title: Genetic or pharmacological depletion of cannabinoid CB1 receptor protects against dopaminergic neurotoxicity induced by methamphetamine in mice.
abstract: 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 36mg/kg and ACEA 16mg/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.
authors.affiliation: Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 24341, Republic of Korea.
authors.forename: Duy-Khanh
authors.initials: DK
authors.lastname: Dang
authors.affiliation: Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 24341, Republic of Korea.
authors.forename: Eun-Joo
authors.initials: EJ
authors.lastname: Shin
authors.affiliation: Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 24341, Republic of Korea.
authors.forename: Anh-Thu
authors.initials: AT
authors.lastname: Mai
authors.affiliation: Department of Pharmacology, School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea.
authors.forename: Choon-Gon
authors.initials: CG
authors.lastname: Jang
authors.affiliation: Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine, Konkuk University, Seoul 05029, Republic of Korea.
authors.forename: Seung-Yeol
authors.initials: SY
authors.lastname: Nah
authors.affiliation: Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul 06974, Republic of Korea.
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Jeong
authors.affiliation: IRIBHM, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Catherine
authors.initials: C
authors.lastname: Ledent
authors.affiliation: Department of Pharmacology, Faculty of Pharmaceutical Sciences, Nagasaki International University, Nagasaki 859-3298, Japan.
authors.forename: Tsuneyuki
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Nabeshima Laboratory, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya 468-8503, Japan.
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Nabeshima
authors.affiliation: Department of Biology, William Paterson University, Wayne, NJ 07470, USA.
authors.forename: Emmanuel S
authors.initials: ES
authors.lastname: Onaivi
authors.affiliation: Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 24341, Republic of Korea. Electronic address: kimhc@kangwon.ac.kr.
authors.forename: Hyoung-Chun
authors.initials: HC
authors.lastname: Kim
mesh_terms: D000818:Animals; D017209:Apoptosis; D002070:Butadienes / Q000494:pharmacology; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000378:metabolism* / Q000473:pathology; D004298:Dopamine / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008694:Methamphetamine / Q000008:administration & dosage*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020258:Neurotoxicity Syndromes / Q000235:genetics / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D018384:Oxidative Stress; D010880:Piperidines / Q000494:pharmacology; D051745:Protein Kinase C-delta / Q000235:genetics / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D000077285:Rimonabant; D013469:Sulpiride / Q000494:pharmacology
chemical_list: D002070:Butadienes; C000600618:DRD2 protein, mouse; D009570:Nitriles; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D017448:Receptors, Dopamine D2; C113580:U 0126; C103505:AM 251; D008694:Methamphetamine; D013469:Sulpiride; D051745:Protein Kinase C-delta; D048049:Extracellular Signal-Regulated MAP Kinases; D000077285:Rimonabant; D004298:Dopamine
keywords: Apoptosis; Dopamine D2 receptor, ERK, cannabinoid CB1 receptor; Dopaminergic and behavioral impairments; Methamphetamine; Oxidative stress; PKCδ; Striatum