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.
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.
Andrews
A M
AM
Laboratory of Clinical Science, National Institute of Mental Health, Bethesda, Maryland.
Murphy
D L
DL
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D003010:Clorgyline / Q000494:pharmacology*; D003891:Desipramine / Q000494:pharmacology; D005473:Fluoxetine / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D020267:MPTP Poisoning; D008297:Male; D051379:Mice; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism*; D017374:Paroxetine / Q000494:pharmacology; D012642:Selegiline / Q000494:pharmacology; D012701:Serotonin / Q000378:metabolism* / Q000502:physiology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology; D013997:Time Factors
D008996:Monoamine Oxidase Inhibitors; D014179:Neurotransmitter Uptake Inhibitors; D017366:Serotonin Receptor Agonists; D005473:Fluoxetine; C079794:1-methyl-4-(2'-aminophenyl)-1,2,3,6-tetrahydropyridine; D012642:Selegiline; D012701:Serotonin; D017374:Paroxetine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D003010:Clorgyline; D003891:Desipramine; D009638:Norepinephrine