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.