皮层电刺激对左旋多巴诱发异动症大鼠纹状体c-fos及ENK表达的影响
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摘要
目的：建立左旋多巴(L-dopa)诱发帕金森病(PD)大鼠的异动症(LID)模型,研究皮层电刺激对LID大鼠纹状体神经元c-fos、脑啡肽(ENK)、细胞外信号调节激酶1/2(ERK1/2)表达的影响,探讨皮层-纹状体通路可塑性改变在LID发生机制中的作用。
方法：6-羟多巴胺(6-OHDA)立体定向注射至大鼠右侧内侧前脑束(MFB)制备偏侧PD大鼠模型。44只造模成功的PD大鼠分为LID诱导组(n=22)和PD对照组(n=22),另取20只正常大鼠作为正常对照组。LID诱导组和正常对照组给予(L-dopa 30mg/kg+Benserazide 10mg/kg溶于2.5ml NS),每日1次,腹腔注射,连续用药21d,PD对照组给予等量生理盐水腹腔注射。对出现异常不自主运动(AIM)的大鼠进行录像并评分,同时观察肢体运动功能及旋转行为改变情况。L-dopa治疗结束后2周,再次给予L-dopa,仍出现不自主运动的PD大鼠,鉴定为成功的LID模型,22只大鼠中成功的LID模型有20只。
行为学实验结束后每组随机抽取十只动物,电刺激大鼠运动皮层。皮层电刺激20分钟后,用4%的多聚甲醛经心脏灌流,断头取脑,做石蜡切片,用免疫组织化学方法(SP法)检测大鼠纹状体区c-fos、ENK、细胞外信号调节激酶1/2(ERK1/2)及其活化形式磷酸化细胞外信号调节激酶1/2(p-ERK1l/2)的表达。每只动物取五张不同层面纹状体切片(前囟前后各1mm,不同动物切片层面相同),每张切片随机在壳核取10个高倍镜视野,采用计算机图像分析系统进行图像分析c-fos、ENK、ERK1/2及p-ERK1/2阳性细胞数和染色强度,同时采用相邻切片行不同指标免疫组化染色以观察c-fos与ENK共表达的情况。
结果：
1、LID模型制备及其运动行为特征：80只大鼠造模后共获得44只成功的偏侧PD模型(成功率55%)；22只接受波动性L-dopa治疗的PD大鼠中,有20只出现了不同程度的AIM(成功率91%),PD大鼠在接受L-dopa慢性治疗后出现不自主运动后评分情况如下：第3天评分：(31.13±0.32)分,第12、15、18、21天AIM评分分别为(44.02±0.85)分、(47.47±0.65)分、(55.08±0.20)分、(59.10±1.01)分,肢体运动功能在接受治疗过程中同时改善；而PD对照组和正常组没有出现不自主运动情况,肢体功能也没有出现明显变化。
2.大鼠纹状体区c-fos、ENK、ERK1/2、p-ERK1/2的表达：与对侧比较,各组皮层电刺激使纹状体c-fos、ENK、ERK1/2、p-ERK1/2的表达均增加(P<0.01)；LID组c-fos的表达(0.67±0.03)较PD组(0.45±0.04)和正常组(0.38±0.02)增加(P<0.05)；LID组ENK(0.21±0.07)的表达和PD组(0.18±0.08)相比较无统计学差异(P>0.05)；三组ERK1／2的表达无统计学差异(P>0.05)；LID组p-ERK1/2的表达(0.17±0.05)较PD组(0.08±0.03)和正常组(0.07±0.02)增加(P<0.01)。
3. c-fos与ENK的共表达：LID组与PD组表达c-fos的阳性细胞在纹状体区域存在着与ENK共表达的现象。LID组中c-fos与ENK共表达的细胞占ENK阳性细胞总数的比率是10.76%±2.34%,而PD组中该比率是7.43%±1.48%,两组相比结果具有统计学意义(P<0.05)。
结论：1.慢性脉冲式L-dopa治疗可诱发PD大鼠出现不自主运动,类似人类剂峰异动症,可作为LID的啮齿类模型。
2.电刺激运动皮层可激活皮层-纹状体通路,诱导纹状体神经元表达c-fos。LID大鼠皮层-纹状体通路活动增强,与ERK1／2磷酸化激活有关。
3.皮层电刺激之后LID组纹状体ENK神经元c-fos表达增多,提示皮层电刺激之后间接通路纹状体神经元活动的增强,可能也参与LID形成。
Objective:To establish rat model of the levodopa-induced dyskinesia(LID) and to examine the effects of the cortical electrical stimulation on the expression of the c-fos,enkephalin(ENK) and extracellular regulated kinase1/2(ERK1/2) in straital neurons of rats with levodopa-induced dyskinesia(LID), in order to provide evidence of neural plasticity modulation of corticostriatal pathway in the pathogenesis of LID.
Methods:Hemi-parkinsomism rat models were made by 6-OHDA microinjection stereotaxically.The successful PD models were randomly applied into LID inducing group (n=22)and PD control group(n=22),twenty normal rats were used as the normal control group (n=20).The animals from the LID group and normal control group were treated with chronic intermittent L-dopa 30mg/kg+Benseridel0mg/kg injection for 21 days,while the animals from the PD control group received equal volume saline treatment. The abnormal involuntary movement(AIM) behavior was recorded by video and the abnormal involuntary movement scores were estimated using the rat AIM rating scale. The cylinder tests of the limb movement function and the rotation behavior were also examined. Two weeks after the conclusion of L-dopa treatment, the animals in the LID inducing group received L-dopa injection again to check the reappearance of AIM,those showed AIM were considered successful LID model animals. Twenty successful LID models were obtained from twenty-two rats. Ten animals from each group recived corticostriatal electrical stimulations after behavior assessment. At the end of stimulation (about 20 minutes), the animal was anesthetized deeply and perfused slowly with a brief saline prewash followed by 150ml of 4% buffered paraformaldehyde. The brain was collected and processed for immunohistochemical staining. Serial paraffin sections(5-10μm thick) of striatum near the coronal suture(±1 mm) were cut in the frontal planes on a microtome. Immunohistochemical staining was performed to determine the expression level of c-fos, ENK, extracellular regulated kinasel/2(ERK1/2) and phosphorylated-ERK1/2 (p-ERK1/2) in striatum. Five brain sections from each animal (with the same coordinate for different animals) were examined under microscope in high multificatin field,the positive expression cells were counted and the staining intensities were analysed using auto-image analysis system in ten randomly selected field in the putamen for each slice. The coexpression of c-fos and ENK was also analysed by obversing the two successive sections which were immunochemically stained for c-fos and ENK expression respectively.
Results
1. Establishment of LID model and its movement behavior characterics:44 successful PD models were obtained from 80 rats,the ratio is 55%. Treatment with levodopa in PD rats gradually induced abnormal involuntary movement (AIM),20 of 22 PD rats which received L-dopa injection developed AIM, and the ratio is 91%. The AIM score of the third day of L-dopa treatment was (31.13±0.32), and the scores of the 12th,15th, 18th,21th day were (44.02±0.85), (47.47±0.65), (55.08±0.20), (59.10±1.01) respectively.The cylinder tests showed the limb motor functions of animals was improved by levodopa treatment.The AIM never appeared and no significant changes of the limb motor functions were observed in both PD control group and the normal control group.
2. The expression of the c-fos, ENK, ERK1/2, p-ERK1/2 in striatum:Compared with the contralateral side, the expression of the c-fos, ENK, ERK1/2 and p-ERKl/2 in ipsilateral striatum in each group increased significantly (P<0.01) after the electrical stimulation. The striatal expression of c-fos in LID rats (0.67±0.03) was significantly higher than that of PD rats (0.45±0.04) and normal rats(0.38±0.02) (P<0.05).ENK expressional level in LID group(0.21±0.07) was not significantly different from that of the PD group(0.18±0.08) (P>0.05).The expression of ERK1/2 was not significantly different among the three groups (P>0.05),but the p-ERK1/2 expressional level in LID rats (0.17±0.05) was significantly higher than that of the PD group (0.08±0.03) and the normal group (0.07±0.02) (P＜0.01)
3.The co-expression of the c-fos and ENK:Co-expression of the c-fos and ENK in striatal neurons was observed in both LID group and PD group,however,the percentage of c-fos postive neurons co-expressing ENK in LID group(10.76%±2.34%) was higher than that of the PD group(7.43%±1.48%) (P＜0.05)
Conclusion
1.Chronic treatment with levodopa intermittently can induce AIM in hemi-parkinsomism rats. These rats showed behavioral and pharmaceutical characterization similar to levedopa induced peak-dose dyskinesia in PD patients and can be used as a rodent LID model.
2. Electric stimulation on motor cortex can activate the corticostriatal pathway, which induced the expression of c-fos in striatum. Enhanced activity of the corticostriatal pathway was involved in the pathogenesis of LID which was suggested by significant higher level of c-fos expression in LID rats in relative to no-dyskinesia PD rats. The corticostriatal eletrical stimulation induced c-fos expression was correlated with phosphorylation modification of ERK1/2 but not with the total ERK1/2 expression, indicating that corticostriatal pathway stimulation induced c-fos expression may mediated by ERK1/2 phosphorylation but not by increasing ERK expression.
3. The increased co-expression of the c-fos and ENK in striatal neurons of LID rats induced by the electric stimulation of coticostriata pathway suggested enhanced activity of the indirect-pathway may be involved in the development of LID.
方法：6-羟多巴胺(6-OHDA)立体定向注射至大鼠右侧内侧前脑束(MFB)制备偏侧PD大鼠模型。44只造模成功的PD大鼠分为LID诱导组(n=22)和PD对照组(n=22),另取20只正常大鼠作为正常对照组。LID诱导组和正常对照组给予(L-dopa 30mg/kg+Benserazide 10mg/kg溶于2.5ml NS),每日1次,腹腔注射,连续用药21d,PD对照组给予等量生理盐水腹腔注射。对出现异常不自主运动(AIM)的大鼠进行录像并评分,同时观察肢体运动功能及旋转行为改变情况。L-dopa治疗结束后2周,再次给予L-dopa,仍出现不自主运动的PD大鼠,鉴定为成功的LID模型,22只大鼠中成功的LID模型有20只。
行为学实验结束后每组随机抽取十只动物,电刺激大鼠运动皮层。皮层电刺激20分钟后,用4%的多聚甲醛经心脏灌流,断头取脑,做石蜡切片,用免疫组织化学方法(SP法)检测大鼠纹状体区c-fos、ENK、细胞外信号调节激酶1/2(ERK1/2)及其活化形式磷酸化细胞外信号调节激酶1/2(p-ERK1l/2)的表达。每只动物取五张不同层面纹状体切片(前囟前后各1mm,不同动物切片层面相同),每张切片随机在壳核取10个高倍镜视野,采用计算机图像分析系统进行图像分析c-fos、ENK、ERK1/2及p-ERK1/2阳性细胞数和染色强度,同时采用相邻切片行不同指标免疫组化染色以观察c-fos与ENK共表达的情况。
结果：
1、LID模型制备及其运动行为特征：80只大鼠造模后共获得44只成功的偏侧PD模型(成功率55%)；22只接受波动性L-dopa治疗的PD大鼠中,有20只出现了不同程度的AIM(成功率91%),PD大鼠在接受L-dopa慢性治疗后出现不自主运动后评分情况如下：第3天评分：(31.13±0.32)分,第12、15、18、21天AIM评分分别为(44.02±0.85)分、(47.47±0.65)分、(55.08±0.20)分、(59.10±1.01)分,肢体运动功能在接受治疗过程中同时改善；而PD对照组和正常组没有出现不自主运动情况,肢体功能也没有出现明显变化。
2.大鼠纹状体区c-fos、ENK、ERK1/2、p-ERK1/2的表达：与对侧比较,各组皮层电刺激使纹状体c-fos、ENK、ERK1/2、p-ERK1/2的表达均增加(P<0.01)；LID组c-fos的表达(0.67±0.03)较PD组(0.45±0.04)和正常组(0.38±0.02)增加(P<0.05)；LID组ENK(0.21±0.07)的表达和PD组(0.18±0.08)相比较无统计学差异(P>0.05)；三组ERK1／2的表达无统计学差异(P>0.05)；LID组p-ERK1/2的表达(0.17±0.05)较PD组(0.08±0.03)和正常组(0.07±0.02)增加(P<0.01)。
3. c-fos与ENK的共表达：LID组与PD组表达c-fos的阳性细胞在纹状体区域存在着与ENK共表达的现象。LID组中c-fos与ENK共表达的细胞占ENK阳性细胞总数的比率是10.76%±2.34%,而PD组中该比率是7.43%±1.48%,两组相比结果具有统计学意义(P<0.05)。
结论：1.慢性脉冲式L-dopa治疗可诱发PD大鼠出现不自主运动,类似人类剂峰异动症,可作为LID的啮齿类模型。
2.电刺激运动皮层可激活皮层-纹状体通路,诱导纹状体神经元表达c-fos。LID大鼠皮层-纹状体通路活动增强,与ERK1／2磷酸化激活有关。
3.皮层电刺激之后LID组纹状体ENK神经元c-fos表达增多,提示皮层电刺激之后间接通路纹状体神经元活动的增强,可能也参与LID形成。
Objective:To establish rat model of the levodopa-induced dyskinesia(LID) and to examine the effects of the cortical electrical stimulation on the expression of the c-fos,enkephalin(ENK) and extracellular regulated kinase1/2(ERK1/2) in straital neurons of rats with levodopa-induced dyskinesia(LID), in order to provide evidence of neural plasticity modulation of corticostriatal pathway in the pathogenesis of LID.
Methods:Hemi-parkinsomism rat models were made by 6-OHDA microinjection stereotaxically.The successful PD models were randomly applied into LID inducing group (n=22)and PD control group(n=22),twenty normal rats were used as the normal control group (n=20).The animals from the LID group and normal control group were treated with chronic intermittent L-dopa 30mg/kg+Benseridel0mg/kg injection for 21 days,while the animals from the PD control group received equal volume saline treatment. The abnormal involuntary movement(AIM) behavior was recorded by video and the abnormal involuntary movement scores were estimated using the rat AIM rating scale. The cylinder tests of the limb movement function and the rotation behavior were also examined. Two weeks after the conclusion of L-dopa treatment, the animals in the LID inducing group received L-dopa injection again to check the reappearance of AIM,those showed AIM were considered successful LID model animals. Twenty successful LID models were obtained from twenty-two rats. Ten animals from each group recived corticostriatal electrical stimulations after behavior assessment. At the end of stimulation (about 20 minutes), the animal was anesthetized deeply and perfused slowly with a brief saline prewash followed by 150ml of 4% buffered paraformaldehyde. The brain was collected and processed for immunohistochemical staining. Serial paraffin sections(5-10μm thick) of striatum near the coronal suture(±1 mm) were cut in the frontal planes on a microtome. Immunohistochemical staining was performed to determine the expression level of c-fos, ENK, extracellular regulated kinasel/2(ERK1/2) and phosphorylated-ERK1/2 (p-ERK1/2) in striatum. Five brain sections from each animal (with the same coordinate for different animals) were examined under microscope in high multificatin field,the positive expression cells were counted and the staining intensities were analysed using auto-image analysis system in ten randomly selected field in the putamen for each slice. The coexpression of c-fos and ENK was also analysed by obversing the two successive sections which were immunochemically stained for c-fos and ENK expression respectively.
Results
1. Establishment of LID model and its movement behavior characterics:44 successful PD models were obtained from 80 rats,the ratio is 55%. Treatment with levodopa in PD rats gradually induced abnormal involuntary movement (AIM),20 of 22 PD rats which received L-dopa injection developed AIM, and the ratio is 91%. The AIM score of the third day of L-dopa treatment was (31.13±0.32), and the scores of the 12th,15th, 18th,21th day were (44.02±0.85), (47.47±0.65), (55.08±0.20), (59.10±1.01) respectively.The cylinder tests showed the limb motor functions of animals was improved by levodopa treatment.The AIM never appeared and no significant changes of the limb motor functions were observed in both PD control group and the normal control group.
2. The expression of the c-fos, ENK, ERK1/2, p-ERK1/2 in striatum:Compared with the contralateral side, the expression of the c-fos, ENK, ERK1/2 and p-ERKl/2 in ipsilateral striatum in each group increased significantly (P<0.01) after the electrical stimulation. The striatal expression of c-fos in LID rats (0.67±0.03) was significantly higher than that of PD rats (0.45±0.04) and normal rats(0.38±0.02) (P<0.05).ENK expressional level in LID group(0.21±0.07) was not significantly different from that of the PD group(0.18±0.08) (P>0.05).The expression of ERK1/2 was not significantly different among the three groups (P>0.05),but the p-ERK1/2 expressional level in LID rats (0.17±0.05) was significantly higher than that of the PD group (0.08±0.03) and the normal group (0.07±0.02) (P＜0.01)
3.The co-expression of the c-fos and ENK:Co-expression of the c-fos and ENK in striatal neurons was observed in both LID group and PD group,however,the percentage of c-fos postive neurons co-expressing ENK in LID group(10.76%±2.34%) was higher than that of the PD group(7.43%±1.48%) (P＜0.05)
Conclusion
1.Chronic treatment with levodopa intermittently can induce AIM in hemi-parkinsomism rats. These rats showed behavioral and pharmaceutical characterization similar to levedopa induced peak-dose dyskinesia in PD patients and can be used as a rodent LID model.
2. Electric stimulation on motor cortex can activate the corticostriatal pathway, which induced the expression of c-fos in striatum. Enhanced activity of the corticostriatal pathway was involved in the pathogenesis of LID which was suggested by significant higher level of c-fos expression in LID rats in relative to no-dyskinesia PD rats. The corticostriatal eletrical stimulation induced c-fos expression was correlated with phosphorylation modification of ERK1/2 but not with the total ERK1/2 expression, indicating that corticostriatal pathway stimulation induced c-fos expression may mediated by ERK1/2 phosphorylation but not by increasing ERK expression.
3. The increased co-expression of the c-fos and ENK in striatal neurons of LID rats induced by the electric stimulation of coticostriata pathway suggested enhanced activity of the indirect-pathway may be involved in the development of LID.
引文
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27. Gravius A, Dekundy A, Nagel J,et al. Investigation on tolerance development to subchronic blockade of mGluR5 in models of learning, anxiety, and levodopa-induced dyskinesia in rats[J].J Neural Transm,2008;115(12):1609-1619
28. Kelleher RJ 3rd, Govindarajan A, Jung HY, et al. Translational control by MAPK signaling in long-term synaptic plasticity and memory. Cell,2004;116(3):467—479
29. Wang JQ, Tang Q, Parelkar, et al. Glutamate signaling to Ras-MAPK in striatal neurons:mechanisms for inducible gene expression and plasticity.Mol Neurobiol,2004;29(1):1-14
30. Sgambato V, Pages C,Rogard M,et al. Extracellular signal-regulated kinase (ERK) controls immediate early gene induction on corticostriatal stimulation.J Neurosci, 1998;18(21):8814-8825
31. Santini E, Valjent E, Usiello A,et al.Critical involvement of cAMP/DARPP-32 and extracellular signal-regulated protein kinase signaling in L-DOPA-induced dyskinesia.J Neurosci,2007;27(26):6995-7005
1. Bibbiani F,Oh JD,Kielaite A,et al. Combined blockade of AMPA and NMDA glutamate receptors reduces levodopa-induced motor complications in animal models of PD [J].Exp Neurol,2005; 196:422-429
2. Verhaqen ML,Del DP, Natte R,et al. Dextromethorphan improves levodopa-induced dyskinesias in Parkinson's disease [J].Neurology,1998;51:203-206
3. 巴茂文,刘振国.左旋多巴诱发异动症的病理生理机制研究进展[J].中华神经科杂志,2005；38：403-404
4. Ouattara B, Belkhir S, Morissette M,et al. Implication of NMDA Receptors in the Antidyskinetic Activity of Cabergoline, CI-1041, and Ro 61-8048 in MPTP Monkeys with Levodopa-induced Dyskinesias [J]. J Mol Neurosci,2008,14:[Epub ahead of print]
5. Silverdale MA,Nicholson SL,Crossman AR,et al. Topiramate reduces levodopa-induced dyskinesia in the MPTP-lesioned marmoset model of Parkinson's disease[J]. Mov Disord,2005;20:403-409
6. Hallett PJ, Dunah AW, Ravenscroft P, et al. Alterations of striatal NMDA receptor subunits associated with the development of dyskinesia in the MPTP-lesioned primate model of Parkinson's disease [J]. Neuropharmacology,2005;48:503-516
7. Dunah AW, Sirianni AC, Fienberg AA,et al. Dopamine D1-dependent trafficking of striatal N-methyl-D-aspartate glutamate receptors requires Fyn protein tyrosine kinase but not DARPP-32[J]. Mol Pharmacol,2004;65:121-129
8. Boehm J, Malinow R. AMPA receptor phosphorylation during synaptic plasticity [J]. Biochem Soc Trans,2005;33:1354-1356
9. Lee HK, Takamiya K, Han JS, et al. Phosphorylation of the AMPA receptor GluRl subunit is required for synaptic plasticity and retention of spatial memory [J]. Cell, 2003;112:631-643
10. Picconi B, Pisani A, Centonze A,et al. Striatal metabotropic glutamate receptor functions following experimental Parkinsonism and chronic levodopa treatment [J]. Brain,2002;125:2635-2645
11. Gravius A, Dekundy A, Nagel J,et al. Investigation on tolerance development to subchronic blockade of mGluR5 in models of learning, anxiety, and levodopa-induced dyskinesia in rats[J].J Neural Transm,2008;115:1609-1619
12. Picconi B, Centonze D, Hakansson K, et al. Loss of bidirectional striatal synaptic plasticity in L-DOPA-induced dyskinesia[J].Nat Neurosci,2003;6:501-506
13. CAO XB, SUN SG, WANG L, et al. Study on corticostriatal synapse ultrastructure and function in rats with levodopa induced dyskinesias [J]. Chin J Neurol,2004;37:126-130
14. St-Hilaire M, Landry E, Levesque D,et al. Denervation and repeated L-DOPA induce complex regulatory changes in neurochemical phenotypes of striatal neurons: implication of a dopamine Dl-dependent mechanism [J]. Neurobiol Dis 2005;20:450-460
15. Aubert I, Guigoni C, Hakansson K, et al. Increased Dl dopamine receptor signaling in levodopa-induced dyskinesia [J]. Ann Neurol,2005;57:17-26
16.巴茂文,刘振国,孔敏,等.帕金森病运动并发症与谷氨酸受体亚型GluR1Ser845磷酸化关系的实验研究[J].中华神经科杂志,2006；39：822-826
17. Morissette M, Dridi M, Calon F, et al. Prevention of dyskinesia by an NMD A receptor antagonist in MPTP monkeys:effect on adenosine A2A receptors [J].Synapse,2006;60:239-250
18. Gubellini P, Picconi B, Bari M,et al. Experimental parkinsonism alters endocannabinoid degradation:implications for striatal glutamatergic transmission [J]. J Neurosci,2002;22:6900-6907
19. Ferrer B, Gorriti MA, Palomino A, et al. Cannabinoid CB1 receptor antagonism markedly increases dopamine receptor-mediated stereotypies [J]. Eur J Pharmacol, 2007; 559:180-183
20. Ferrer B, Asbrock N, Kathuria S, et al. Effects of levodopa on endocannabinoid levels in rat basal ganglia:implications for the treatment of levodopa-induced dyskinesias [J]. Eur J Neurosci.2003;18:1607-1614
21. Guo Y,Wang HL,Xiang XH,et al. The role of glutamate and its receptors in mesocorticolimbic dopaminergic regions in opioid addiction [J].Neurosci Biobehav Rev,2009;33:864-873
22. Henry B, Crossman AR, Brotchie JM. Effect of repeated L-DOPA, bromocriptine, or lisuride administration on preproenkephalin-A and preproenkephalin-B mRNA levels in the striatum of the 6-hydroxydopamine-lesioned rat [J]. Exp Neurol, 1999;155:204-220
23. Niu YX, Sun SG, Wei GR, et al. Relationship between Changes of Specific Neuropeptide Gene in Striatum and Pathogenesis of Levodopa-induced Dyskinesia[J].Acta Med Univ Sci Technol Huazhong,2008;37:35-38
2. Brotchie JM, Lee J, Venderova K. L-dopa-induced dyskinesia. [J] Neural Transm, 2005; (19):583-585
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7. Calabresi P, Giacomini P, Centonze D, et al. Levodopa-induced Dyskinesia:a pathological form of striatal synaptic plasticity? Ann Neurol,2000; 47 (4 suppl 1): 60-68
8. 巴茂文,刘振国,孔敏等.纹状体神经元GluR1Ser831磷酸化对帕金森异动症发病机制的影响.中华老年医学杂志,2007；26：205-208
9. St-Hilaire M., Landry E., Levesque D. and Rouillard C. Denervation and repeated L-DOPA induce complex regulatory changes in neurochemical phenotypes of striatal neurons:implication of a dopamine D1-dependent mechanism. Neurobiol Dis,2005;20(2):450-460
10. North American symptomatic Carotid Endarterectomy Trial Collaborato-rs. Beneficial effects of carotid endarterectomy in symp tomatic patients with high grade carotid stenosis. N Engl J Med,1991;325(7):445-451
11. Picconi B, Centonze D, Hakansson K, et al.Loss of bidirectional striatal synaptic plasticity in L-DOPA-induced dyskinesia. Nat Neurosci,2003; 6(5):501-506
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16. Daniel M. Togasaki, Peter Protell, Louis C.S, et al. Dyskinesias in normal squirrel monkeys induced by nomifensine and levodopa. Neuropharmacology,2005;48(3):398-405
17. M. Lundblad, B. Picconi, H. Lindgren. et al.A model of L-DOPA-induced dyskinesia in 6-hydroxydopamine lesioned mice:relation to motor and cellular parameters of nigrostriatal function. Neurobiol Dis,2002; 16(1):110-123
18. Winkler, C., Kirik, D., Bjorklund, A., et al. L-DOPA induced dyskinesia in the intrastriatal 6-hydroxydopamine model of Parkinson's disease:relation to motor and cellular parameters of nigrostriatal function.Neurobiol Dis,2002; 10(2):165-186
19.徐岩,孙圣刚,曹学兵.左旋多巴诱发异动症大鼠模型的制作及其行为学评估. 中华物理医学与康复杂志,2005；27：649-652
20. Bibbiani F,Oh JD,Kielaite A,et al. Combined blockade of AMPA and NMDA glutamate receptors reduces levodopa-induced motor complications in animal models of PD [J].ExpNeurol,2005; 196(2):422-429
21. Verhaqen ML,Del DP, Natte R,et al. Dextromethorphan improves levodopa-induced dyskinesias in Parkinson's disease [J].Neurology,1998; 51(1):203-206
22.徐岩,孙圣刚,曹学兵慢性左旋多巴治疗对帕金森病大鼠行为及基底节Fos表达的影响.[J]中国神经科学杂志,2003；19(6)：389-394
23.巴茂文,刘振国.左旋多巴诱发异动症的病理生理机制研究进展[J].中华神经科杂志,2005；38：403-404
24. Silverdale MA,Nicholson SL,Crossman AR,et al. Topiramate reduces levodopa-induced dyskinesia in the MPTP-lesioned marmoset model of Parkinson's disease [J]. Mov Disord,2005; 20(4):403-409
25. Boehm J, Malinow R. AMPA receptor phosphorylation during synaptic plasticity [J]. Biochem Soc Trans,2005;33(6):1354-1356
26. Lee HK, Takamiya K, Han JS, et al. Phosphorylation of the AMPA receptor GluRl subunit is required for synaptic plasticity and retention of spatial memory [J]. Cell, 2003; 112(5):631-643
27. Gravius A, Dekundy A, Nagel J,et al. Investigation on tolerance development to subchronic blockade of mGluR5 in models of learning, anxiety, and levodopa-induced dyskinesia in rats[J].J Neural Transm,2008;115(12):1609-1619
28. Kelleher RJ 3rd, Govindarajan A, Jung HY, et al. Translational control by MAPK signaling in long-term synaptic plasticity and memory. Cell,2004;116(3):467—479
29. Wang JQ, Tang Q, Parelkar, et al. Glutamate signaling to Ras-MAPK in striatal neurons:mechanisms for inducible gene expression and plasticity.Mol Neurobiol,2004;29(1):1-14
30. Sgambato V, Pages C,Rogard M,et al. Extracellular signal-regulated kinase (ERK) controls immediate early gene induction on corticostriatal stimulation.J Neurosci, 1998;18(21):8814-8825
31. Santini E, Valjent E, Usiello A,et al.Critical involvement of cAMP/DARPP-32 and extracellular signal-regulated protein kinase signaling in L-DOPA-induced dyskinesia.J Neurosci,2007;27(26):6995-7005
1. Bibbiani F,Oh JD,Kielaite A,et al. Combined blockade of AMPA and NMDA glutamate receptors reduces levodopa-induced motor complications in animal models of PD [J].Exp Neurol,2005; 196:422-429
2. Verhaqen ML,Del DP, Natte R,et al. Dextromethorphan improves levodopa-induced dyskinesias in Parkinson's disease [J].Neurology,1998;51:203-206
3. 巴茂文,刘振国.左旋多巴诱发异动症的病理生理机制研究进展[J].中华神经科杂志,2005；38：403-404
4. Ouattara B, Belkhir S, Morissette M,et al. Implication of NMDA Receptors in the Antidyskinetic Activity of Cabergoline, CI-1041, and Ro 61-8048 in MPTP Monkeys with Levodopa-induced Dyskinesias [J]. J Mol Neurosci,2008,14:[Epub ahead of print]
5. Silverdale MA,Nicholson SL,Crossman AR,et al. Topiramate reduces levodopa-induced dyskinesia in the MPTP-lesioned marmoset model of Parkinson's disease[J]. Mov Disord,2005;20:403-409
6. Hallett PJ, Dunah AW, Ravenscroft P, et al. Alterations of striatal NMDA receptor subunits associated with the development of dyskinesia in the MPTP-lesioned primate model of Parkinson's disease [J]. Neuropharmacology,2005;48:503-516
7. Dunah AW, Sirianni AC, Fienberg AA,et al. Dopamine D1-dependent trafficking of striatal N-methyl-D-aspartate glutamate receptors requires Fyn protein tyrosine kinase but not DARPP-32[J]. Mol Pharmacol,2004;65:121-129
8. Boehm J, Malinow R. AMPA receptor phosphorylation during synaptic plasticity [J]. Biochem Soc Trans,2005;33:1354-1356
9. Lee HK, Takamiya K, Han JS, et al. Phosphorylation of the AMPA receptor GluRl subunit is required for synaptic plasticity and retention of spatial memory [J]. Cell, 2003;112:631-643
10. Picconi B, Pisani A, Centonze A,et al. Striatal metabotropic glutamate receptor functions following experimental Parkinsonism and chronic levodopa treatment [J]. Brain,2002;125:2635-2645
11. Gravius A, Dekundy A, Nagel J,et al. Investigation on tolerance development to subchronic blockade of mGluR5 in models of learning, anxiety, and levodopa-induced dyskinesia in rats[J].J Neural Transm,2008;115:1609-1619
12. Picconi B, Centonze D, Hakansson K, et al. Loss of bidirectional striatal synaptic plasticity in L-DOPA-induced dyskinesia[J].Nat Neurosci,2003;6:501-506
13. CAO XB, SUN SG, WANG L, et al. Study on corticostriatal synapse ultrastructure and function in rats with levodopa induced dyskinesias [J]. Chin J Neurol,2004;37:126-130
14. St-Hilaire M, Landry E, Levesque D,et al. Denervation and repeated L-DOPA induce complex regulatory changes in neurochemical phenotypes of striatal neurons: implication of a dopamine Dl-dependent mechanism [J]. Neurobiol Dis 2005;20:450-460
15. Aubert I, Guigoni C, Hakansson K, et al. Increased Dl dopamine receptor signaling in levodopa-induced dyskinesia [J]. Ann Neurol,2005;57:17-26
16.巴茂文,刘振国,孔敏,等.帕金森病运动并发症与谷氨酸受体亚型GluR1Ser845磷酸化关系的实验研究[J].中华神经科杂志,2006；39：822-826
17. Morissette M, Dridi M, Calon F, et al. Prevention of dyskinesia by an NMD A receptor antagonist in MPTP monkeys:effect on adenosine A2A receptors [J].Synapse,2006;60:239-250
18. Gubellini P, Picconi B, Bari M,et al. Experimental parkinsonism alters endocannabinoid degradation:implications for striatal glutamatergic transmission [J]. J Neurosci,2002;22:6900-6907
19. Ferrer B, Gorriti MA, Palomino A, et al. Cannabinoid CB1 receptor antagonism markedly increases dopamine receptor-mediated stereotypies [J]. Eur J Pharmacol, 2007; 559:180-183
20. Ferrer B, Asbrock N, Kathuria S, et al. Effects of levodopa on endocannabinoid levels in rat basal ganglia:implications for the treatment of levodopa-induced dyskinesias [J]. Eur J Neurosci.2003;18:1607-1614
21. Guo Y,Wang HL,Xiang XH,et al. The role of glutamate and its receptors in mesocorticolimbic dopaminergic regions in opioid addiction [J].Neurosci Biobehav Rev,2009;33:864-873
22. Henry B, Crossman AR, Brotchie JM. Effect of repeated L-DOPA, bromocriptine, or lisuride administration on preproenkephalin-A and preproenkephalin-B mRNA levels in the striatum of the 6-hydroxydopamine-lesioned rat [J]. Exp Neurol, 1999;155:204-220
23. Niu YX, Sun SG, Wei GR, et al. Relationship between Changes of Specific Neuropeptide Gene in Striatum and Pathogenesis of Levodopa-induced Dyskinesia[J].Acta Med Univ Sci Technol Huazhong,2008;37:35-38