Nrf2 gene deletion fails to alter psychostimulant-induced behavior or neurotoxicity

Brain Res. 2007 Jan 5;1127(1):26-35. doi: 10.1016/j.brainres.2006.10.036. Epub 2006 Nov 17.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Transport System y+ / metabolism
  • Animals
  • Brain / drug effects*
  • Brain / metabolism
  • Brain / physiopathology
  • Cocaine / toxicity*
  • Cocaine-Related Disorders / genetics*
  • Cocaine-Related Disorders / metabolism
  • Cocaine-Related Disorders / physiopathology
  • Disease Models, Animal
  • Dopamine / metabolism
  • Dopamine Uptake Inhibitors / toxicity
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Glutamic Acid / metabolism
  • Methamphetamine / toxicity*
  • Mice
  • Mice, Knockout
  • NF-E2-Related Factor 2 / genetics*
  • Nerve Degeneration / chemically induced*
  • Nerve Degeneration / genetics
  • Nerve Degeneration / physiopathology
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / metabolism
  • Nucleus Accumbens / physiopathology
  • Oxidative Stress / drug effects
  • Oxidative Stress / genetics
  • Regulatory Elements, Transcriptional / drug effects
  • Regulatory Elements, Transcriptional / genetics

Substances

  • Amino Acid Transport System y+
  • Dopamine Uptake Inhibitors
  • NF-E2-Related Factor 2
  • Slc7a11 protein, mouse
  • Glutamic Acid
  • Methamphetamine
  • Cocaine
  • Dopamine