Elsevier

Biological Psychiatry

Volume 66, Issue 6, 15 September 2009, Pages 603-613
Biological Psychiatry

Archival Report
Genetic Inactivation of Dopamine D1 but Not D2 Receptors Inhibits L-DOPA–Induced Dyskinesia and Histone Activation

https://doi.org/10.1016/j.biopsych.2009.04.025Get rights and content

Background

Pharmacologic studies have implicated dopamine D1-like receptors in the development of dopamine precursor molecule 3,4-dihydroxyphenyl-L-alanine (L-DOPA)-induced dyskinesias and associated molecular changes in hemiparkinsonian mice. However, pharmacologic agents for D1 or D2 receptors also recognize other receptor family members. Genetic inactivation of the dopamine D1 or D2 receptor was used to define the involvement of these receptor subtypes.

Methods

During a 3-week period of daily L-DOPA treatment (25 mg/kg), mice were examined for development of contralateral turning behavior and dyskinesias. L-DOPA-induced changes in expression of signaling molecules and other proteins in the lesioned striatum were examined immunohistochemically.

Results

Chronic L-DOPA treatment gradually induced rotational behavior and dyskinesia in wildtype hemiparkinsonian mice. Dyskinetic symptoms were associated with increased FosB and dynorphin expression, phosphorylation of extracellular signal-regulated kinase, and phosphoacetylation of histone 3 (H3) in the lesioned striatum. These molecular changes were restricted to striatal areas with complete dopaminergic denervation and occurred only in dynorphin-containing neurons of the direct pathway. D1 receptor inactivation abolished L-DOPA-induced dyskinesias and associated molecular changes. Inactivation of the D2 receptor had no significant effect on the behavioral or molecular response to chronic L-DOPA.

Conclusions

Our results demonstrate that the dopamine D1 receptor is critical for the development of L-DOPA-induced dyskinesias in mice and in the underlying molecular changes in the denervated striatum and that the D2 receptor has little or no involvement. In addition, we demonstrate that H3 phosphoacetylation is blocked by D1 receptor inactivation, suggesting that inhibitors of H3 acetylation and/or phosphorylation may be useful in preventing or reversing dyskinesia.

Section snippets

Animals

This study was carried out in mice lacking D1R (15, 16, 19, 20) or D2R (21, 22, 23) generated by homologous recombination as described previously. Wildtype (WT) and homozygote D1−/− and D2−/− (knockout [KO]) mice used in this study were derived from mating heterozygous mice. Genotype was determined by polymerase chain reaction analysis. The maintenance of animals followed guidelines from European Union Council Directive (86/609/European Economic Community) and experimental protocols were

Dopamine D1, but Not D2, Receptors Are Required for Rotational Sensitization Induced by L-DOPA in Hemiparkinsonian Mice

To establish the role of the D1 and D2 dopamine receptor subtypes in the development of behavioral sensitization and dyskinesias, we used genetically engineered mice lacking either the dopamine D1 or D2 receptor. Contralateral rotations were evaluated as a measure of behavioral sensitization to L-DOPA (25 mg/kg/day) for 3 weeks (3). Twice a week, we measured the total number of contralateral turns for 120 min. We also counted the contralateral turns during the first 20 min after L-DOPA

Discussion

The findings we describe here strongly support a compulsory role for the D1R subtype in the development of dyskinesia and rotational response following L-DOPA administration as well as in the molecular changes associated with these behaviors. In contrast, the D2R appears to have little effect on any of these. We demonstrate that these L-DOPA-induced molecular changes, including the phosphoacetylation of H3, occur in the direct pathway neurons within the fully denervated region of the striatum.

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