Genetic inactivation of dopamine D1 but not D2 receptors inhibits L-DOPA-induced dyskinesia and histone activation.

摘要

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.