Neurodegeneration, Neuroprotection, and Disease-Oriented NeuroscienceResearch PaperImpact of methamphetamine on dopamine neurons in primates is dependent on age: implications for development of Parkinson's disease
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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Classic and evolving animal models in Parkinson's disease
2020, Pharmacology Biochemistry and BehaviorPKCδ-dependent p47phox activation mediates methamphetamine-induced dopaminergic neurotoxicity
2018, Free Radical Biology and MedicineCitation Excerpt :However, different and conflicting effects of PKCs on apoptosis in various model systems have made it difficult to define their role in toxicity [5]. It has been well-recognized that high doses of methamphetamine (MA) result in impaired dopaminergic systems in rodents [6–10] and primates [11]. Although the pathogenesis of the MA-induced dopaminergic neurotoxicity remains to be further elucidated, this neurotoxicity may be, at least in part, related to oxidative stress [9,10,12–16], inflammatory changes [10,12,17,18], and pro-apoptosis [10,15,16,19–22].
Prenatal methamphetamine exposure is associated with reduced subcortical volumes in neonates
2018, Neurotoxicology and TeratologyCitation Excerpt :Methamphetamine exposure appears to have differential effects on dopamine neurons depending on the age at which exposure occurs (Morrow et al., 2011); in non-human primates in the second gestational trimester, neurons of the nigrostriatal pathway have been shown to be particularly vulnerable to methamphetamine-induced damage (Morrow et al., 2011). During this period primate dopamine neurons undergo natural cell death as part of the normal development and maturation of the neuronal population (Morrow et al., 2007), and it has been hypothesised that this might render them more highly susceptible to damage (Morrow et al., 2011). To our knowledge, this is the first study in which reductions in volume of subcortical structures is demonstrated in neonates with prenatal methamphetamine exposure.