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

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, Gαolf 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 Gαolf 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 Gαolf 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.

Research Highlights►Denervation increases activity and expression of adenylyl cyclase V/VI. ►l-DOPA treatment induces mild or severe dyskinesia in hemiparkinsonian rats. ►l-DOPA restores the increased activity and expression of AC in mild dyskinetic rats. ►l-DOPA treatment normalize the expression of Golf protein in hemiparkinsonian rats.