Protection against dopaminergic nigrostriatal cell death by excitatory input ablation

The importance of enhanced glutamatergic neurotransmission in the basal gan glia and related structures has recently been highlighted in the developmen t of Parkinson's disease. The pedunculopontine tegmental nucleus (PPN) is t he major origin of excitatory, glutamatergic input to dopaminergic nigrostr iatal neurons of which degeneration is well known to cause Parkinson's dise ase. Based on the concept that an excitatory mechanism mediated by glutamat ergic neurotransmission underlies the pathogenesis of neurodegenerative dis orders, we made an attempt to test the hypothesis that removal of the gluta matergic input to the nigrostriatal neurons by PPN lesions might prevent 1- methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in t he macaque monkey. The PPN was lesioned unilaterally with microinjection of kainic acid, and, then, MPTP was administered systemically. In these monke ys, the degree of parkinsonian motor signs was behaviourally evaluated, and the histological changes in the dopaminergic nigrostriatal system were ana lysed by means of tyrosine hydroxylase immunohistochemistry. The present re sults revealed that nigrostriatal cell loss and parkinsonian motor deficits were largely attenuated in the MPTP-treated monkey group whose PPN had bee n lesioned, compared with the control, MPTP-treated monkey group with the P PN intact. This clearly indicates that the onset of MPTP neurotoxicity is s uppressed or delayed by experimental ablation of the glutamatergic input to the nigrostriatal neurons. Such a protective action of excitatory input ab lation against nigrostriatal cell death defines evidence that nigral excita tion driven by the PPN may be implicated in the pathophysiology of Parkinso n's disease.