Mouse model of Parkinsonism: A comparison between subacute MPTP and chronic MPTP/probenecid treatment

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is widely used to induc e an animal model of Parkinsonism. The conventional mouse model, which usua lly involves acute or subacute injections of MPTP, results in a significant but reversible loss of dopaminergic functions. We have developed an altern ative mouse model, in which co-administration of MPTP with probenecid resul ts in the chronic loss of striatal dopamine for at least 6 months after ces sation of treatment. In the present study. we compare the neurochemical, mo rphological and behavioral changes that occur in this alternative, chronic model with those in the conventional, subacute model. In the chronic model, we demonstrate an almost 80% loss of striatat dopamine and dopamine uptake 6 months after withdrawal from treatment, The neurochemical signs match un biased stereological measures that demonstrate gradual loss of substantia n igra neurons, Rotarod performance further substantiates these findings by s howing a progressive decline in motor performance. Based on the comparisons made in this study in mice, the chronic MPTP/probe necid model shows considerable improvements over the conventional. subacute MPTP model. The sustained alterations in the nigrostriatal pathway resembl e the cardinal signs of human Parkinson's disease and suggest that this chr onic mouse model is potentially useful to study the pathophysiology and mec hanisms of Parkinsonism. It should also prove useful for the development of neuroprotection strategies. (C) 2001 IBRO. Published by Elsevier Science L td. All rights reserved.