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

J Neurochem. 1993 Mar;60(3):1167-70. doi: 10.1111/j.1471-4159.1993.tb03271.x.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / analogs & derivatives*
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / pharmacology
  • Animals
  • Brain / metabolism*
  • Cerebral Cortex / metabolism
  • Corpus Striatum / metabolism
  • Dopamine / metabolism*
  • Dopamine Agents / pharmacology
  • Hippocampus / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Norepinephrine / metabolism*
  • Serotonin / metabolism*
  • Tissue Distribution

Substances

  • Dopamine Agents
  • 1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine
  • 1-methyl-4-(2'-aminophenyl)-1,2,3,6-tetrahydropyridine
  • Serotonin
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Dopamine
  • Norepinephrine