beta AR blockade, we subsequently examined each enantiomer separately because only the (-)enantiomer has significant beta AR affinity. We next investigated the effects of a localized striatal beta AR blockade on LID by cannulating the region and microinfusing (+/-)propranolol before systemic L-DOPA injections. Results showed that a dose range of (+/-)propranolol reduced LID without deleteriously affecting motor activity. Pharmacologically, only (+/-)propranolol had anti-LID properties indicating beta AR-specific effects. Aberrant striatal signaling associated with LID was normalized with (+/-)propranolol cotreatment, and intrastriatal (+/-)propranolol was acutely able to reduce LID. This research confirms previous work suggesting that (+/-)propranolol reduces LID through beta AR antagonism and presents novel evidence indicating a potential striatal locus of pharmacological action.