title: Nrf2 gene deletion fails to alter psychostimulant-induced behavior or neurotoxicity.
abstract: The transcription factor NF-E2-related factor (Nrf2) regulates the induction of phase 2 detoxifying enzymes by oxidative stress, including synthesis of the catalytic subunit (xCT) of the heterodimeric cystine-glutamate exchanger (system xc-). Repeated cocaine treatment in rats causes persistent neuroadaptations in glutamate neurotransmission in the nucleus accumbens that result, in part, from reduced activity of system xc-. Since in vitro under- or over-expression of Nrf2 regulates system xc- activity and xCT content, it was hypothesized that in vivo deletion of the Nrf2 gene would: 1) decrease system xc- activity, 2) produce a behavioral phenotype resembling that elicited by chronic cocaine administration, and 3) enhance dopamine depletion after methamphetamine-induced oxidative stress. In all three experiments no genotypic difference was measured between mice sustaining homozygous Nrf2 gene deletion and wild-type littermates. Thus, while Nrf2 is a transcriptional regulator of xCT and capable of protecting cells from oxidative stress, following Nrf2 gene deletion this role can be partially compensated by other mechanisms and methamphetamine-induced oxidative stress and dopamine toxicity does not significantly involve Nrf2.
authors.affiliation: Department of Neurosciences, Medical University of South Carolina, 173 Ashley Avenue, BSB 403C, Charleston, SC 29425, USA. pacchio@musc.edu
authors.forename: Alejandra M
authors.initials: AM
authors.lastname: Pacchioni
authors.forename: Joseph
authors.initials: J
authors.lastname: Vallone
authors.forename: Roberto I
authors.initials: RI
authors.lastname: Melendez
authors.forename: Andy
authors.initials: A
authors.lastname: Shih
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Murphy
authors.forename: Peter W
authors.initials: PW
authors.lastname: Kalivas
mesh_terms: D027182:Amino Acid Transport System y+ / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D003042:Cocaine / Q000633:toxicity*; D019970:Cocaine-Related Disorders / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000633:toxicity; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D018698:Glutamic Acid / Q000378:metabolism; D008694:Methamphetamine / Q000633:toxicity*; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000235:genetics / Q000503:physiopathology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D050436:Regulatory Elements, Transcriptional / Q000187:drug effects / Q000235:genetics
chemical_list: D027182:Amino Acid Transport System y+; D018765:Dopamine Uptake Inhibitors; D051267:NF-E2-Related Factor 2; C492255:Slc7a11 protein, mouse; D018698:Glutamic Acid; D008694:Methamphetamine; D003042:Cocaine; D004298:Dopamine