SUSTAINED DEPLETION OF CORTICAL AND HIPPOCAMPAL SEROTONIN AND NOREPINEPHRINE BUT NOT STRIATAL DOPAMINE BY 1-METHYL-4-(2'-AMINOPHENYL)-1,2,3,6-TETRAHYDROPYRIDINE (2'-NH2-MPTP) - A COMPARATIVE-STUDY WITH 2'-CH3-MPTP AND MPTP

Unlike 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which produces consistent decreases in levels of striatal dopamine (DA) with considerably smaller and more variable effects on mouse brain levels of serotonin (5-HT) and norepinephfine (NE), a novel amine-substituted MPTP analogue, 1-methyl-4-(2'-aminophenyl)-1,2,3,6-tetrahydropyridine (2'-NH2-MPTP), administered in a standard mouse dosing paradigm for MPTP (20 mg/kg x 4) did not affect striatal DA but led to marked reductions (60-70%) in levels of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), and NE measured in frontal cortex and hippocampus 1 week after treatment. Another 2'-substituted MPTP analogue, 1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine, affected cortical and hippocampal 5-HT, 5-HIAA, and NE only minimally, while markedly reducing the DA content in striatum (90%), thus indicating that the substituent (-NH2 versus -CH3) at the 2' position is important for the differential effects of these MPTP analogues. In a replication study with a 3-week end point, hippocampal and cortical 5-HT, 5-HIAA, and NE levels remained depressed with no indication of recovery. These results suggest that 2'-NH2-MPTP may be a novel, regionally selective neurotoxin for serotonergic and noradrenergic nerve terminals.