The neurotoxic effects of 1 -methyl-4-(2'-amino-phenyl)-1,2,3,6-tetrahydropyridine (2'-amino-MPTP) on brain serotonin and norepinephrine in mice

The aim of this study was to characterize the effects of 1-methyl-4-(2$\sp\prime$-aminophenyl)-1,2,3,6-tetrahydropyridine (2$\sp\prime$-NH$\sb2$-MPTP) in mouse brain and to begin to explore the mechanism of action of this novel neurotoxin, especially as it compares to the parent compound 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The results indicate that 2$\sp\prime$-NH$\sb2$-MPTP is capable of causing substantial dose-dependent depletions in the monoamine neurotransmitters serotonin and norepinephrine in two different strains of mice. Across all regions analyzed however, 2$\sp\prime$-NH$\sb2$-MPTP had negligible effects on brain dopamine, in sharp contrast with MPTP or 1-methyl-4-(2$\sp\prime $-methylphenyl)-1,2,3,6-tetrahydropyridine (2$\sp\prime$-CH$\sb3$-MPTP), both of which cause relatively selective depletions in striatal dopamine and its metabolites. The effects of 2$\sp\prime$-NH$\sb2$-MPTP on cortical and hippocampal serotonin and norepinephrine were still present 6 months post-treatment as evidenced by a persistent 50% decrease in these brain regions. 2$\sp\prime$-NH$\sb2$-MPTP was also found to have a functionally relevant effect on serotonergic neurotransmission as demonstrated by an attenuated temperature response to pharmacologic challenge with the serotonin agonist m-chlorophenylpiperazine in 2$\sp\prime$-NH$\sb2$-MPTP-treated mice compared to saline-treated mice. Similarities in the mechanism of action between 2$\sp\prime$-NH$\sb2$-MPTP and MPTP were demonstrated even though 2$\sp\prime$-NH$\sb2$-MPTP acts on a different subpopulation of monoaminergic neurons. The decreases in serotonin and norepinephrine caused by 2$\sp\prime$-NH$\sb2$-MPTP were differentially prevented by pretreatment with uptake inhibitors selective for either the serotonergic or noradrenergic transporters, respectively. In addition, the effects of 2$\sp\prime$-NH$\sb2$-MPTP could be blocked by prior inhibition of monoamine oxidase, suggesting that 2$\sp\prime$-NH$\sb2$-MPTP is converted to a toxic metabolite by this endogenous enzyme. Although disturbances in the central serotonergic and noradrenergic transmitter systems are thought to be related to various neuropsychiatric illnesses, much remains to be discovered about the role of these neurotransmitters in normal and dysfunctional behavior. Having a new chemical neurotoxin like 2$\sp\prime$-NH$\sb2$-MPTP which is capable of causing selective long-term toxicity in forebrain serotonin and norepinephrine systems may benefit research efforts aimed at understanding the roles of these neurotransmitters in mammalian brain function.