Non-NMDA receptor-mediated mechanisms are involved in levodopa-induced motor response alterations in parkinsonian rats

Chronic dopaminomimetic administration to parkinsonian animal models or Par kinson's disease patients leads to characteristic alteration in motor respo nse. Previous studies suggested that the nonphysiologic stimulation of dopa minergic receptors on striatal medium spiny neurons enhances the synaptic e fficacy of juxtaposed glutamate receptors of the N-methyl-D-aspartate (NMDA ) subtype. Resultant NMDA receptor sensitization due to differential change s in subunit phosphorylation appears to favor alterations in striatal outpu t in ways that influence motor function. To detail the involvement of NMDA receptors further as well as to determine whether similar functional change s might develop in alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (A MPA) receptors, the effects of selective antagonist of AMPA receptors (6-ni tro-7-sulfamoyl-benzo[f]-quinoxaline-2,3 (1H,4H)-dione sodium salt, NBQX, 1 0 mg/kg) on levodopa-induced response alterations in 6-hydroxydopamine (6-O HDA) lesioned rats were compared with drugs which act competitively (3-(+/- )-2-carboxypiperazin-4-yl)-propyl-1-phosphonicacid, CPP, 6.25 mg/kg) or non competitively (dextromethorphan, 40 mg/kg) to block NMDA receptors, or a no nselective inhibitor of glutamatergic transmission (2-amino-6-trifluorometh oxy benzothiazole, riluzole, 5 mg/kg). We found that the shortened duration of the motor response to levodopa, which underlies human wearing-off fluct uations, was reversed to a similar degree by the acute coadministration of CPP, NBQX, or riluzole (n = 4-6) but dextromethorphan did not. These observ ations strengthen the possibility that a reduction in levodopa-associated c hanges in motor response by inhibitors of glutamatergic transmission acting generally or selectively at the glutamate binding-sites may relate to thei r ability to attenuate pathologic gain in striatal glutamatergic function. The capacity of NBQX to reverse these altered responses suggests that an en hanced synaptic efficacy of striatal AMPA receptors may also participate in the generation of these motor response changes in levodopa-treated parkins onian rats. Synapse 36:267-274, 2000. (C) 2000 Wiley-Liss, Inc.