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

Abstract

RationaleRepeated 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.ObjectiveThe present study investigated molecular and functional alterations in GABAA receptor (GABAAR) and metabotropic glutamate receptor (mGluR) responsivity in transgenic mice that chronically overexpress CRF.MethodsCRF1 receptor, GABAAR, and mGluR sensitivity were determined in CRF-overexpressing mice using the stress-induced hyperthermia (SIH) test. In addition, we measured mRNA expression levels of GABAAR α subunits and mGluRs in the amygdala and hypothalamus.ResultsCRF-overexpressing mice were less sensitive to the anxiolytic effects of the CRF1 receptor antagonists CP154,526 and DMP695, the GABAAR α3-selective agonist TP003 (0–3 mg/kg) and the mGluR2/3 agonist LY379268 (0–10 mg/kg) in the SIH test. The hypothermic effect of the non-selective GABAAR agonist diazepam (0–4 mg/kg) and the α1-subunit-selective GABAAR agonist zolpidem (0–10 mg/kg) was reduced in CRF-overexpressing mice. No genotype differences were found using the GABAAR α5-subunit preferential compound SH-053-2′F-R-CH3 and mGluR5 antagonists MPEP and MTEP. CRF-overexpressing mice showed decreased expression levels of GABAAR α2 subunit and mGluR3 mRNA levels in the amygdala, whereas these expression levels were increased in the hypothalamus. CRF-overexpressing mice also showed increased hypothalamic mRNA levels of α1 and α5 GABAAR subunits.ConclusionsWe found that lifelong CRF overproduction is associated with altered gene expression and reduced functional sensitivity of discrete GABAA 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.