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

• Published in: Biological psychiatry (1969) 2009-09, Vol.66 (6), p.603-613
• Main Authors: Darmopil, Sanja, Martín, Ana B, De Diego, Irene Ruiz, Ares, Sara, Moratalla, Rosario
• Format: Article
• Language: English
• Subjects: Acetylation - drug effects; Adult and adolescent clinical studies; Analysis of Variance; Animals; Antiparkinson Agents - adverse effects; Behavior, Animal - drug effects; Biological and medical sciences; Corpus Striatum - pathology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Models, Animal; Dopaminergic denervation; dynorphin; Dynorphins - metabolism; Dyskinesia, Drug-Induced - etiology; Dyskinesia, Drug-Induced - genetics; Dyskinesia, Drug-Induced - metabolism; ERK1/2; Extracellular Signal-Regulated MAP Kinases - metabolism; FosB; Functional Laterality; Gene Expression Regulation - drug effects; Gene Expression Regulation - genetics; Histones - metabolism; Levodopa - adverse effects; Medical sciences; Mice; Mice, Knockout; Motor Activity - drug effects; Motor Activity - genetics; Nervous system (semeiology, syndromes); Nervous system as a whole; Neurology; Neurons - drug effects; Neurons - pathology; Organic mental disorders. Neuropsychology; Oxidopamine; Parkinson's disease; Parkinsonian Disorders - chemically induced; Parkinsonian Disorders - drug therapy; phosphoacetylated histone 3; Phosphorylation - drug effects; Proto-Oncogene Proteins c-fos - metabolism; Psychiatry; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Receptors, Dopamine D1 - deficiency; Receptors, Dopamine D2 - deficiency; Statistics as Topic; Tyrosine 3-Monooxygenase - metabolism
• ISSN: 0006-3223; 1873-2402
• DOI: 10.1016/j.biopsych.2009.04.025

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.