[Influence of chronic variable stress (CVS) on the association of glucocorticoid receptor with heat-shock protein (HSP) 90 in rat hippocampus].

Dysregulation in the negative feedback of the hypothalamus-pituitary-adrenal (HPA) system is observed in a subgroup of major depression. Recent studies have postulated that tricyclic antidepressant treatment increases the glucocorticoid receptor (GR) in the brain and that such GR up-regulation normalizes the hyperactivity of HPA systems. The GR is associated with heat-shock proteins (HSPs) as a functional complex with a high affinity for steroid binding. In this study, we have examined the effects of chronic fixed (restraint) stress (CFS) and chronic variable stress (CVS) on the subcellular localization of GR and HSP90 in rat hippocampus using an immunoblotting procedure. A single restraint stress for 1-2 h and a single treatment with dexamethasone (DEX) 0.5 mg/kg, s.c. induced a translocation of the cytosolic GR to nuclei. Long-term treatment with DEX 0.1 mg/kg, s.c. for 14 days caused a significant decrease in both cytosolic and nucleic GR. There was no significant change in either cytosolic or nucleic GR after CFS for 14 days. However, CVS for 14 days increased both cytosolic GRs and HSP90 while nucleic GR was not changed. CFS for 14 days had no influence on the DEX-induced translocation of GR to nuclei, whereas GR translocation by DEX was not observed after CVS for 14 days. Gel filtration chromatography of the hippocampal cytosol after CVS indicated an increase in monomeric GR (approximately 90 kDa) and a decrease in the GR-HSP complex (approximately 300 kDa). Since CVS has been reported to increase serum corticosterone in rats, our results suggest that CVS prevents formation of the GR-HSP complex. A new intracellular environment rather than excessive serum corticosterone caused by CVS may contribute to inhibition of the formation of GR-HSP complex. It is proposed that the CVS could be an appropriate model for disturbance in the negative feedback control of HPA systems.