Role of dopamine D1 receptor in 3-fluoromethamphetamine-induced neurotoxicity in mice

Phuong Tram Nguyen, Eun Joo Shin, Duy Khanh Dang, Hai Quyen Tran, Choon Gon Jang, Ji Hoon Jeong, Yu Jeung Lee, Hyo Jong Lee, Yong Sup Lee, Kiyofumi Yamada, Toshitaka Nabeshima, Hyoung Chun Kim

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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.

Original languageEnglish
Pages (from-to)69-84
Number of pages16
JournalNeurochemistry International
Volume113
DOIs
Publication statusPublished - 01-02-2018

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Dopamine D1 Receptors
Methamphetamine
Sulpiride
Dopamine D2 Receptors
Phenotype
Dopamine
Designer Drugs
Vesicular Monoamine Transport Proteins
Dopamine Agents
Dopamine Plasma Membrane Transport Proteins
Dopamine Antagonists
DNA Nucleotidylexotransferase
Drug and Narcotic Control
Dopamine Receptors
Tyrosine 3-Monooxygenase
Oxidative Stress
Fever
SCH 23390
Mortality

All Science Journal Classification (ASJC) codes

  • Cellular and Molecular Neuroscience
  • Cell Biology

Cite this

Nguyen, P. T., Shin, E. J., Dang, D. K., Tran, H. Q., Jang, C. G., Jeong, J. H., ... Kim, H. C. (2018). Role of dopamine D1 receptor in 3-fluoromethamphetamine-induced neurotoxicity in mice. Neurochemistry International, 113, 69-84. https://doi.org/10.1016/j.neuint.2017.11.017
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. / Role of dopamine D1 receptor in 3-fluoromethamphetamine-induced neurotoxicity in mice. In: Neurochemistry International. 2018 ; Vol. 113. pp. 69-84.
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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.",
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Nguyen, PT, Shin, EJ, Dang, DK, Tran, HQ, Jang, CG, Jeong, JH, Lee, YJ, Lee, HJ, Lee, YS, Yamada, K, Nabeshima, T & Kim, HC 2018, 'Role of dopamine D1 receptor in 3-fluoromethamphetamine-induced neurotoxicity in mice', Neurochemistry International, vol. 113, pp. 69-84. https://doi.org/10.1016/j.neuint.2017.11.017

Role of dopamine D1 receptor in 3-fluoromethamphetamine-induced neurotoxicity in mice. / 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.

In: Neurochemistry International, Vol. 113, 01.02.2018, p. 69-84.

Research output: Contribution to journalArticle

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T1 - Role of dopamine D1 receptor in 3-fluoromethamphetamine-induced neurotoxicity in mice

AU - Nguyen, Phuong Tram

AU - Shin, Eun Joo

AU - Dang, Duy Khanh

AU - Tran, Hai Quyen

AU - Jang, Choon Gon

AU - Jeong, Ji Hoon

AU - Lee, Yu Jeung

AU - Lee, Hyo Jong

AU - Lee, Yong Sup

AU - Yamada, Kiyofumi

AU - Nabeshima, Toshitaka

AU - Kim, Hyoung Chun

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N2 - 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.

AB - 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.

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