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 rece ptors MK-801 ,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine) potent iates the circling response induced by direct stimulation of the stria tal dopaminergic receptors through intracerebral application of dopami ne. Microinjection of dopamine (1, 5, 25 or 50 mu g/1.0 mu l) induced a dose-dependent contralateral circling response, when injected direct ly into the lesioned side of unilaterally 6-hydroxydopamine-lesioned r ats. Interestingly, intrastriatal application of dopamine (1, 5, 25 or 50 mu g/1.0 mu l) followed by a systemic administration of MK-801 (10 0 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 respons e produced by MK-801 when given alone. Moreover, the potentiated respo nses persist 4-fold longer compared to the circling induced by dopamin e alone. The results suggest that the potentiation by NMDA receptor an tagonists 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.