AUTHOR=Maheux Jérôme , St-Hilaire Michel , Voyer David , Tirotta Emanuele , Borrelli Emiliana , Rouillard Claude , Rompré Pierre-Paul , Lévesque Daniel 

TITLE=Dopamine D2 Antagonist-Induced Striatal Nur77 Expression Requires Activation of mGlu5 Receptors by Cortical Afferents

JOURNAL=Frontiers in Pharmacology

VOLUME=3

YEAR=2012

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2012.00153

DOI=10.3389/fphar.2012.00153

ISSN=1663-9812

ABSTRACT=<p>Dopamine D<sub>2</sub> receptor antagonists modulate gene transcription in the striatum. However, the molecular mechanism underlying this effect remains elusive. Here we used the expression of <italic>Nur77</italic>, a transcription factor of the orphan nuclear receptor family, as readout to explore the role of dopamine, glutamate, and adenosine receptors in the effect of a dopamine D<sub>2</sub> antagonist in the striatum. First, we investigated D<sub>2</sub> antagonist-induced <italic>Nur77</italic> mRNA in D<sub>2L</sub> receptor knockout mice. Surprisingly, deletion of the D<sub>2L</sub> receptor isoform did not reduce eticlopride-induced upregulation of <italic>Nur77</italic> mRNA levels in the striatum. Next, we tested if an ibotenic acid-induced cortical lesion could block the effect of eticlopride on <italic>Nur77</italic> expression. Cortical lesions strongly reduced eticlopride-induced striatal upregulation of <italic>Nur77</italic> mRNA. Then, we investigated if glutamatergic neurotransmission could modulate eticlopride-induced <italic>Nur77</italic> expression. A combination of a metabotropic glutamate type 5 (mGlu5) and adenosine A<sub>2A</sub> receptor antagonists abolished eticlopride-induced upregulation of <italic>Nur77</italic> mRNA levels in the striatum. Direct modulation of <italic>Nur77</italic> expression by striatal glutamate and adenosine receptors was confirmed using corticostriatal organotypic cultures. Taken together, these results indicate that blockade of postsynaptic D<sub>2</sub> receptors is not sufficient to trigger striatal transcriptional activity and that interaction with corticostriatal presynaptic D<sub>2</sub> receptors and subsequent activation of postsynaptic glutamate and adenosine receptors in the striatum is required. Thus, these results uncover an unappreciated role of presynaptic D<sub>2</sub> heteroreceptors and support a prominent role of glutamate in the effect of D<sub>2</sub> antagonists.</p>