Does the blockade of excitatory amino acid transmission in the basal ganglia simply reverse reaction time deficits induced by dopamine inactivation?
It has recently been hypothesized that excessive excitatory amino acid (EAA) activity in the corticostriatal pathway and in the subthalamic nucleus could account for the expression of the motor deficits resulting from alteration in dopamine function in the basal ganglia. The present study investigated the potential benefit of blocking excitatory amino acid transmission in the basal ganglia, subsequent to the inactivation of dopaminergic function of rats performing a reaction time (RT) task. Disruption of dopamine activity by the neurotoxin 6-hydroxydopamine (6-OHDA) injected in the striatum or by systemic administration of the D2 dopamine receptor antagonist raclopride, impaired the performance of rats trained to release a lever quickly after a visual stimulus. RTs, measured by the time elapsing from the stimulus onset to the lever release, were lengthened after both treatments. The blockade of EAA transmission at the N-methyl-D-aspartate (NMDA) receptor, by systemic injections of the NMDA receptor antagonist dizocilpine or by excitotoxic lesions of the subthalamic nucleus, in animals with dopamine lesions, significantly reversed the increase of RTs. Performance of animals with subthalamic nucleus lesions did not return to pre-operative values, however. The blockade of NMDA receptors in the striatum, by a local injection of the NMDA receptor antagonist DL-2-amino-5-phosphonovaleric acid (APV), in animals treated with raclopride, was found to decrease RTs and improve performance. Analysis of RT distributions in the three groups of animals revealed that blocking EAA activity with NMDA receptor antagonists improved performance by shifting RTs back towards baseline values, preserving a normal distribution. In contrast, lesions of the subthalamic nucleus disrupted performance, as shown by the scattered distribution of RTs. The results indicate that treatment with NMDA receptor antagonists but not subthalamotomy provides a possible beneficial treatment in the present model of Parkinsonism.
Laboratoire de Neurobiologie Cellulaire et Fonctionnelle, CNRS, 31 chemin J, Aiguier, 13402 Marseille, Cedex 20, France; Laboratoire associé à l'Université de la Méditerranée (Aix-Marseille II).
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Amalric
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Baunez
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Nieoullon