Abstract：
L-3,4-dihydroxyphenylalanine (L-DOPA) is the treatment of choice for Parkinson\'s disease (PD) motor symptoms, but its chronic use is hindered by complications such as dyskinesia. Pre-clinical studies discovered that activation of metabotropic glutamate type 2 and 3 (mGlu2/3) receptors alleviates L-DOPA-induced dyskinesia. To gain mechanistic insight into the anti-dyskinetic activity of mGlu2/3 activation, we performed autoradiographic binding with [3H]-LY-341,495 in brain sections from L-DOPA-treated 6-hydroxydopamine (6-OHDA)-lesioned rats that developed mild or severe dyskinesia, as well as L-DOPA-untreated 6-OHDA-lesioned and sham-lesioned animals. In the ipsilateral hemisphere, mildly dyskinetic 6-OHDA-lesioned rats showed a decrease in [3H]-LY-341,495 binding in the entopeduncular nucleus (EPN, 30 % vs sham-lesioned rats, P<0.05), globus pallidus (GP, 28 % vs sham-lesioned rats, P<0.05; 23 % vs L-DOPA-untreated 6-OHDA-lesioned rats, P<0.001), and primary motor cortex (49 % vs sham-lesioned rats, P<0.05; 45 % vs L-DOPA-untreated 6-OHDA-lesioned rats, P<0.001). Severely dyskinetic 6-OHDA-lesioned rats exhibited an increase in binding in the primary motor cortex (43 % vs mildly dyskinetic 6-OHDA-lesioned rats, P<0.05). In the contralateral hemisphere, mildly dyskinetic 6-OHDA-lesioned rats harboured a decrease in binding in the EPN (30 % vs sham-lesioned rats; 24 % vs L-DOPA-untreated 6-OHDA-lesioned rats, both P<0.05), GP (34 % vs sham-lesioned rats, P<0.05; 23 % vs L-DOPA-untreated 6-OHDA-lesioned rats, P<0.001), and primary motor cortex (50 % vs sham-lesioned rats; 44 % vs L-DOPA-untreated 6-OHDA-lesioned rats, both P<0.05). Severely dyskinetic 6-OHDA-lesioned rats presented a decrease in binding in the GP (30 % vs sham-lesioned rats; 19 % vs L-DOPA-untreated 6-OHDA-lesioned rats, both P<0.05). Abnormal involuntary movements scores of 6-OHDA-lesioned animals were positively correlated with [3H]-LY-341,495 binding in the ipsilateral striatum, ipsilateral EPN, ipsilateral primary motor cortex and contralateral primary motor cortex (all P<0.05). These results suggest that alterations in mGlu2/3 receptor levels may be part of an endogenous compensatory mechanism to alleviate dyskinesia.
摘要：
L-3,4-二羟基苯丙氨酸(L-DOPA)是帕金森病(PD)运动症状的首选治疗方法,但是它的长期使用受到诸如运动障碍等并发症的阻碍。临床前研究发现，2型和3型代谢型谷氨酸（mGlu2/3）受体的激活减轻了L-DOPA诱导的运动障碍。为了深入了解mGlu2/3激活的抗运动障碍活性，我们用[3H]-LY-341,495在L-DOPA处理的6-羟基多巴胺（6-OHDA）损伤的大鼠发生轻度或重度运动障碍的脑切片中进行放射自显影结合，以及未经L-DOPA处理的6-OHDA损伤和假损伤动物。在同侧半球，轻度运动障碍的6-OHDA损伤的大鼠显示[3H]-LY-341,495在足核内的结合减少（EPN，30%vs假损伤大鼠，P<0.05),苍白球（GP，28%vs假损伤大鼠，P<0.05；23%vsL-DOPA未处理的6-OHDA损伤大鼠，P<0.001)，和初级运动皮质(49%vs假损伤大鼠，P<0.05；45%vsL-DOPA未处理的6-OHDA损伤大鼠，P<0.001)。严重运动障碍的6-OHDA损伤大鼠在运动皮质中的结合增加（43％与轻度运动障碍的6-OHDA损伤大鼠相比，P<0.05)。在对侧半球，轻度运动障碍的6-OHDA损伤大鼠在EPN中的结合减少（30％vs假损伤大鼠；24％vsL-DOPA未处理的6-OHDA损伤大鼠，两者P<0.05)，GP（34%vs假病变大鼠，P<0.05；23%vsL-DOPA未处理的6-OHDA损伤大鼠，P<0.001)，和初级运动皮质(50%vs假损伤大鼠；44%vsL-DOPA未处理的6-OHDA损伤大鼠，均P<0.05)。严重运动障碍的6-OHDA损伤大鼠在GP中的结合降低（与假损伤大鼠相比，30％；与未处理的6-OHDA损伤大鼠相比，19％，均P<0.05)。6-OHDA病变动物的异常不自主运动评分与同侧纹状体中的[3H]-LY-341,495结合呈正相关，同侧EPN,同侧初级运动皮层和对侧初级运动皮层(均P<0.05)。这些结果表明，mGlu2/3受体水平的改变可能是减轻运动障碍的内源性代偿机制的一部分。
