1-Methyl-4(2′-methylphenyl)-1,2,3,6-tetrahydropyridine (2′CH₃-MPTP)-induced degeneration of mesostriatal dopaminergic neurons in the mouse: biochemical and neuroanatomical studies

The neurotoxic effects of 1-methyl-4-(2′-methylphenyl)-1,2,3,6-tetrahydropyridine (2′CH₃-MPTP), a substituted analog of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, were studied in BALB/cJ mice. Moderate doses of 2′CH₃-MPTP produced a greater depletion of dopamine (DA) in the striatum (45%) than in the nucleus accumbens (23%), and in these same animals, there was a 35% loss of midbrain DA neurons. The greatest loss of DA cells occurred within the substantia nigra (43%), and there was also a significant loss of cells within the ventral tegmental area (28%). Higher doses of 2′CH₃-MPTP decreased levels of DA more in the axon terminal/forebrain region (72%) than in the cell body/midbrain region (25%). Similar forebrain/midbrain DA depletion ratios were also found in mice that received an electrolytic lesion of the midbrain DA neurons; there was a greater DA depletion in the forebrain (29%) than in the midbrain (8%). In both 2′CH₃-MPTP and electrolytically lesioned animals there was a significant increase in DA turnover in the forebrain region, as measured by the homovanillic acid/DA ratio. These data indicate that 2′CH₃-MPTP: (1) destroys DA neurons within two midbrain regions containing cells which project to the striatum (i.e. mesostriatal DA neurons), rather than just nigrostriatal DA neurons; (2) produces a greater loss of DA in the axon terminal region than in the cell body region; and (3) influences the mesostriatal DA neurons in the same way as does a lesion to the cell bodies. These data are discussed with regard to the pathophysiology of 2′CH₃-MPTP.