Lifelong CRF overproduction is associated with altered gene expression and sensitivity of discrete GABA A and mGlu receptor subtypes

Abstract

Rationale: 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 AR) and metabotropic glutamate receptor (mGluR) responsivity in transgenic mice that chronically overexpress CRF. Methods: CRF 1 receptor, GABA AR, 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 AR 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 AR 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 AR agonist diazepam (0-4 mg/kg) and the α 1-subunit-selective GABA AR agonist zolpidem (0-10 mg/kg) was reduced in CRF-overexpressing mice. No genotype differences were found using the GABA AR 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 AR 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 AR 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. © 2011 The Author(s).