Elsevier

Neuroscience

Volume 189, 25 August 2011, Pages 277-285
Neuroscience

Neurodegeneration, Neuroprotection, and Disease-Oriented Neuroscience
Research Paper
Impact of methamphetamine on dopamine neurons in primates is dependent on age: implications for development of Parkinson's disease

https://doi.org/10.1016/j.neuroscience.2011.05.046Get rights and content

Abstract

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.

Highlights

▶Impact of methamphetamine on primate dopamine neurons during development is examined. ▶At mid-gestation and as adults, dopamine neurons are sensitive to methamphetamine. ▶In the young monkey, dopamine neurons are resistant to methamphetamine. ▶3 h after a dose of methamphetamine, drug levels are highest in young monkeys. ▶GDNF production is stimulated by methamphetamine in young, but not adult, monkeys.

Section snippets

Animals

African green monkeys (Chlorocebus sabaeus) were housed and treated at the St. Kitts Biomedical Research Foundation, an AAALAC accredited facility. The gestational age of fetal monkeys was estimated by ultrasonography (Morrow et al., 2005). The gestation period in this species is approximately 165 days. Studies were carried out in accordance with the National Institutes of Health Guide for the Care and Use on Animals. All studies were approved by the IACUC of both Yale University and St. Kitts

Experiment 1: age-dependent effect of methamphetamine on striatal TH-ir and DA concentration

Treatment with methamphetamine reduced TH-ir OD in all striatal subregions examined in adult male monkeys compared with controls (Fig. 1, Fig. 2, F(1,18)=90.55, P<0.0001). This effect was significantly larger in the caudate nucleus (70% loss) and putamen (63%) compared with nucleus accumbens (40%) (F(2,18)=6.86, P=0.006). A similar effect of methamphetamine on striatal TH-ir OD was noted in mid-gestational fetal monkeys. Treatment in utero with methamphetamine resulted in a lower OD of TH-ir in

Discussion

The results from these studies indicate that during development, primate nigrostriatal DA neurons have differing sensitivity to methamphetamine, as indicated by a loss of striatal TH immunoreactivity and DA concentration, which is believed to be instigated by oxidative stress. Specifically, mid-gestational and mature nigrostriatal DA neurons both displayed marked vulnerability to methamphetamine, yet early in life these neurons were resistant to damage. The protection of young DA neurons from

Conclusions

Several novel observations are reported here. Nigrostriatal DA neurons from fetal and adult monkeys are sensitive to the DA-depleting effects of methamphetamine, which previous evidence indicates is exerted by oxidative stress. On the other hand, DA neurons from young animals are resistant to methamphetamine effects on nigrostriatal DA terminals, despite evidence that striatal levels of the drug were higher than in adults. Data were obtained to suggest that elevated striatal GDNF concentration

Acknowledgments

This work was supported by grant NS056181 from NINDS. We thank Feng-Pei Chen and Dorothy Cameron for their excellent technical work, and the following members of the St Kitts Biomedical Research Foundation staff for their invaluable assistance in animal treatments and excellent care of the animals: Dr. Rodrigo Valles, Alexis Nisbett, Dr. Milton C. Whittaker, Ernell Nisbett, Clive Wilson, and David Charles.

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