l-DOPA-induced dyskinesia in hemiparkinsonian rats is associated with up-regulation of adenylyl cyclase type V/VI and increased GABA release in the substantia nigra reticulata

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• 作者：Claudia Rangel-Barajas ; Isaac Silva ; Luz Marí ; a Lopé ; z-Santiago ; Jorge Aceves ; David Erlij ; Benjamí ; n Florá ; n
• 关键词：l-DOPA ; Basal ganglia ; GABA release ; cAMP ; Hemiparkinsonism ; Substantia nigra
• 刊名：Neurobiology of Disease
• 出版年：2011
• 出版时间：January 2011
• 年：2011
• 卷：41
• 期：1
• 页码：51-61
• 全文大小：1540 K

文摘

l-DOPA treatment induces abnormal involuntary movements (AIMs) in Parkinson's patients and experimental animals. We examined the relationship between the development of AIMs (dyskinesia) and changes in [³H]-GABA release and cAMP signaling in striatonigral terminals of rats with unilateral 6-OHDA lesions. Analysis of AIMs scores in hemiparkinsonian rats treated with l-DOPA for 20 days was fitted by the sum of two Gaussian distributions showing the presence of two populations: one with mild and the other with severe dyskinesia. cAMP signaling was evaluated in the two populations by determining changes in cAMP formation, Gα_olf and adenylyl cyclase type V/VI levels. In animals that were not treated with l-DOPA, all the parameters were significantly increased in the denervated side. In the animals that had mild dyskinesia, l-DOPA treatment normalized these parameters. In contrast, in the animals in which l-DOPA treatment induced severe dyskinesia all the parameters, except for Gα_olf levels, were significantly higher in the denervated side. Similarly, D1-stimulated [³H]-GABA release was not elevated in l-DOPA-treated animals with mild dyskinesia but was increased in animals with severe dyskinesia. Changes in Gα_olf and adenylyl cyclase type V/VI levels in the striatum paralleled the response in the SNr. The linkage between the changes in [³H]-GABA release and cAMP activity was further evaluated with the selective adenylyl cyclase V/VI antagonist NKY80. This inhibitor blocked the increases of both [³H]-GABA release and cAMP production. These results indicate that increased expression of adenylyl cyclase V/VI is a major determinant of increased GABAergic transmission in the substantia nigra pars reticulata of animals in which l-DOPA induces severe dyskinesia.