SYSTEMIC ADMINISTRATION OF THE NMDA RECEPTOR ANTAGONIST MK-801 POTENTIATES CIRCLING INDUCED BY INTRASTRIATAL MICROINJECTION OF DOPAMINE

Systemic administration of the non-competitive antagonist of NMDA receptors MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine) potentiates the circling response induced by direct stimulation of the striatal dopaminergic receptors through intracerebral application of dopamine. Microinjection of dopamine (1, 5, 25 or 50 mu g/1.0 mu l) induced a dose-dependent contralateral circling response, when injected directly into the lesioned side of unilaterally 6-hydroxydopamine-lesioned rats. Interestingly, intrastriatal application of dopamine (1, 5, 25 or 50 mu g/1.0 mu l) followed by a systemic administration of MK-801 (100 mu g/kg i.p.) produced a potentiated contralateral circling response in unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats. This motor effect is reversed compared to the marked ipsilateral circling response produced by MK-801 when given alone. Moreover, the potentiated responses persist 4-fold longer compared to the circling induced by dopamine alone. The results suggest that the potentiation by NMDA receptor antagonists of motor activity induced by dopaminergic agonists in animal models of Parkinson's disease cannot be ascribed simply to increased release of dopamine. Other mechanisms including increased sensitivity of dopamine D-1 receptors or blockade or glutamatergic transmission in output structures must be considered.