Antiparkinsonian actions of glutamate antagonists--alone and with L-DOPA: a review of evidence and suggestions for possible mechanisms

There has been much speculation of late as to whether antagonists of glutamate receptors can be used to combat the motor difficulties of Parkinson's disease, either as monotherapy, or as polytherapy to boost the effects of conventional L-DOPA treatment. The latter seems to be the more practical approach and the therapeutic implications of such treatment have been discussed in some detail. However, the mechanisms by which glutamate antagonists potentiate the antiparkinsonian actions of L-DOPA, remain cryptic. In this review we have explored the evidence and considered the practicality of using NMDA and non-NMDA receptor blockers to treat parkinsonism, as well as focusing on the ways in which the behavioural synergy between dopamine and glutamate systems could conceivably arise at the cellular level. Particular attention has been paid to the differential interaction between glutamate antagonists and postsynaptic dopamine D1 and D2 receptory mechanisms, since these are currently believed to reflect the activity of the two major basal ganglia output circuits: the so-called direct pathway to the substantia nigra and the indirect pathway to the globus pallidus. Finally, we have considered the new proposal, that inhibiting glutamate transmission in the basal ganglia accelerates the enzymic conversion of L-DOPA to dopamine at presynaptic sites.