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  • 2510 Dopaminergic signaling involves a delicate balance betw

    2020-07-31

    Dopaminergic signaling involves a delicate balance between DA release and re-uptake by the pre-synaptic nerve terminal. Normally, neuronal activation promotes vesicular release of DA into the synapse. DAT removes DA from the synapse and VMAT-2 transports cytoplasmic DA into vesicles for storage, and protection from 2510 and reactive consequences (Riddle et al., 2006, Volz et al., 2009). Accordingly, dysfunction of DAT and/or VMAT-2 leads to dopaminergic damage (Riddle et al., 2005). The rapid decrease in DAT activity may be the result of MA-induced ROS, because DAT is especially susceptible to oxidative damage formed after MA administration (Fleckenstein et al., 1997). Our results suggest that the significant depletion of DA terminal markers (TH, DAT and VMAT-2) induced by 3-FMA or MA may reflect oxidative stress and neuroinflammation as cascade of events leading to DA terminal damage. We (Shin et al., 2012, Shin et al., 2014, Dang et al., 2017a) and others (Itoh et al., 1987, Chen et al., 2012, Ares-Santos et al., 2014) demonstrated that treatment with MA resulted in motor impairments in mice. Clinical evidences also indicated that the relationship between motor performance and MA-induced psychiatric effects in adolescent abusers (King et al., 2010, Moratalla et al., 2017). This behavioral losses may result from impaired dopaminergic system (Grace et al., 2010). Previous reports demonstrated that a possible correlation between a reduction in behavioral activity and the degree of striatal DA loss (Lenard and Beer, 1975, Jung et al., 2010). These reports indicated that behavioral impairments occur after a significant reduction in the striatal dopamine level. Although it remains to be futher eluciated, we raise the possibility that initial oxidative stress, neuroinflammation and the condition of impaired phosphorylation of TH (Dang et al., 2015) are prerequisite for dopaminergic neuronal dysfunction and behavioral deficits. Henley et al. (1989) investigated the anatomical localization of glutamate receptor subtype-selective ligand binding sites in chick brain using quantitative autoradiography. It has been demonstrated that [3H]l-glutamate binding is densely localized in the telencephalon, particularly in the neostriatum (Henley et al., 1989). A recent study demonstrated that MA induced decreases in transcript and protein expression of glutamate receptors, which are associated with decreased glutamatergic responses in striatal neurons (Jayanthi et al., 2014). Therefore, the precise role of glutamate receptors in the neurotoxic effects of 3-FMA remains to be determined.
    Conclusion
    Conflicts of interest
    Acknowledgements This study was supported by a grant (14182MFDS979) from the Korea Food and Drug Administration, by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (#NRF-2017R1A2B1003346), Republic of Korea, and by a grant (17H04252) from the Japan Society for the Promotion of Science (JSPS). Phuong-Tram Nguyen, Duy-Khanh Dang and Hai-Quyen Tran were supported by the BK21 PLUS program, National Research Foundation of Korea, Republic of Korea. Equipment at the Institute of New Drug Development Research (Kangwon National University) was used for this study. The English in this document has been checked by at least two professional editors, both native speakers of English.