Neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in the substantia nigra and the locus coeruleus in BALB/c mice.

The purpose of the present study was to determine whether 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), administered systemically or as a local infusion, has a direct neurotoxic action upon dopamine (DA) neurons in the substantia nigra (SN) and norepinephrine (NE) neurons in the locus coeruleus (LC) in BALB/c mice. Results indicated that both acute and repeated MPTP infusions (2 micrograms/0.3 microliter per side) significantly impaired locomotor activity, decreased stereotyped behavior and caused a disturbed pattern of locomotion in mice. The biochemical changes parallel the behavioral changes. Repeated MPTP infusions to the SN decreased DA levels markedly in the SN and the striatum; chronic MPTP infusions to the LC reduced NE levels markedly in the LC and the hippocampus. Furthermore, repeated MPTP injections for 7 days (30 mg/kg, one injection per day) have resulted in a long-lasting effect on both the nigral-striatal and the coeruleus-hippocampal systems. DA levels in the SN and the striatum were decreased at 1, 3, 7 and 28 days after the last MPTP injection. Similarly, NE levels in the LC and the hippocampus were also reduced markedly at the same time intervals examined. Behaviorally, repeated MPTP treatment also produced long-lasting motor deficits in mice at all time intervals studied. Moreover, the LC appeared to be more sensitive than the SN to the neurotoxic effects of MPTP. Immunohistochemical results have similarly revealed that repeated MPTP treatment markedly decreased tyrosine hydroxylase-positive cells and fibers in the SN and the LC. It also markedly decreased DA-beta-hydroxylase-positive cells and fibers in the LC.(ABSTRACT TRUNCATED AT 250 WORDS)