CHOLINERGIC SYSTEMS AND MPTP NEUROTOXICITY

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There is now clinical and experimental evidence that 1-methyl-4- phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) induces parkinsonism in humans and monkeys. Treatment with L-DOPA can reverse the clinical signs. With Parkinson's disease, an alternative and complementary approach to restore the normal balance of cholinergic and dopaminergic influences on basal ganglia is to administer anticholinergic drugs. The proposed studies are designed, in part, to evaluate the interaction of dopaminergic and cholinergic neuronal systems in the MPTP-mouse model. Our observations with the mouse model suggests that there may be a positive feedback system that accelerates the loss of dopamine (DA) if acetylcholine (Ach) activity is not controlled with anticholinergic drugs. For example, we have found that following MPTP administration to the mouse that there is a fall of DA and a rise of ACh in the striatum. Moreover, the administration of anticholinergic drugs block the fall of DA and the rise of ACh. Furthermore, we have evidence that chronic treatment with atropine after treatment with MPTP may enable the striatum to recover its DA content. We also have data suggesting that treatment with GM1 ganglioside, an endogenous substance that has been reported to play a role in synaptogenesis, may enable the striatum to recover its DA content as well. Our general plan of research includes: studies of the characteristics of neurotransmitter change in mouse brain after administering MPTP especially DA and ACh content, their rat of formation and their synthetic enzymes; comparison of the changes induced by MPTP with the changes induced by 6-hydroxydopamine; and studies of the morphological changes after MPTP administration, especially after atropine and GM1 treatment. Our understanding of movement disorders that have been attributed to disturbances of the basal ganglia would be significantly advanced if the relationship between DA- and ACh-containing neurons were understood better; indeed, the progression of Parkinson's disease might be altered with appropriate drug treatment.