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Dopamine D 2  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 D 2  antagonist in the striatum. First, we investigated D 2  antagonist-induced  Nur77  mRNA in D 2L  receptor knockout mice. Surprisingly, deletion of the D 2L  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 A 2A  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 D 2  receptors is not sufficient to trigger striatal transcriptional activity and that interaction with corticostriatal presynaptic D 2  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 2  heteroreceptors and support a prominent role of glutamate in the effect of D 2  antagonists.

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