GluR1 phosphorylation and persistent expression of levodopa-induced motor response alterations in the...

The phosphorylation of glutamate receptor 1 (GluR1) has been increasingly implicated in the formation and maintenance of plastic responses. To investigate molecular mechanisms that underlie the persisting alterations in motor response occurring with levodopa treatment of parkinsonian patients, we evaluated the time course of these changes in relation to the phosphorylation of GluR1 in 6-hydroxydopamine (6-OHDA) lesioned animals. Three weeks of twice-daily levodopa administration to rats shortened the duration of the rotational responses and increased the peak turning responses, which lasted at least 7 days after withdrawal of chronic levodopa treatment. The shortened response duration and increased peak turning, resembling human wearing-off fluctuations and dyskinesia, were associated with a marked increase in Ser-845 phosphorylated GluR1 (pGluR1S845) immunoreactivity in lesioned striatum in response to levodopa treatment. The time course of changes in GluR1 phosphorylation correlated with the time course of changes in motor behavior after withdrawal of chronic levodopa therapy. Our immunostaining data showed that these changes were confined to parvalbumin-positive neurons where GluR1 are exclusively expressed. Both the altered motor response and the degree of pGluR1S845 were attenuated by the intrastriatal administration of protein kinase A (PKA) inhibitor Rp-cAMPS or GluR1 antisense oligonucleotides. The results suggest that Ser-845 GluR1 phosphorylation within parvalbumin-positive neurons contributes to the persistence of the motor response alterations produced by chronic intermittent dopaminergic stimulation.