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ERK phosphorylation and FosB expression are associated with L-DOPA-induced dyskinesia in hemiparkinsonian mice.
Biol Psychiatry. 2006 Jan 01; 59(1):64-74.BP

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.

Authors+Show Affiliations

Instituto Cajal, Consejo Superior de Investigaciones Científicas, Madrid, Spain.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16139809

Citation

Pavón, Nancy, et al. "ERK Phosphorylation and FosB Expression Are Associated With L-DOPA-induced Dyskinesia in Hemiparkinsonian Mice." Biological Psychiatry, vol. 59, no. 1, 2006, pp. 64-74.
Pavón N, Martín AB, Mendialdua A, et al. ERK phosphorylation and FosB expression are associated with L-DOPA-induced dyskinesia in hemiparkinsonian mice. Biol Psychiatry. 2006;59(1):64-74.
Pavón, N., Martín, A. B., Mendialdua, A., & Moratalla, R. (2006). ERK phosphorylation and FosB expression are associated with L-DOPA-induced dyskinesia in hemiparkinsonian mice. Biological Psychiatry, 59(1), 64-74.
Pavón N, et al. ERK Phosphorylation and FosB Expression Are Associated With L-DOPA-induced Dyskinesia in Hemiparkinsonian Mice. Biol Psychiatry. 2006 Jan 1;59(1):64-74. PubMed PMID: 16139809.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - ERK phosphorylation and FosB expression are associated with L-DOPA-induced dyskinesia in hemiparkinsonian mice. AU - Pavón,Nancy, AU - Martín,Ana B, AU - Mendialdua,Ainhoa, AU - Moratalla,Rosario, Y1 - 2005/09/01/ PY - 2004/01/27/received PY - 2005/04/27/revised PY - 2005/05/31/accepted PY - 2005/9/6/pubmed PY - 2006/2/24/medline PY - 2005/9/6/entrez SP - 64 EP - 74 JF - Biological psychiatry JO - Biol Psychiatry VL - 59 IS - 1 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. SN - 0006-3223 UR - https://www.unboundmedicine.com/medline/citation/16139809/ERK_phosphorylation_and_FosB_expression_are_associated_with_L_DOPA_induced_dyskinesia_in_hemiparkinsonian_mice_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-3223(05)00707-9 DB - PRIME DP - Unbound Medicine ER -