Regulation of phosphorylation of the GluR1 AMPA receptor by dopamine D 2 receptors

In the striatum, stimulation of dopamine D 2 receptors results in attenuation of glutamate responses. This effect is exerted in large part via negative regulation of AMPA glutamate receptors. Phosphorylation of the GluR1 subunit of the AMPA receptor has been proposed to play a critical role in the modulation of glutamate transmission, in striatal medium spiny neurons. Here, we have examined the effects of blockade of dopamine D 2 ‐like receptors on the phosphorylation of GluR1 at the cAMP‐dependent protein kinase (PKA) site, Ser845, and at the protein kinase C and calcium/calmodulin‐dependent protein kinase II site, Ser831. Administration of haloperidol, an antipsychotic drug with dopamine D 2 receptor antagonistic properties, increases the phosphorylation of GluR1 at Ser845, without affecting phosphorylation at Ser831. The same effect is observed using eticlopride, a selective dopamine D 2 receptor antagonist. In contrast, administration of the dopamine D 2 ‐like agonist, quinpirole, decreases GluR1 phosphorylation at Ser845. The increase in Ser845 phosphorylation produced by haloperidol is abolished in dopamine‐ and cAMP‐regulated phosphoprotein of 32 kDa (DARPP‐32) knockout mice, or in mice in which the PKA phosphorylation site on DARPP‐32 (i.e. Thr34) has been mutated (Thr34 → Ala mutant mice), and requires tonic activation of adenosine A 2A receptors. These results demonstrate that dopamine D 2 antagonists increase GluR1 phosphorylation at Ser845 by removing the inhibitory tone exerted by dopamine D 2 receptors on the PKA/DARPP‐32 cascade.