Enhanced tyrosine phosphorylation of striatal NMDA receptor subunits: effect of dopaminergic denervation and L-DOPA administration

Sensitization of striatal N-methyl-D-aspartate receptors (NMDAR) has been l inked to events leading to the motor response changes associated with the a dministration of dopaminomimetics to parkinsonian animals and patients. To determine whether tyrosine phosphorylation of NMDAR subunits contributes to the apparent long-term enhancement in synaptic efficacy of these receptors , we examined the effect of unilateral nigrostriatal dopamine system ablati on with 6-hydroxydopamine followed by twice-daily treatment with L-DOPA on the phosphorylation state of rat striatal NR2A and NR2B subunits. Three wee ks of intermittent L-DOPA administration produced a shortening in the durat ion of the rotational response to dopaminergic challenge and other changes mimicking those occurring in patients with Parkinson's disease. Concurrentl y, tyrosine phosphorylation of NR2A and especially of NR2B subunits increas ed ipsilateral to the lesion (20 +/- 5% and 46 +/- 7% of intact striatum, r espectively; p < 0.01) without attendant changes in subunit protein levels. Selective blockade of NR2B subunits with ACEA 10-1244, but not of NR2A sub units with MDL 100,453, reversed the L-DOPA-induced response alterations. T he intrastriatal injection of a tyrosine kinase inhibitor, genistein, at a dose (2.0 mu g) that normalized the response shortening, attenuated the NR2 A and NR2B phosphorylation increase by about 12% and 24%, respectively(p < 0.01). Taken together, these results suggest that augmented tyrosine phosph orylation of NR2B subunits, alone or in combination with the smaller rise i n NR2A subunit phosphorylation, contributes to the apparent enhancement in striatal NMDAR sensitivity and thus to the plastic alterations in dopaminer gic responses in L-DOPA-treated parkinsonian rats. (C) 1998 Published by El sevier Science B.V. All rights reserved.