Studies on the effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on central catecholamine neurons in C57BL/6 mice. Comparison with three other strains of mice.

The effect of the parkinsonism-inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on central catecholamine neurons in C57BL/6 mice has been studied employing neuro- and histochemical techniques. The number of dopamine (DA) cell bodies in substantia nigra pars compacta (SNC) was reduced by 70% in MPTP-treated C57BL/6 mice, as demonstrated both by tyrosine hydroxylase (TH) immunohistochemistry and conventional histology (Cresyl violet staining) and an almost complete loss of DA fibers in striatum was also found. A detailed analysis of the effects of MPTP on endogenous catecholamine levels in various brain regions revealed that MPTP caused a severe reduction of endogenous DA in substantia nigra and striatum (35 and 5% of control) which was accompanied by an increase in the 3,4-dihydroxyphenylacetic acid (DOPAC)/DA ratio. There was also a decrease of DA in nucleus accumbens and the olfactory tubercle to 41 and 44% of control, respectively, without any significant change in the DOPAC/DA ratio and density of TH-positive fibers. Small but significant decreases of the noradrenaline (NA) levels in septum, entorhinal cortex and frontal cortex were seen, although the uptake of [3H]NA in frontal cortex was not significantly changed. Minor MPTP-induced decreases of the serotonin levels in frontal cortex, occipital cortex and spinal cord were also seen. The MPTP treatment also induced a 55% increase of adrenaline levels in hypothalamus, while no changes were seen in pons-medulla and spinal cord. Comparing this with 3 other strains of mice, the MPTP-induced reduction of endogenous DA in striatum was most pronounced in C57BL/6, less in N.M.R.I. and CBA/Ca mice, and least in Swiss-Webster. Concerning the effect of MPTP on cortical NA levels, the same relation was at hand except for C57BL/6, where, as mentioned, the effect was merely detectable. No reduction of DA perikarya in SNC was seen in Swiss-Webster mice. These findings show that in mice major differences exist in sensitivity of catecholamine neurons to MPTP between different strains. The data show that MPTP can produce an almost complete, permanent and relatively selective degeneration of the nigrostriatal DA neurons in C57BL/6 mice similar to that seen in primates. This strain may therefore serve as a useful model for studies on various aspects of MPTP-induced parkinsonism.