FosB null mutant mice show enhanced methamphetamine neurotoxicity: potential involvement of FosB in intracellular feedback signaling and astroglial function

Neuropsychopharmacology. 2010 Feb;35(3):641-55. doi: 10.1038/npp.2009.169. Epub 2009 Nov 4.

Abstract

Previous studies show that (1) two members of fos family transcription factors, c-Fos and FosB, are induced in frontal brain regions by methamphetamine; (2) null mutation of c-Fos exacerbates methamphetamine-induced neurotoxicity; and (3) null mutation of FosB enhances behavioral responses to cocaine. Here we sought a role of FosB in responses to methamphetamine by studying FosB null mutant (-/-) mice. After a 10 mg/kg methamphetamine injection, FosB(-/-) mice were more prone to self-injury. Concomitantly, the intracellular feedback regulators of Sprouty and Rad-Gem-Kir (RGK) family transcripts had lower expression profiles in the frontoparietal cortex and striatum of the FosB(-/-) mice. Three days after administration of four 10 mg/kg methamphetamine injections, the frontoparietal cortex and striatum of FosB(-/-) mice contained more degenerated neurons as determined by Fluoro-Jade B staining. The abundance of the small neutral amino acids, serine, alanine, and glycine, was lower and/or was poorly induced after methamphetamine administration in the frontoparietal cortex and striatum of FosB(-/-) mice. In addition, methamphetamine-treated FosB(-/-) frontoparietal and piriform cortices showed more extravasation of immunoglobulin, which is indicative of blood-brain barrier dysfunction. Methamphetamine-induced hyperthermia, brain dopamine content, and loss of tyrosine hydroxylase immunoreactivity in the striatum, however, were not different between genotypes. These data indicate that FosB is involved in thermoregulation-independent protective functions against methamphetamine neurotoxicity in postsynaptic neurons. Our findings suggest two possible mechanisms of FosB-mediated neuroprotection: one is induction of negative feedback regulation within postsynaptic neurons through Sprouty and RGK. Another is supporting astroglial function such as maintenance of the blood-brain barrier, and metabolism of serine and glycine, which are important glial modulators of nerve cells.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / drug effects
  • Astrocytes / physiology*
  • Body Temperature / genetics
  • Body Temperature Regulation / genetics
  • Feedback, Physiological / drug effects
  • Feedback, Physiological / physiology*
  • Intracellular Fluid / drug effects
  • Intracellular Fluid / physiology*
  • Male
  • Methamphetamine / toxicity*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Motor Activity / drug effects
  • Motor Activity / genetics
  • Neurons / physiology
  • Proto-Oncogene Proteins c-fos / deficiency*
  • Proto-Oncogene Proteins c-fos / genetics*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics*
  • Synaptic Transmission / genetics

Substances

  • Fosb protein, mouse
  • Proto-Oncogene Proteins c-fos
  • Methamphetamine