Genetic or pharmacological depletion of cannabinoid CB1 receptor protects against dopaminergic neurotoxicity induced by methamphetamine in mice

Duy Khanh Dang, Eun Joo Shin, Anh Thu Mai, Choon Gon Jang, Seung Yeol Nah, Ji Hoon Jeong, Catherine Ledent, Tsuneyuki Yamamoto, Toshitaka Nabeshima, Emmanuel S. Onaivi, Hyoung Chun Kim

研究成果: Article

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Accumulating evidence suggests that cannabinoid ligands play delicate roles in cell survival and apoptosis decisions, and that cannabinoid CB1 receptors (CB1R) modulate dopaminergic function. However, the role of CB1R in methamphetamine (MA)-induced dopaminergic neurotoxicity in vivo remains elusive. Multiple high doses of MA increased phospho-ERK and CB1R mRNA expressions in the striatum of CB1R (+/+) mice. These increases were attenuated by CB1R antagonists (i.e., AM251 and rimonabant), an ERK inhibitor (U0126), or dopamine D2R antagonist (sulpiride). In addition, treatment with MA resulted in dopaminergic impairments, which were attenuated by CB1R knockout or CB1R antagonists (i.e., AM251 and rimonabant). Consistently, MA-induced oxidative stresses (i.e., protein oxidation, lipid peroxidation and reactive oxygen species) and pro-apoptotic changes (i.e., increases in Bax, cleaved PKCδ- and cleaved caspase 3-expression and decrease in Bcl-2 expression) were observed in the striatum of CB1R (+/+) mice. These toxic effects were attenuated by CB1R knockout or CB1R antagonists. Consistently, treatment with four high doses of CB1R agonists (i.e., WIN 55,212-2 36 mg/kg and ACEA 16 mg/kg) also resulted in significant oxidative stresses, pro-apoptotic changes, and dopaminergic impairments. Since CB1R co-immunoprecipitates PKCδ in the presence of MA or CB1R agonists, we applied PKCδ knockout mice to clarify the role of PKCδ in the neurotoxicity elicited by CB1Rs. CB1R agonist-induced toxic effects were significantly attenuated by CB1R knockout, CB1R antagonists or PKCδ knockout. Therefore, our results suggest that interaction between D2R, ERK and CB1R is critical for MA-induced dopaminergic neurotoxicity and that PKCδ mediates dopaminergic damage induced by high-doses of CB1R agonist.

元の言語English
ページ(範囲)204-224
ページ数21
ジャーナルFree Radical Biology and Medicine
108
DOI
出版物ステータスPublished - 01-07-2017

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All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physiology (medical)

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