Dopamine/glutamate interactions in Parkinson's disease.
In Parkinson's disease, the tonic inhibition by basal ganglia output structures may be exacerbated by the action of the subthalamic nucleus. As expected, the reduction of excitatory impact from this structure has been shown to reduce akinesia in monkeys with experimental parkinsonism. The findings of receptor binding studies supporting an increased neuronal activity of efferents of the subthalamic nucleus in patients with Parkinson's disease, suggest that subthalamic nucleotomy or pallidotomy may be effective lesions in the neurosurgical treatment of Parkinson's disease. Systemic administration of glutamate antagonists has been shown to have anti-akinetic effects in animal models of Parkinson's disease. Other observations in monkeys indicate that excitatory amino acids such as glutamate are involved in the pathophysiological cascade of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced neuronal cell death. The neuroprotective effects of competitive and non-competitive NMDA (N-methyl-D-aspartate) receptor antagonists against MPTP toxicity support the hypothesis that NMDA receptor-mediated events are involved in the neurotoxicity of MPTP. Glutamate antagonists may therefore be able to retard the progression and to improve the symptomatology of Parkinson's disease. Several compounds with anti-parkinsonian effects such as amantadine, memantine, budipine and orphenadrine have been shown to be non-competitive NMDA receptor antagonists and are candidates for clinical trials on the neuroprotective efficacy of NMDA receptor antagonism. Furthermore, glutamate antagonists are useful in the treatment of the akinetic parkinsonian crisis, a severe form of clinical deterioration in patients with Parkinson's disease.
Lange
K W
KW
Department of Neuropsychology and Behavioural Neurobiology, University of Freiburg, Germany.
Kornhuber
J
J
Riederer
P
P
D000818:Animals; D001479:Basal Ganglia / Q000503:physiopathology; D004298:Dopamine / Q000502:physiology*; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use; D018698:Glutamic Acid / Q000502:physiology*; D006801:Humans; D010300:Parkinson Disease / Q000188:drug therapy / Q000503:physiopathology*; D009435:Synaptic Transmission / Q000502:physiology
D018691:Excitatory Amino Acid Antagonists; D018698:Glutamic Acid; D004298:Dopamine