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  • Title: 2'-NH2-MPTP in Swiss Webster mice: evidence for long-term (6-month) depletions in cortical and hippocampal serotonin and norepinephrine, differential protection by selective uptake inhibitors or clorgyline and functional changes in central serotonin neurotransmission.
    Author: Andrews AM, Murphy DL.
    Journal: J Pharmacol Exp Ther; 1993 Dec; 267(3):1432-9. PubMed ID: 8263805.
    Abstract:
    The i.p. administration of 1-methyl-4-(2'-aminophenyl)-1,2,3,6-tetrahydropyridine (2'-NH2-MPTP; 4 x 20 mg/kg) to Swiss Webster mice caused substantial decreases in cortical and hippocampal 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid and norepinephrine (NE) measured 1 week post-treatment. Compared with the authors' previously reported results in C57BL/6 mice, these effects were significantly greater in hippocampus (80-90% vs. 60%) and of a similar magnitude in frontal cortex (60-75%). A long-term study showed that cortical and hippocampal 5-HT, 5-hydroxyindoleacetic acid and NE were still decreased 40% to 50% 6 months after treatment. Regional brain dopamine was essentially unchanged during the 6-month period. Pretreatment with the 5-HT-selective uptake inhibitors, fluoxetine or paroxetine, or with the NE-selective uptake inhibitor, desipramine, prevented decreases in cortical and hippocampal 5-HT and NE, respectively, 3 weeks after 2'-NH2-MPTP (4 x 20 mg/kg). In addition, pretreatment with the monoamine oxidase type-A inhibitor, clorgyline, also prevented the more modest decreases in 5-HT and NE caused by 4 x 15 mg/kg 2'-NH2-MPTP. Selegiline, a monoamine oxidase-B inhibitor, did not provide similar protection. Lastly, 2'-NH2-MPTP administered 3 weeks earlier, abolished hypothermia caused by the serotonin agonist, m-chlorophenylpiperazine, which provided preliminary evidence for an associated functional change in the central serotonergic system. Together, these data suggest that 2'-NH2-MPTP is a novel agent capable of producing long-lasting depletions in forebrain 5-HT and NE but not dopamine in two different strains of mice by some mechanisms that resemble those of the parent dopamine-depleting neurotoxin, MPTP.
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