title: Reversal of parkinsonian symptoms in primates by antagonism of excitatory amino acid transmission: potential mechanisms of action.
abstract: Parkinsonism is characterised by overactive glutamatergic transmission in the cortico-striatal and subthalamo-medial pallidal pathways. Local blockade of glutamatergic transmission in these pathways can alleviate parkinsonian symptoms. The effectiveness of the treatment, however, is often limited by the simultaneous appearance of unwanted side-effects. These side-effects, including ataxia and dissociative anaesthesia, are particularly problematic when N-methyl-D-aspartate (NMDA) antagonists are used. In an attempt to overcome these problems we have attempted to manipulate excitatory amino acid (EAA)-mediated neurotransmission indirectly by targeting the NMDA receptor associated modulatory sites. We review evidence which demonstrates that antagonists for both the NMDA associated glycine and polyamine sites can reverse parkinsonian symptoms when injected intra-cerebrally in both MPTP-treated and bilateral 6-OHDA lesioned marmosets without eliciting unwanted side-effects. 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 neuroanatomical locus of action. The anti-parkinsonian efficacy of intra-striatally administered EAA antagonists leads us to question the view of dopamine acting in the striatum as a simple neuromodulator.
authors.affiliation: School of Psychology, University of Birmingham, UK.
authors.forename: I J
authors.initials: IJ
authors.lastname: Mitchell
authors.forename: C B
authors.initials: CB
authors.lastname: Carroll
mesh_terms: D000818:Animals; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D011323:Primates / Q000502:physiology*
chemical_list: D018691:Excitatory Amino Acid Antagonists