Pharmacological analysis demonstrates dramatic alteration of D1 dopamine receptor neuronal distribution in the rat analog of L-DOPA-induced dyskinesia.
Journal of Neuroscience. 2009-04-15; 29(15): 4829-4835
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1. J Neurosci. 2009 Apr 15;29(15):4829-35. doi: 10.1523/JNEUROSCI.5884-08.2009.
Pharmacological analysis demonstrates dramatic alteration of D1 dopamine receptor
neuronal distribution in the rat analog of L-DOPA-induced dyskinesia.
Berthet A(1), Porras G, Doudnikoff E, Stark H, Cador M, Bezard E, Bloch B.
(1)Université Victor Segalen-Bordeaux 2, Centre National de Recherche
Scientifique, Bordeaux Institute of Neuroscience, UMR 5227, 33076 Bordeaux Cedex,
We have associated behavioral, pharmacological, and quantitative
immunohistochemical study in a rat analog of l-DOPA-induced dyskinesia to
understand whether alterations in dopamine receptor fate in striatal neurons may
be involved in mechanisms leading to movement abnormalities. Detailed analysis at
the ultrastructural level demonstrates specific alterations of dopamine D(1)
receptor (D(1)R) subcellular localization in striatal medium spiny neurons in
l-DOPA-treated 6-hydroxydopamine-lesioned rats with abnormal involuntary
movements (AIMs). This includes exaggerated D(1)R expression at the plasma
membrane. However, D(1)R retains ability of internalization, as a challenge with
the potent D(1)R agonist SKF-82958 induces a strong decrease of labeling at
membrane in animals with AIMs. Since a functional cross talk between D(1)R and
D(3)R has been suggested, we hypothesized that their coactivation by dopamine
derived from l-DOPA might anchor D(1)R at the membrane. Accordingly, cotreatment
with l-DOPA and the D(3)R antagonist ST 198 restores normal level of
membrane-bound D(1)R. Together, these results demonstrate that AIMs are related
to abnormal D(1)R localization at the membrane and intraneuronal trafficking
dysregulation, and suggest that strategies aiming at disrupting the D(1)R-D(3)R
cross talk might reduce l-DOPA-induced dyskinesia by reducing D(1)R availability
at the membrane.
PMID: 19369551 [Indexed for MEDLINE]