Neurochemical and Histochemical Characterization of Neurotoxic Effects of 1‐Methyl‐4‐Phenyl‐1,2,3,6‐Tetrahydropyridine on Brain Catecholamine Neurones in the Mouse

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Abstract
Systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP[which causes chronic parkinsonism]) caused a rapid and long-lasting reduction of both 3,4-dihydroxyphenylalanine (dopamine, DA) and noradrenaline[norepinephrine] (NA) in mouse brain, as observed histo- and neurochemically. The depleting effects were more pronounced after repeated MPTP administration and the most marked reductions were observed after 2 .times. 50 mg MPTP/kg s.c. when DA in striatum and NA in frontal cortex were reduced by > 90% 1 wk after MPTP. Mice with such catecholamine depletions were markedly sedated and almost completely immobilized. The behavioral syndrome after MPTP resembled that seen after reserpine, a monoamine-depleting drug. MPTP also caused a long-lasting reduction of catecholamine uptake in striatal DA and cortical NA nerve terminals and reduced tyrosine hydroxylase activity in these regions. There was no evidence that MPTP caused any marked DA and NA cell body death. MPTP given acutely transiently elevated serotonin[5-hydroxytryptamine] levels. The results are compatible with a neurotoxic action of MPTP on both DA and NA nerve terminals. The nigro-striatal DA and the locus coeruleus NA neuron systems appeared to be most susceptible. Synthesis and utilization of residual striatal DA and cortical NA were increased, as often observed in partially denervated monoamine-innervated brain regions. Both DA and NA showed a gradual recovery, which took months to become complete and may have been related to a regrowth of catecholamine nerve terminals.