Age- and duration-dependent effects of MPTP on cortical serotonin systems

▸ MPTP produced decreases in striatal DA which partially recovered 18 months later. ▸ By contrast, striatal 5-HT was increased 18 months after MPTP treatment. ▸ In the cortex, decreases in NE were transient but those in 5-HT were long-lasting. ▸ Only striatal DA and NE exhibited age-related vulnerability to MPTP. ▸ 5-HT neurons lack the plasticity exhibited by DA neurons to MPTP toxicity. It has been well established that aging is the most prominent risk factor for PD. In the MPTP mouse model which has been widely used to study PD, studies have shown that MPTP exhibits its neurotoxic effects on the dopaminergic system in an age-dependent manner. Although it is recognized the serotonergic system is impacted in PD, how aging influences serotonergic neurodegeneration in PD has not been adequately investigated. In the present studies, we examined the long-term effects of MPTP treatment on regional concentrations of dopamine (DA), serotonin (5-HT) and norepinephrine (NE) in the striatum and prefrontal cortex (PFC). We also determined if there are differences in the age-dependent vulnerability of the monoaminergic system to MPTP. In young (3-month-old) mice, MPTP produced significant decreases in striatal DA but no changes in striatal 5-HT and NE three weeks after MPTP treatment. There was partial recovery of striatal DA concentrations 18 months later. This was accompanied by elevated striatal 5-HT. In the PFC, NE was decreased but there was complete recovery 18 months later. By contrast, we observed a long-term decrease in prefrontal 5-HT with no recovery of 5-HT concentrations 18 months after MPTP treatment. Striatal DA and NE but not 5-HT neurons exhibited age-dependent vulnerability to MPTP. Aging had no influence on the neurotoxic effects of MPTP in the PFC. Thus, there is divergence in the response of DA and 5-HT systems to MPTP neurotoxicity.