title: FosB null mutant mice show enhanced methamphetamine neurotoxicity: potential involvement of FosB in intracellular feedback signaling and astroglial function.
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.
authors.affiliation: Unit for Affiliative Social Behavior, RIKEN Brain Science Institute, Saitama, Japan. asbcontact@brain.riken.jp
authors.forename: Kumi O
authors.initials: KO
authors.lastname: Kuroda
authors.forename: Veravej G
authors.initials: VG
authors.lastname: Ornthanalai
authors.forename: Tadafumi
authors.initials: T
authors.lastname: Kato
authors.forename: Niall P
authors.initials: NP
authors.lastname: Murphy
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology*; D001831:Body Temperature / Q000235:genetics; D001833:Body Temperature Regulation / Q000235:genetics; D025461:Feedback, Physiological / Q000187:drug effects / Q000502:physiology*; D007424:Intracellular Fluid / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008694:Methamphetamine / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009474:Neurons / Q000502:physiology; D016760:Proto-Oncogene Proteins c-fos / Q000172:deficiency* / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D009435:Synaptic Transmission / Q000235:genetics
chemical_list: C483819:Fosb protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D008694:Methamphetamine