Naslov
Genetic inactivation of dopamine D1 but not D2 receptors inhibits L-DOPA-induced dyskinesia and chromatin modification

Autori
Moratalla, Rosario ; Darmopil, Sanja ; Ruiz de Diego, Irene ; Ares, Sara ; Granado, Noelia ; Liu, Tao

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Skup
Neuroscience 2009, the 39 th Annual Meeting of the Society for Neuroscience

Mjesto i datum
Chicago (IL), Sjedinjene Američke Države, 17.10.2009. - 21.10.2009

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
dopaminergic denervation; dynorphin; ERK1/2; FosB;
(Dopaminergic denervation; dynorphin; ERK1/2; FosB;)

Sažetak
Pharmacological studies have implicated dopamine D1-like receptors in the development of L-DOPA-induced dyskinesias and associated molecular changes in hemiparkinsonian mice. However, pharmacological agents for D1 or D2 receptors also recognize other receptor family members. Genetic inactivation of either the dopamine D1 or D2 receptor was used to define the involvement of these receptor subtypes. Dyskinesias were assessed during a three-week period after daily treatment with 25mg/kg L-DOPA. Changes in expression of signaling molecules and other proteins in the lesioned striatum were examined immunohistochemically, 2 h after the last L-DOPA injection. Chronic L-DOPA treatment gradually induced rotational behavior and dyskinesia in wild type hemiparkinsonian mice. Dyskinetic symptoms were associated with increased FosB and dynorphin expression, phosphorylation of ERK 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 completely abolished L-DOPA-induced dyskinesias and the associated molecular changes. Inactivation of the D2 receptor had no significant effect on the behavioral or molecular response to chronic L-DOPA. Our results demonstrate that the dopamine D1 receptor is critical for the development of LDOPA-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, a read out for chromatin modification, is blocked by D1 receptor inactivation, suggesting that inhibitors of H3 acetylation and/or phosphorylation may be useful in preventing or reversing dyskinesia and the chromatin modification involved.

Izvorni jezik
Engleski

Znanstvena područja
Biologija, Temeljne medicinske znanosti

POVEZANOST RADA