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.
Key Words
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Article info
Publication history
Published online: June 12, 2009
Accepted:
April 17,
2009
Received in revised form:
April 7,
2009
Received:
February 12,
2009
Identification
Copyright
© 2009 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
