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-OHD...

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Main Authors: Claudia Rangel-Barajas, Isaac Silva, Luz María Lopéz-Santiago, Jorge Aceves, David Erlij, Benjamín Florán
Format: Article
Language:English
Published: Elsevier 2011-01-01
Series:Neurobiology of Disease
Subjects:
Online Access:http://www.sciencedirect.com/science/article/pii/S0969996110002779
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author Claudia Rangel-Barajas
Isaac Silva
Luz María Lopéz-Santiago
Jorge Aceves
David Erlij
Benjamín Florán
author_facet Claudia Rangel-Barajas
Isaac Silva
Luz María Lopéz-Santiago
Jorge Aceves
David Erlij
Benjamín Florán
author_sort Claudia Rangel-Barajas
collection DOAJ
description 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.
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spelling doaj.art-60d1919d96e64c34b5d69f980c43ec012022-12-21T21:57:40ZengElsevierNeurobiology of Disease1095-953X2011-01-014115161l-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 reticulataClaudia Rangel-Barajas0Isaac Silva1Luz María Lopéz-Santiago2Jorge Aceves3David Erlij4Benjamín Florán5Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, D.F. MéxicoFacultad de Ciencias Naturales, Universidad Autonóma de Queretaro Qro. MéxicoDepartamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, D.F. MéxicoDepartamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, D.F. MéxicoDepartment of Physiology, SUNY Downstate Medical Center, Brooklyn, NY 11203, USADepartamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, D.F. México; Corresponding author. Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Apartado Postal 14-740, 07000, México D.F., México. Fax: +52 55 57473754.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.http://www.sciencedirect.com/science/article/pii/S0969996110002779l-DOPABasal gangliaGABA releasecAMPHemiparkinsonismSubstantia nigra
spellingShingle Claudia Rangel-Barajas
Isaac Silva
Luz María Lopéz-Santiago
Jorge Aceves
David Erlij
Benjamín Florán
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
Neurobiology of Disease
l-DOPA
Basal ganglia
GABA release
cAMP
Hemiparkinsonism
Substantia nigra
title 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
topic l-DOPA
Basal ganglia
GABA release
cAMP
Hemiparkinsonism
Substantia nigra
url http://www.sciencedirect.com/science/article/pii/S0969996110002779
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