• 2018-07
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  • Impaired dopaminergic systems associated with MA have been w


    Impaired dopaminergic systems associated with MA have been well-documented (Walsh and Wagner, 1992, Kim et al., 1999, Nakajima et al., 2004, Shin et al., 2012, Shin et al., 2017b, Dang et al., 2016, Dang et al., 2017b). Previous reports have suggested that early MA use may be linked to higher risk for Parkinson's disease development (Callaghan et al., 2010, Callaghan et al., 2012, Curtin et al., 2015). Several studies have supported that exposure to MA causes persistent neurotoxicity in dopaminergic neurons, as evidenced by long-term reductions of dopamine transporter (DAT), decreases in the levels of DA and its metabolites, and tyrosine hydroxylase (TH) in the striatum (Yu et al., 2002, Xu et al., 2005, Zhu et al., 2005, Bowyer et al., 2008, Dang et al., 2016, Dang et al., 2017b, Shin et al., 2017a). Escalating evidence suggested that oxidative stress is a critical element in MA neurotoxicity (Jayanthi et al., 1998, Gluck et al., 2001, Iwashita et al., 2004, Shin et al., 2012, Shin et al., 2014, Dang et al., 2016). In addition, previous studies from our group (Shin et al., 2012, Shin et al., 2014, Dang et al., 2016) and others (Deng et al., 1999, Deng et al., 2001, Choi et al., 2002) demonstrated that MA treatment induces terminal deoxynucleotidyl transferase dUDP nick end labeling (TUNEL)-positive Methicillin sodium salt receptor in the striatum. Further, numerous in vivo studies have demonstrated that neurotoxic dose of MA facilitates reactive microgliosis in the nigrostriatal area, possibly leading to neuronal injury (Thomas et al., 2004, Fantegrossi et al., 2008, Sekine et al., 2008, Dang et al., 2016).
    Materials and methods
    Discussion In the present study, we demonstrated that treatment with 3-FMA or MA resulted in hyperthermia, oxidative stress, microglial activation (microglial differentiation into M1 phenotype), and pro-apoptotic changes, followed by dopaminergic impairments (i.e., increase in DA turnover rate, and decreases in TH level, DAT-, and VMAT-2-expression) with behavioral impairments. We observed that dopamine D1 receptor mediates 3-FMA-induced neurotoxicities as well as mortality. In contrast, both dopamine D1 and D2 receptors mediate MA-induced hyperthermia, neurotoxicity and behavioral impairments; however, dopamine D2 receptor activation is more pronounced than dopamine D1 receptor activation in MA-induced neurotoxic consequences. Our finding reflects on the specific role for the dopamine receptors in the neurotoxic effects induced by amphetamine derivatives (Fig. 8). The hyperthermic response appears to be an important factor in the neurotoxicity induced by MA (Bowyer et al., 1994, Albers and Sonsalla, 1995, Farfel and Seiden, 1995). Hyperthermia, at least in part, has been shown to alter DAT function, and thereby increase intracellular accumulation of MA (Xie et al., 2000), promoting production of free radicals in the brain (Kil et al., 1996). The oxidation of DA induced by free radicals might potentiate dopaminergic damage (LaVoie and Hastings, 1999, Spencer et al., 2002). Here we propose that hyperthermia facilitates oxidative stress induced by 3-FMA or MA, which is associated with neurotoxic consequences. Nevertheless, regulation of causes to produce hypothermia or prevent increases in core body temperature are, at least, protective against MA toxicity (Bowyer et al., 1994, Albers and Sonsalla, 1995). Accumulating evidence indicated that genetic or pharmacological inhibition of dopamine D1 or D2 receptor protected against hyperthermia induced by MA (Ito et al., 2008, Granado et al., 2011a, Ares-Santos et al., 2012, Dang et al., 2017a). Consistently, our results showed that dopamine D1 and D2 receptor antagonists protected MA-induced hyperthermia. In particular, the protective effect by dopamine D1 receptor antagonism against hyperthermia induced by 3-FMA was more evident than D2 receptor antagonism. Therefore, it is possible that hyperthermia induced by 3-FMA or MA requires activations of dopamine D1 and/or D2 receptor.