title: Lifelong CRF overproduction is associated with altered gene expression and sensitivity of discrete GABA(A) and mGlu receptor subtypes.
abstract: BACKGROUND
  Repeated activation of corticotropin-releasing factor (CRF) receptors is associated with increased anxiety and enhanced stress responsivity, which may be mediated via limbic GABAergic and glutamatergic transmission.
  
  
  OBJECTIVE
  The present study investigated molecular and functional alterations in GABA(A) receptor (GABA(A)R) and metabotropic glutamate receptor (mGluR) responsivity in transgenic mice that chronically overexpress CRF.
  
  
  METHODS
  CRF(1) receptor, GABA(A)R, and mGluR sensitivity were determined in CRF-overexpressing mice using the stress-induced hyperthermia (SIH) test. In addition, we measured mRNA expression levels of GABA(A)R α subunits and mGluRs in the amygdala and hypothalamus.
  
  
  RESULTS
  CRF-overexpressing mice were less sensitive to the anxiolytic effects of the CRF(1) receptor antagonists CP154,526 and DMP695, the GABA(A)R α(3)-selective agonist TP003 (0-3 mg/kg) and the mGluR(2/3) agonist LY379268 (0-10 mg/kg) in the SIH test. The hypothermic effect of the non-selective GABA(A)R agonist diazepam (0-4 mg/kg) and the α(1)-subunit-selective GABA(A)R agonist zolpidem (0-10 mg/kg) was reduced in CRF-overexpressing mice. No genotype differences were found using the GABA(A)R α(5)-subunit preferential compound SH-053-2'F-R-CH(3) and mGluR(5) antagonists MPEP and MTEP. CRF-overexpressing mice showed decreased expression levels of GABA(A)R α(2) subunit and mGluR(3) mRNA levels in the amygdala, whereas these expression levels were increased in the hypothalamus. CRF-overexpressing mice also showed increased hypothalamic mRNA levels of α(1) and α(5) GABA(A)R subunits.
  
  
  CONCLUSIONS
  We found that lifelong CRF overproduction is associated with altered gene expression and reduced functional sensitivity of discrete GABA(A) and mGluR receptor subtypes. These findings suggest that sustained over-activation of cerebral CRF receptors may contribute to the development of altered stress-related behavior via modulation of GABAergic and glutamatergic transmission.
authors.affiliation: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences and Rudolf Magnus Institute of Neuroscience, Utrecht University, Universiteitsweg 99, 3584CG Utrecht, The Netherlands. c.h.vinkers@uu.nl
authors.forename: Christiaan H
authors.initials: CH
authors.lastname: Vinkers
authors.forename: Hendrikus
authors.initials: H
authors.lastname: Hendriksen
authors.forename: Ruud
authors.initials: R
authors.lastname: van Oorschot
authors.forename: James M
authors.initials: JM
authors.lastname: Cook
authors.forename: Sundari
authors.initials: S
authors.lastname: Rallipalli
authors.forename: Shengming
authors.initials: S
authors.lastname: Huang
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Millan
authors.forename: Berend
authors.initials: B
authors.lastname: Olivier
authors.forename: Lucianne
authors.initials: L
authors.lastname: Groenink
mesh_terms: D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018755:GABA Agonists / Q000494:pharmacology; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D011963:Receptors, GABA-A / Q000502:physiology*; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: C437952:(N-(2-chloro-4,6-dimethylphenyl)-1-(1-methoxymethyl)-(2-methoxymethyl)-6-methyl-1H-1,2,3-triazolo(4,5-c)pyridin-4-amine) mesylate; C101628:CP 154526; D018691:Excitatory Amino Acid Antagonists; D018755:GABA Agonists; D011725:Pyridines; D011743:Pyrimidines; D011758:Pyrroles; D011963:Receptors, GABA-A; D018094:Receptors, Metabotropic Glutamate; D003346:Corticotropin-Releasing Hormone