REVERSAL OF PARKINSONIAN SYMPTOMS IN PRIMATES BY ANTAGONISM OF EXCITATORY AMINO-ACID TRANSMISSION - POTENTIAL MECHANISMS OF ACTION

Parkinsonism is characterised by overactive glutamatergic transmission in the cortico-striatal and subthalamo-medial pallidal pathways. Loca l blockade of glutamatergic transmission in these pathways can allevia te parkinsonian symptoms. The effectiveness of the treatment, however, is often limited by the simultaneous appearance of unwanted side-effe cts. These side-effects, including ataxia and dissociative anaesthesia , are particularly problematic when N-methyl-D-aspartate (NMDA) antago nists are used. In an attempt to overcome these problems we have attem pted to manipulate excitatory amino acid (EAA)-mediated neurotransmiss ion indirectly by targeting the NMDA receptor associated modulatory si tes. We review evidence which demonstrates that antagonists for both t he NMDA associated glycine and polyamine sires can reverse parkinsonia n symptoms when injected intra-cerebrally in both MPTP-treated and bil ateral 6-OHDA lesioned marmosets without eliciting unwanted side-effec ts. We further review preliminary data which suggest that ifenprodil, a polyamine site antagonist, has striking anti-parkinsonian actions in the marmoset. Potential mechanisms of action underlying these effects are discussed in terms of NMDA receptor subtypes and the neuroanatomi cal locus of action. The anti-parkinsonian efficacy of intra-striatall y administered EAA antagonists leads us to question the view of dopami ne acting in the striatum as a simple neuromodulator. (C) 1997 Elsevie r Science Ltd.