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TOXICOLOGY

Neuronal and Astroglial Responses to the Serotonin and Norepinephrine Neurotoxin: 1-Methyl-4-(2'-aminophenyl)-1,2,3,6-tetrahydropyridine

Department of Chemistry and Huck Institute for Life Sciences, The Pennsylvania State University, University Park, Pennsylvania (B.A.L., A.C.C., A.M.A.); Laboratory of Neurotoxicology, Centers for Disease Control and Prevention/National Institute of Environmental Health Sciences, Morgantown, West Virginia (D.B.M., J.P.O.); and Laboratory of Clinical Science, National Institutes of Mental Health, Bethesda, Maryland (D.L.M.)

1-Methyl-4-(2'-aminophenyl)-1,2,3,6-tetrahydropyridine (2'-NH₂-MPTP) causes long-term loss of forebrain serotonin (5-HT) and norepinephrine (NE) and consequently, is unlike 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its other 2'-analogs that primarily deplete striatal dopamine (DA). In the present investigation into the acute effects of 2'-NH₂-MPTP in mice, profound decreases in cortical and hippocampal 5-HT and NE to 10 to 40% of control were observed as early as 30 min post-treatment and lasted throughout the ensuing 21 days. Striatal DA was decreased to 60 to 80% of control during the first 48 h but returned to normal by 72 h. Reactive gliosis, which occurs in response to neurodegeneration was not evident by immunocytochemistry but was detected by enzyme-linked immunosorbent assay, where glial fibrillary acidic protein (GFAP) was increased to 130% of control in cortex, hippocampus, and brain stem 48 to 72 h post-treatment. To explore the possibility that 5-HT modulates the astrocytic response to injury, 2'-NH₂-MPTP was used to damage 5-HT axons 2 weeks before administration of the potent DA neurotoxin 1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'-CH₃-MPTP). Despite a 90% decrement in striatal DA in 2'-NH₂-MPTP/2'-CH₃-MPTP-treated mice, increases in GFAP were attenuated compared to mice treated with 2'-CH₃-MPTP alone. Thus, 2'-NH₂-MPTP causes severe and immediate decrements in 5-HT and NE in frontal cortex and hippocampus, yet induces a modest GFAP response compared with other MPTP analogs that have their primary effect on DA. These results demonstrate the importance of obtaining quantitative assessments of GFAP to detect astroglial responses associated with selective damage to neurotransmitter systems with low-density innervation and suggest that serotonin may facilitate the astrocytic response to striatal injury.

Address correspondence to: Dr. Anne Milasincic Andrews, The Pennsylvania State University, 152 Davey Laboratory, University Park, PA 16802. E-mail: ama11{at}psu.edu

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