Rationale: Phosphorylation in the α-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.
Objectives: 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 Ca(2+)-dependent protein kinases.
Results: 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, Ca(2+)/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.
Conclusions: These findings suggest that phosphorylation of AMPA receptors at GluR1-S845 is upregulated by interactions of glutamate receptor-coupled Ca(2+)-dependent protein kinases following repeated cocaine administration in the dorsal striatum.