MODEL OF PARKINSON'S DISEASE USING MPTP

The objective of the following studies is to rigorously evaluate the behavioral deficits observed in the rodent model of Parkinson's Disease using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Exposure to MPTP caused parkinsonian-like symptoms in a number of individuals. This observation has led to an intensive effort to develop animal models of MPTP-induced toxicity in the hope of gaining insight into the etiology of Parkinson's Disease. It is clear that the administration of MPTP to subhuman primates causes the parkinsonian-like symptoms. However, initial studies using rats and mice concluded that MPTP was without effect in these species. One of the major issues was that there were no overt parkinsonian-like behavioral symptoms observed in rodents following MPTP administration. In this proposal, it is argued that MPTP does indeed produce marked behavioral deficits in rodents but, more sensitive behavioral paradigms are required to unmask these deficits. Among the advantages of using rodents rather than subhuman primates to study MPTP-induced toxicity are substantially reduced expenses and the wealth of data already available on rodent models of Parkinson's Disease. For example, the classic work of Carlsson on the effects of 1-dopa in reversing performance deficits of reserpinized mice in the shuttle box paradigm led to the clinical trials of 1-dopa in Parkinson's Disease patients. In preliminary studies, a substantial deficit in shuttle box avoidance responding was observed in mice following the administration of MPTP. The deficit was reversed by 1-dopa. Accordingly, the first objective of the studies in this proposal is to replicate and extend these initial findings in an attempt to systematically evaluate the behavioral deficits following MPTP administration to rats. A second behavioral paradigm which has been employed for the analysis of behavioral deficits associated with brain dopamine depletions is the force lever paradigm. This paradigm provides a sensitive measure of the fine motor control of the subject and serves as an excellent compliment to the more molar behaviors assessed in the shuttle box. Accordingly, the second objective of these studies is to determine if MPTP administration causes a deficit in fine motor control of the rat. Conclusions concerning the utility of the rodent model of Parkinson's Disease using MPTP can be made only after a rigorous and systematic evaluation of the resulting behavioral deficits as measured in sensitive behavioral paradigms.