Differential interactive effects of gliotoxin and MPTP in the substantia nigra and the locus coeruleus in BALB/c mice.

We have previously demonstrated that chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) infusion to the substantia nigra (SN) and the locus coeruleus (LC) both produce a long-lasting neurotoxicity on dopamine (DA) and norepinephrine (NE) neurons in these two areas, respectively. In the present study, we further examined the toxicity of MPTP in these two areas by using the immunohistochemical method. We have also assessed the role of glia cells in the SN and LC in mediating the toxicity of MPTP. Immunohistochemical results have confirmed the direct toxicity of MPTP in the SN, as revealed by significant decreases of tyrosine hydroxylase (TH)-positive cells in the SN and TH-positive fibers in the striatum. The specific gliotoxin alpha-aminoadipic acid (alpha-AA), when administered to the SN at 48 h interval, partially antagonized DA depletions and behavioral deficits produced by chronic MPTP treatment. When alpha-AA was administered to the SN every 24 h, it completely abolished the toxicity of MPTP. On the other hand, chronic MPTP infusions to the LC significantly decreased DA-beta-hydroxylase-positive cells in this area. When alpha-AA was injected into the LC at 48 h intervals, it did not prevent depletions of NE in the LC and the hippocampus caused by chronic MPTP infusions. It did not protect against the behavioral deficits produced by MPTP, either. When alpha-AA was injected into the LC every 24 h, it only partially prevented the toxicity of MPTP on NE in the LC. It also partially prevented the motor-impairing effect of MPTP; however, it barely protected against MPTP's toxicity on NE in the hippocampus and it did not antagonize the stereotypy deficit produced by chronic MPTP, either. Phasic tremor and rigidity were observed following MPTP infusions to the SN and the LC every day, but these symptoms were less frequently observed during the later experimental stage. Serotonin measures were not significantly altered by these treatments throughout these experiments. Immunoblotting results of glial fibrillary acidic protein (GFAP), a marker protein of astrocytes, have confirmed proper lesions of astrocytes by alpha-AA. These results together suggest that chronic MPTP treatment exerts a direct and long-lasting toxicity on DA neurons along the nigrostriatal pathway and NE neurons along the coeruleus-hippocampal pathway. The neurotoxicity of MPTP is probably mediated through astrocytes in the SN, and may be partly mediated through astrocytes in the LC also. These results imply a role for dendritic uptake of DA and NE in these cell body regions. However, these findings also suggest the possibility of differential mechanisms of MPTP's toxicity in these two areas.