AMPHs facilitate dopamine release which further triggers
AMPHs facilitate dopamine release, which further triggers dopamine depletion . Indeed, we observed that repeated treatment of MPA significantly inhibited TH-, DAT-, and VMAT-2 levels. Since DAT and VMAT-2 are important for dopaminergic terminal markers , their decreases suggest that MPA-induced reduction in TH levels is mainly due to dopaminergic degeneration.
Neurons in the striatum, unlike those in the CORM-3 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 [, , ]. The matrix compartment is densely stained with acetylcholinesterase, and calbindin and somatostatin are expressed at relatively high levels [, , ]. The striosome compartment is rich in μ-opioid receptors [74,75,78,79]. Granado et al.  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. A similar pattern of greater striosomal damage in the striatum has been observed following administration of MDMA [81,82]. Therefore, we raise the possibility that MPA also could induce similar striosomal damage in the striatum.
Previous reports have demonstrated that a correlation between behavioral (motor) dysfunctions and dopaminergic impairments may be possible [, , ,12,37,83,84]. In consistent with these reports, current findings suggest that initial oxidative stress, neuroinflammatory, and proapoptotic properties might be critical for inducing dopaminergic degeneration, and behavioral deficits.
Conflicts of interest
Acknowledgements This study was supported by a grant (14182MFDS979) from the Korea Food and Drug Administration, and by Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Science and ICT (#NRF-2017R1A2B1003346), Republic of Korea. 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.
Introduction Dopaminergic pathways in the human brain are integral for behavioral reward, motivation, emotion, and movement coordination. Dysfunction of these circuits has been implicated in many neurological disorders including drug and alcohol dependence, Parkinson’s disease, schizophrenia, and attention deficit hyperactivity disorder (ADHD) [, , , , , , ]. Dopamine receptors are divided into two major types, D1-like (D1 and D5) and D2-like (D2, D3, and D4) , with the D2 family of receptors often targeted by medications that are used clinically to treat neuropsychiatric disorders . The cloning of the dopamine D3 receptor by Sokoloff et al. in 1990  has proven to be an important milestone in dopamine receptor pharmacology. For example, the observation that typical antipsychotics have a higher in vitro binding affinity for D2 versus D3 receptors whereas atypical antipsychotics displayed a similar affinity for both receptor subtypes  implicated the D3 receptor as a target for drug development. The high localization of the D3 receptor in limbic structures in brain [, , , ] and that dopamine had a much higher affinity for the D3 versus D2 receptor , further implicated its role in other neuropsychiatric disorders. However, the high sequence homology in the transmembrane domains (∼80%) [2,3,13], the region thought to bind dopamine and other small molecules, presented a serious challenge towards developing compounds having a high selectivity for the D3 receptor.