ERK phosphorylation and FosB expression are associated with L-DOPA-induced dyskinesia in hemiparkinsonian mice. Export

@article{citeulike:1028993, abstract = {BACKGROUND: The dopamine precursor 3,4-dihydroxyphenyl-L-alanine (L-DOPA) is currently the most efficacious noninvasive therapy for Parkinson's disease. A major complication of this therapy, however, is the appearance of the abnormal involuntary movements known as dyskinesias. We have developed a model of L-DOPA-induced dyskinesias in mice that reproduces the main clinical features of dyskinesia in humans. METHODS: Dyskinetic symptoms were triggered by repetitive administration of a constant dose of L-DOPA (25 mg/kg, twice a day, for 25 days) in unilaterally 6-hydroxydopamine (6-OHDA) lesioned mice. Mice were examined for behavior, expression of FosB, neuropeptides, and externally regulated kinase (ERK) phosphorylation. RESULTS: Dyskinetic symptoms appear toward the end of the first week of treatment and are associated with L-DOPA-induced changes in DeltaFosB and prodynorphin expression. L-DOPA also induces activation of ERK1/2 in the dopamine-depleted striatum. Interestingly, elevated FosB/DeltaFosB expression occurs exclusively within completely lesioned regions of the striatum, displaying an inverse correlation with remaining dopaminergic terminals. Following acute L-DOPA treatment, FosB expression occurs in direct striatal output neurons, whereas chronic L-DOPA also induces FosB expression in nitric oxide synthase-positive striatal interneurons. CONCLUSIONS: This model provides a system in which genetic manipulation of individual genes can be used to elucidate the molecular mechanisms responsible for the development and expression of dyskinesia.}, address = {Instituto Cajal, Consejo Superior de Investigaciones Cient\'{\i}ficas, Madrid, Spain.}, author = {Pav\'{o}n, N. and Mart\'{\i}n, A. B. and Mendialdua, A. and Moratalla, R.}, citeulike-article-id = {1028993}, citeulike-linkout-0 = {http://dx.doi.org/10.1016/j.biopsych.2005.05.044}, citeulike-linkout-1 = {http://linkinghub.elsevier.com/retrieve/pii/S0006322305007079}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/16139809}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=16139809}, day = {1}, doi = {10.1016/j.biopsych.2005.05.044}, issn = {0006-3223}, journal = {Biol Psychiatry}, keywords = {dyskinesia, erk, fosb, hemiparkinsonian, l-dopa}, month = {January}, number = {1}, pages = {64--74}, posted-at = {2009-06-12 14:59:20}, priority = {2}, title = {ERK phosphorylation and FosB expression are associated with L-DOPA-induced dyskinesia in hemiparkinsonian mice.}, url = {http://dx.doi.org/10.1016/j.biopsych.2005.05.044}, volume = {59}, year = {2006} }

TY - JOUR ID - citeulike:1028993 L3 - citeulike-article-id:1028993 N2 - BACKGROUND: The dopamine precursor 3,4-dihydroxyphenyl-L-alanine (L-DOPA) is currently the most efficacious noninvasive therapy for Parkinson's disease. A major complication of this therapy, however, is the appearance of the abnormal involuntary movements known as dyskinesias. We have developed a model of L-DOPA-induced dyskinesias in mice that reproduces the main clinical features of dyskinesia in humans. METHODS: Dyskinetic symptoms were triggered by repetitive administration of a constant dose of L-DOPA (25 mg/kg, twice a day, for 25 days) in unilaterally 6-hydroxydopamine (6-OHDA) lesioned mice. Mice were examined for behavior, expression of FosB, neuropeptides, and externally regulated kinase (ERK) phosphorylation. RESULTS: Dyskinetic symptoms appear toward the end of the first week of treatment and are associated with L-DOPA-induced changes in DeltaFosB and prodynorphin expression. L-DOPA also induces activation of ERK1/2 in the dopamine-depleted striatum. Interestingly, elevated FosB/DeltaFosB expression occurs exclusively within completely lesioned regions of the striatum, displaying an inverse correlation with remaining dopaminergic terminals. Following acute L-DOPA treatment, FosB expression occurs in direct striatal output neurons, whereas chronic L-DOPA also induces FosB expression in nitric oxide synthase-positive striatal interneurons. CONCLUSIONS: This model provides a system in which genetic manipulation of individual genes can be used to elucidate the molecular mechanisms responsible for the development and expression of dyskinesia. IS - 1 JF - Biol Psychiatry SN - 0006-3223 AD - Instituto Cajal, Consejo Superior de Investigaciones Científicas, Madrid, Spain. EP - 74 TI - ERK phosphorylation and FosB expression are associated with L-DOPA-induced dyskinesia in hemiparkinsonian mice. VL - 59 SP - 64 KW - dyskinesia KW - erk KW - fosb KW - hemiparkinsonian KW - l-dopa AU - Pavón, N AU - Martín, AB AU - Mendialdua, A AU - Moratalla, R PY - 2006/01/01/ UR - http://dx.doi.org/10.1016/j.biopsych.2005.05.044 ER -