Neurons in the striatum unlike those in the cerebral cortex
Neurons in the striatum, unlike those in the (±)-Bay K 8644 and cerebellum, do not form a layered or columnar structure. Although they appear to be randomly distributed, they are actually scattered in two embryologically different compartments called striosomes (often referred to as “patches” in rodents) and the matrix. The striosome compartment is embryologically older and the “dopamine island,” observed only during development, corresponds to patch/striosome. The matrix develops later and eventually accounts for approximately 85% of the entire striatum (Johnston et al., 1990, Nakamura et al., 2009, Fujiyama et al., 2015). The matrix compartment is densely stained with acetylcholinesterase, and calbindin and somatostatin are expressed at relatively high levels (Graybiel and Ragsdale, 1978, Gerfen, 1992, Fujiyama et al., 2015). The striosome compartment is rich in μ-opioid receptors (Delfs et al., 1994, Mansour et al., 1994, Nakamura et al., 2009, Fujiyama et al., 2015). Granado et al. (2010) provide the first evidence that MA produces a greater loss of TH/DAT-positive terminals in the striosomes than in the matrix, suggesting that the striosomes are differentially affected by MA. They also propose that the increased susceptibility of the striosomal compartment to the damaging effects of MA may be related to a lower antioxidant capacity in striosomes than in matrix (Granado et al., 2010). A similar pattern of greater striosomal damage in the striatum has been observed following administration of MDMA (Granado et al., 2008a, Granado et al., 2008b). Therefore, we raise the possibility that 3-FMA also could induce similar striosomal damage in the striatum. 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 oxidation 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.