Role of dopamine D1 receptor in 3-fluoromethamphetamine-induced neurotoxicity in mice. (February 2018)

• Record Type: Journal Article
• Authors: Nguyen, Phuong-Tram; Shin, Eun-Joo; Dang, Duy-Khanh; Tran, Hai-Quyen; Jang, Choon-Gon; Jeong, Ji Hoon; Lee, Yu Jeung; Lee, Hyo Jong; Lee, Yong Sup; Yamada, Kiyofumi; Nabeshima, Toshitaka; Kim, Hyoung-Chun
• Is Part Of: Neurochemistry international. Volume 113(2017)
• Page Start: 69
• Page End: 84
• Publication Date: 2018-02
• Subjects: 3-Fluoromethamphetamine -- Dopaminergic deficits -- Striatum -- Dopamine receptors -- Oxidative stress -- Apoptosis; Neurochemistry -- Periodicals; Neurochemistry -- Periodicals; Neurochimie -- Périodiques; Neurochemistry; Periodicals; 612.804205
• DOI: 10.1016/j.neuint.2017.11.017
• Languages: English
• ISSNs: 0197-0186

Abstract

Abstract: 3-Fluoromethamphetamine (3-FMA) is an illegal designer drug of methamphetamine (MA) derivative. Up to date, little is known about the neurotoxic potential of 3-FMA. In the present study, we investigated the role of dopamine receptors in neurotoxicity induced by 3-FMA in comparison with MA (35 mg/kg, i.p.) as a control drug. Here we found that 3-FMA (40, 60 or 80 mg/kg, i.p.) produced mortality in a dose-dependent manner in mice. Treatment with 3-FMA (40 mg/kg, i.p.) resulted in significant hyperthermia, oxidative stress and microgliosis (microglial differentiation into M1 phenotype) followed by pro-apoptotic changes and the induction of terminal deoxynucleotidyl transferase dUDP nick end labeling (TUNEL)-positive cells. Moreover, 3-FMA significantly produced dopaminergic impairments [i.e., increase in dopamine (DA) turnover rate and decreases in DA level, and in the expression of tyrosine hydroxylase (TH), dopamine transporter (DAT), and vesicular monoamine transporter 2 (VMAT-2)] with behavioral impairments. These dopaminergic neurotoxic effects of 3-FMA were comparable to those of MA. SCH23390, a dopamine D1 receptor antagonist, but not sulpiride, a dopamine D2 receptor antagonist significantly attenuated 3-FMA-induced neurotoxicity. Although both SCH23390 and sulpiride attenuated MA-induced dopaminergic neurotoxicity, sulpiride is more effective than SCH23390 on the dopaminergic neurotoxicity. Interestingly, SCH23390 treatment positively modulated 3-FMA-induced microglial activation (i.e., SCH23390 inhibited M1 phenotype from 3-FMA insult, but activated M2 phenotype). Therefore, our results suggest that the activation of dopamine D1 receptor is critical to 3-FMA-induced neurotoxicity, while both dopamine D1 and D2 receptors (dopamine D2 receptor > dopamine D1 receptor) mediate MA-induced dopaminergic neurotoxicity. Graphical abstract: Highlights: 3-FMA facilitates mortality in a dose-dependent manner. 3-FMA-induced initial oxidative burdens are prerequisite for the neurotoxicity. D1R facilitates microglial and pro-apoptotic changes induced by 3-FMA. D1R mediates dopaminergic impairments induced by 3-FMA. The neurotoxicity induced by 3-FMA are comparable to that induced by MA.