Fluoxetine and desipramine selectively attenuate 2'-NH2-MPTP-induced depletions in serotonin and norepinephrine.
We recently reported that the novel MPTP analog 1-methyl-4-(2'-aminophenyl)-1,2,3,6-tetrahydropyridine (2'-NH2-MPTP) administered to C57BL/6 mice produced substantial decreases in forebrain serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), and norepinephrine, with negligible effects on brain dopamine or dopamine metabolites. In the present report, we confirm and extend our original results to include dose-response data and the effect of selective uptake inhibition on the levels of monoamine neurotransmitters in various regions of the mouse brain following treatment with 2'-NH2-MPTP. In a dose-ranging study, 2'-NH2-MPTP (10 mg/kg x 4) produced a 25-30% reduction in frontal cortex 5-HT, 5-HIAA, and norepinephrine. When 4 x 20 mg/kg 2'-NH2-MPTP was administered, 70-75% reductions in 5-HT, 5-HIAA, and norepinephrine in both frontal cortex and hippocampus were seen 1 week after treatment. No changes in dopamine were found in striatum or in any of the other brain regions examined at either dose. Doses of 40 and 60 mg/kg were lethal shortly after a single injection. In mice receiving either fluoxetine or desipramine (10 mg/kg) prior to 2'-NH2-MPTP (20 mg/kg x 4), decreases in 5-HT and norepinephrine, respectively, were significantly attenuated by approximately 30-40%. These data suggest that 2'-NH2-MPTP acts in a dose-dependent manner and that the serotonergic and noradrenergic uptake systems are involved in the mechanism by which 2'-NH2-MPTP causes selective deficits in cortical and hippocampal 5-HT and norepinephrine.
Andrews
A M
AM
Laboratory of Clinical Science, National Institute of Mental Health, Bethesda, MD 20892.
Murphy
D L
DL
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003891:Desipramine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005473:Fluoxetine / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism*; D050484:Norepinephrine Plasma Membrane Transport Proteins; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D027981:Symporters
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D002352:Carrier Proteins; D003891:Desipramine; D005473:Fluoxetine; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D014179:Neurotransmitter Uptake Inhibitors; D009638:Norepinephrine; D050484:Norepinephrine Plasma Membrane Transport Proteins; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D027981:Symporters; C493228:Slc6a2 protein, mouse; C493231:Slc6a4 protein, mouse; C079794:1-methyl-4-(2'-aminophenyl)-1,2,3,6-tetrahydropyridine