Activation of protein kinase C is required for AMPA receptor GluR1 phosphorylation at serine 845 in the dorsal striatum following repeated cocaine administration

Phosphorylation in the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors plays a crucial role in the regulation of AMPA receptor plasticity associated with drugs of abuse. It is well known that phosphorylation of AMPA receptor GluR1 subunit at serine 845 (S845) is regulated by protein kinase A downstream to dopamine D1 receptors in the striatum. This study was performed to determine whether GluR1-S845 phosphorylation in the rat dorsal striatum is altered by repeated cocaine via a signaling mechanism involving glutamate receptor-associated and Ca2+-dependent protein kinases. Systemic administration of cocaine (20 mg/kg, once a day for 7 days) upregulated GluR1-S845 phosphorylation. This upregulation was mediated via a mechanism involving stimulation of group I metabotropic glutamate receptor 1, N-methyl-d-aspartate receptors, and inositol 1,4,5-triphosphate-sensitive receptors. Interactions of several protein kinases, including protein kinase C, Ca2+/calmodulin-dependent protein kinase II, and extracellular signal-regulated kinases, are also involved in this event. Protein phosphatases further control S845 phosphorylation by dephosphorylating S845 and phosphorylated protein kinases. These findings suggest that phosphorylation of AMPA receptors at GluR1-S845 is upregulated by interactions of glutamate receptor-coupled Ca2+-dependent protein kinases following repeated cocaine administration in the dorsal striatum.