THE NEUROTOXIN MPTP CAUSES DEGENERATION OF SPECIFIC NUCLEUS A8, A9 AND A10 DOPAMINERGIC-NEURONS IN THE MOUSE

The neurotoxin MPTP has been used to create an animal model of Parkins on's disease in the mouse, in part, because it causes a significant lo ss of dopaminergic neurons in the substantia nigra (nucleus A9). The p urpose of the present study was to determine whether MPTP also causes degeneration of midbrain dopaminergic neurons in nuclei A8 and A10 in the mouse, as occurs in humans with Parkinson's disease. Two commonly used strains of mice were used: FVB/N and C578L/6. MPTP was administer ed in cumulative doses of 50-300 mg/kg. Seven days later, dopamine con centrations were measured in the striatum using high performance liqui d chromatography, and midbrain dopaminergic neurons were identified us ing an antibody against tyrosine hydroxylase. The cell locations were mapped with a computer imaging system. In the FVB/N strain, there was a dose-dependent decrease in striatal dopamine concentrations. Althoug h the highest dose (300 mg/kg) caused an 86% reduction in striatal dop amine concentrations, there was only a moderate and non-significant lo ss of midbrain dopaminergic neurons. In the C57BL/6 strain, however, a high dose of MPTP (240 mg/kg) caused a significant reduction in both striatal dopamine concentrations (95%), and midbrain dopaminergic cell s; 69% loss of nucleus A8 cells, 75% loss of nucleus A9 cells, and in nucleus A10 subnuclei there was 42% loss of ventral tegmental area cel ls, 55% loss of interfascicular nucleus cells, and no loss of cells in the central linear nucleus. These data (1) provide further evidence f or differential susceptibility to MPTP toxicity among different mouse strains, (2) indicate that a significant depletion of striatal dopamin e is not necessarily due to degeneration of midbrain dopaminergic neur ons, (3) provide the precise locations of midbrain dopaminergic cells that are vulnerable to MPTP, which will aid future studies that seek t o determine the mechanism/s by which MPTP selectively destroys only ce rtain midbrain dopaminergic neurons, and (4) indicate that MPTP produc es midbrain dopaminergic neuronal degeneration in the same nuclei in t he C57BL16 mouse that degenerate in humans with Parkinson's disease. ( C) 1996 Academic Press Limited