Abstract
Methamphetamine (METH) is a widely abused psychostimulant and a stress-inducing compound, which leads to neurotoxicity for nigrostriatal dopamine (DA) terminals in rodents and primates including humans. In vitro studies indicate that autophagy is a strong modulator of METH toxicity. In detail, suppressing autophagy increases METH toxicity, while stimulating autophagy prevents METH-induced toxicity in cell cultures. In the present study, the role of autophagy was investigated in vivo. In the whole brain, METH alone destroys meso-striatal DA axon terminals, while fairly sparing DA cell bodies within substantia nigra pars compacta (SNpc). No damage to either cell bodies or axons from ventral tegmental area (VTA) is currently documented. According to the hypothesis that ongoing autophagy prevents METH-induced DA toxicity, we tested whether systemic injection of autophagy inhibitors such as asparagine (ASN, 1000 mg/Kg) or glutamine (GLN, 1000 mg/Kg), may extend METH toxicity to DA cell bodies, both within SNpc and VTA, where autophagy was found to be inhibited. When METH (5 mg/Kg × 4, 2 h apart) was administered to C57Bl/6 mice following ASN or GLN, a frank loss of cell bodies takes place within SNpc and a loss of both axons and cell bodies of VTA neurons is documented. These data indicate that, ongoing autophagy protects DA neurons and determines the refractoriness of cell bodies to METH-induced toxicity.
Highlights
Environmental stress leads to deleterious effects on the central nervous system (CNS), where brain dopamine (DA) pathways are mostly affected in both meso-cortico-limbic and meso-striatal systems [1]
Striking parallels exist between stress and methamphetamine (METH) concerning both neurochemistry and neurotoxicity, which witnesses for a deleterious overlapping and synergism between molecular mechanisms operating following both stimuli [7,8,9,10,11,12,13]
Levels, which is concomitant with a decrease in striatal TH immunostaining. These findings are consistent with previous literature, which indicates that in vivo METH produces a damage to DA neurons, which is limited to axon terminals and it is confined to the mesostriatal pathway [8,47,48]
Summary
Environmental stress leads to deleterious effects on the central nervous system (CNS), where brain dopamine (DA) pathways are mostly affected in both meso-cortico-limbic and meso-striatal systems [1]. Striking parallels exist between stress and methamphetamine (METH) concerning both neurochemistry and neurotoxicity, which witnesses for a deleterious overlapping and synergism between molecular mechanisms operating following both stimuli [7,8,9,10,11,12,13]. This explains translational relevance of psychostimulants and stressful agents, which converge on DA transmission [14,15,16,17,18].
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