2'-NH2-MPTP: A serotonin and norepinephrine neurotoxin

Abstract

Altered serotonin and norepinephrine neurotransmission has been implicated in a variety of psychiatric and neurodegenerative diseases. Selective ablation of these systems represents one avenue for studying their roles in normal behavior, disease processes, and therapeutic interventions. 20-NH2-MPTP, an amine-substituted analog of the dopaminergic neurotoxin MPTP, can be used to degenerate serotonin and/or norepinephrine forebrain innervation to investigate pathophysiological and behavioral consequences in several strains of mice, rats, and nonhuman primates. 2'-NH2-MPTP is converted to a toxic metabolite by monoamine oxidase type-A and type-B. This metabolite, a presumed pyridinium, is a substrate for serotonin and norepinephrine transporters. Acute effects immediately following 2'-NH2-MPTP administration are characteristic of serotonin syndrome. Genetic, biochemical, and immunocytochemical evidence indicates that neurodegeneration caused by 2'-NH2-MPTP is selective, long lasting, and occurs by an oxyradical mechanism.