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To purchase or authenticate to the full-text of this article, please visit this link: http://dx.doi.org/10.1111/j.1471-4159.2005.03558.x Byline: Kerstin Hakansson (*), Stacey Galdi ([dagger]), Joseph Hendrick ([dagger]), Gretchen Snyder ([dagger]), Paul Greengard ([double dagger]), Gilberto Fisone (,) Keywords: adenosine A receptor; cyclic AMP-dependent protein kinase; dopamine- and cyclic AMP-regulated phosphoprotein of 32 kDa; haloperidol; mouse; striatum Abstract: Abstract In the striatum, stimulation of dopamine D.sub.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.sub.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.sub.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.sub.2 receptor antagonist. In contrast, administration of the dopamine D.sub.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 [double right arrow] Ala mutant mice), and requires tonic activation of adenosine A.sub.2A receptors. These results demonstrate that dopamine D.sub.2 antagonists increase GluR1 phosphorylation at Ser845 by removing the inhibitory tone exerted by dopamine D.sub.2 receptors on the PKA/DARPP-32 cascade. Author Affiliation: (*)Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden ([dagger])Department of Neuropharmacology, Intra-Cellular Therapies Inc., New York, USA ([double dagger])Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, USA Article History: Received July 8, 2005; revised manuscript received September 26, 2005; accepted September 26, 2005. Article note: Address correspondence and reprint requests to Gilberto Fisone, Department of Neuroscience, Karolinska Institutet, Retzius vag 8, 171 77 Stockholm, Sweden. E-mail: gilberto.fisone@ki.se