Impact of methamphetamine on dopamine neurons in primates is dependent on age: implications for development of Parkinson's disease.

Methamphetamine is a CNS stimulant with limited therapeutic indications, but is widely abused. Short-term exposure to higher doses, or long-term exposure to lower doses, of methamphetamine induces lasting damage to nigrostriatal dopamine neurons in man and animals. Strong evidence indicates that the mechanism for this detrimental effect on dopamine neurons involves oxidative stress exerted by reactive oxygen species. This study investigates the relative susceptibility of dopamine neurons in mid-gestation, young, and adult (not aged) monkeys to four treatments with methamphetamine over 2 days. Primate dopamine neurons undergo natural cell death at mid-gestation, and we hypothesized that during this event they are particularly vulnerable to oxidative stress. The results indicated that at mid-gestation and in adults, dopamine neurons were susceptible to methamphetamine-induced damage, as indicated by loss of striatal tyrosine hydroxylase (TH) immunoreactivity and dopamine concentration. However, dopamine neurons in young animals appeared totally resistant to the treatment, despite this group having higher brain levels of methamphetamine 3 h after administration than the adults. As a possible explanation for the protection, striatal glial-derived neurotrophic factor (GDNF) levels were elevated in young animals 1 week after treatment, but not in adults following methamphetamine treatment. Implications of these primate studies are: (1) the susceptibility of dopamine neurons at mid-gestation to methamphetamine warns against the risk of exposing pregnant women to the drug or oxidative stressors, and supports the hypothesis of Parkinson's disease being associated with oxidative stress during development, (2) elucidation of the mechanism of resistance of dopamine neurons in the young animals to methamphetamine-induced oxidative stress may provide targets for slowing or preventing age- or disease-related loss of adult nigrostriatal dopamine (DA) neurons, and (3) the increased striatal production of GDNF in young animals, but not in adults, in response to methamphetamine, suggests the possibility of an age-related change in the neurotrophic capacity of the striatal dopamine system.