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 norepinephrine (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.
Andrews
A M
AM
Laboratory of Clinical Science, National Institute of Mental Health, Bethesda, Maryland 20892.
Murphy
D L
DL
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009638:Norepinephrine / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D014018:Tissue Distribution
D015259:Dopamine Agents; C048977:1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine; C079794:1-methyl-4-(2'-aminophenyl)-1,2,3,6-tetrahydropyridine; D012701:Serotonin; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D004298:Dopamine; D009638:Norepinephrine