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

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

doi:10.3389/fphar.2012.00153

Abstract

Dopamine D2 receptor antagonists modulate gene transcription in the striatum. However, the molecular mechanism underlying this effect remains elusive. Here we used the expression of Nur77, 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 D2 antagonist in the striatum. First, we investigated D2 antagonist-induced Nur77 mRNA in D2L receptor knockout mice. Surprisingly, deletion of the D2L receptor isoform did not reduce eticlopride-induced upregulation of Nur77 mRNA levels in the striatum. Next, we tested if an ibotenic acid-induced cortical lesion could block the effect of eticlopride on Nur77 expression. Cortical lesions strongly reduced eticlopride-induced striatal upregulation of Nur77 mRNA. Then, we investigated if glutamatergic neurotransmission could modulate eticlopride-induced Nur77 expression. A combination of a metabotropic glutamate type 5 (mGlu5) and adenosine A2A receptor antagonists abolished eticlopride-induced upregulation of Nur77 mRNA levels in the striatum. Direct modulation of Nur77 expression by striatal glutamate and adenosine receptors was confirmed using corticostriatal organotypic cultures. Taken together, these results indicate that blockade of postsynaptic D2 receptors is not sufficient to trigger striatal transcriptional activity and that interaction with corticostriatal presynaptic D2 receptors and subsequent activation of postsynaptic glutamate and adenosine receptors in the striatum is required. Thus, these results uncover an unappreciated role of presynaptic D2 heteroreceptors and support a prominent role of glutamate in the effect of D2 antagonists.

Highlights

Dopamine antagonists have been used to alleviate schizophrenia symptoms for more than a half-century
In the present study, using Nur77 mRNA expression as readout, we show that D2 antagonist-induced transcriptional activity in the striatum is mediated by interaction of the drug with presynaptic D2 short (D2S) heteroreceptors located at corticostriatal terminals and subsequent activation of postsynaptic glutamate metabotropic glutamate type 5 (mGlu5) and adenosine A2A receptors
D2 long (D2L)(−/−) mice displayed a significant reduction in basal Nur77 mRNA levels in the dorsomedial striatum, but basal transcript levels were unchanged in all other striatal subterritories, as compared with their wild type littermates (Figure 1)

Summary

Introduction

Dopamine antagonists have been used to alleviate schizophrenia symptoms for more than a half-century. Because of the in vivo reciprocal functional relationships between dopamine, glutamate, and adenosine receptor activities, it is difficult to pin point the specific contribution of these different receptor subtypes. Striatal cells express glutamate receptors and a functional interaction between the activity of dopamine D2 and metabotropic glutamate receptors has been described. Blockade of metabotropic glutamate type 5 (mGlu5) receptor reduces haloperidol (D2 antagonist)-induced catalepsy (Ossowska et al, 2001). An interaction between dopamine D2, adenosine A2A, and mGlu receptors has been demonstrated in the striatum (Ferré et al, 2002; Kachroo et al, 2005; Cabello et al, 2009). MGlu receptor antagonist-induced locomotor activity was abolished in postnatal forebrain-specific conditional (Cre/loxP system) A2A receptor knockout mice (Kachroo et al, 2005). Using combination of bimolecular fluorescence complementation and bioluminescence resonance energy www.frontiersin.org

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