Archival ReportGenetic Inactivation of Dopamine D1 but Not D2 Receptors Inhibits L-DOPA–Induced Dyskinesia and Histone Activation
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.
References (56)
- et al.
ERK phosphorylation and FosB expression are associated with L-DOPA-induced dyskinesia in hemiparkinsonian mice
Biol Psychiatry
(2006) - et al.
Denervation and repeated L-DOPA induce complex regulatory changes in neurochemical phenotypes of striatal neurons: Implication of a dopamine D1-dependent mechanism
Neurobiol Dis
(2005) - et al.
Spatiotemporal pattern of striatal ERK1/2 phosphorylation in a rat model of L-DOPA-induced dyskinesia and the role of dopamine D1 receptors
Biol Psychiatry
(2007) - et al.
Behavioral sensitization to different dopamine agonists in a parkinsonian rodent model of drug-induced dyskinesias
Behav Brain Res
(2004) - et al.
Chronic 3,4-dihydroxyphenylalanine treatment induces dyskinesia in aphakia mice, a novel genetic model of Parkinson's disease
Neurobiol Dis
(2007) - et al.
Validation of the L-DOPA-induced dyskinesia in the 6-OHDA model and evaluation of the effects of selective dopamine receptor agonists and antagonists
Brain Res Bull
(2005) - et al.
Dopamine D1 and D2 receptor contributions to L-DOPA-induced dyskinesia in the dopamine-depleted rat
Pharmacol Biochem Behav
(2005) - et al.
A review of the receptor-binding and pharmacokinetic properties of dopamine agonists
Clin Ther
(2006) - et al.
High agonist-independent activity is a distinguishing feature of the dopamine D1B receptor subtype
J Biol Chem
(1994) - et al.
Dopamine D1 receptor mutant mice are deficient in striatal expression of dynorphin and in dopamine-mediated behavioral responses
Cell
(1994)