title: Hyper-phosphorylation of GSK-3β: possible roles in chlorpyrifos-induced behavioral alterations in animal model of depression.
abstract: In recent years, the widespread use of chlorpyrifos (CPF) has aroused concerns regarding its potential neurotoxic effects, especially in developing individuals. One of the major consequences of CPF exposure is mood disorders such as depression. Epidemiological studies have demonstrated susceptibility to depression in populations with a history of CPF exposure. Our previous study indicated that repeated CPF exposure in doses from 10 to 160 mg/kg elicits depression- and anxiety-like alterations. However, whether this alteration is due to persistent inhibition of acetylcholinesterase (AChE) was not determined. In this study, we used lower doses of CPF to avoid evident inhibition of AChE to investigate other potential target systems that contribute to CPF's neurotoxic effect. Four-week-old adolescent male rats were repeatedly exposed to CPF at doses of 2.5, 5, or 10mg/kg (s.c., 10 days) and then were subjected to either neurobehavioral testing or immunoblot analysis. Depression-like behaviors as manifested by increased immobility time was observed in force swimming test, while immunoblot analysis revealed a dramatically increased phosphorylation of glycogen synthase kinase-3β (GSK-3β) in the hippocampus and striatum, with no effect on the levels of Wnt2, GSK-3β, or β-catenin. These results suggest a noncholinergic mechanism, the hyper-phosphorylation of GSK-3β, which may contribute to the cellular neurotoxicity of CPF, thus increasing the susceptibility to mood disorders.
authors.affiliation: Department of New Drug Evaluation, Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing 100850, PR China.
authors.forename: Wen-Qiang
authors.initials: WQ
authors.lastname: Chen
authors.forename: Hao
authors.initials: H
authors.lastname: Ma
authors.forename: Jia-Ming
authors.initials: JM
authors.lastname: Bian
authors.forename: You-Zhi
authors.initials: YZ
authors.lastname: Zhang
authors.forename: Jin
authors.initials: J
authors.lastname: Li
mesh_terms: D000818:Animals; D004390:Chlorpyrifos / Q000633:toxicity*; D003342:Corpus Striatum / Q000378:metabolism; D003863:Depression / Q000139:chemically induced / Q000523:psychology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000378:metabolism; D007306:Insecticides / Q000633:toxicity*; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D051154:Wnt2 Protein / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D007306:Insecticides; D051154:Wnt2 Protein; D051176:beta Catenin; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D004390:Chlorpyrifos