GCs are the major hormone secreted during stress and we show that a variety of stressors, both physical and psychological, influenced CBG mRNA levels in vivo. In addition, we found that the severity of the stressor modulated the amplitude of the response. Specifically, voluntary running, considered the least stressful intervention, showed little effect on hepatic CBG mRNA expression, while both of the involuntary stressors, swimming and restraint, resulted in a significant inhibition of CBG mRNA. The psychological stress Nomifensine Maleate induced through restraint of the rats, considered the most stressful event, showed the highest inhibition of rat CBG mRNA expression. These results suggest that the severity of the stressor influences the degree of CBG expression modulation, and that stress affects CBG expression at a transcriptional level. This is in agreement with earlier reports for both rats and humans. During stress endogenous GCs are released from the adrenals due to the activation of the hypothalamic-pituitary-adrenal axis and the resulting increased circulating levels of GCs are believed to be responsible for the inhibition of CBG expression. In support of the fact that GCs directly regulate CBG expression, we Flufenamic acid observed that treatment with the potent GC, DEX, on its own resulted in a significant decrease in both CBG mRNA and protein levels in hepatoma cell lines. This is in agreement with a previous study showing that in rats treated with DEX for 48 hrs, hepatic CBG mRNA levels and CBG serum protein concentrations were significantly decreased. Having shown that stress, and specifically GCs, repress CBG levels we determined that the effect is mediated by the GR, the ligand-activated transcription factor required for the intracellular effects of GCs. Specifically, we showed that overexpression of GR potentiated the DEX-induced repression of CBG, whereas co-treatment with the GR antagonist, RU486, attenuated DEX-mediated repression of a Cbg promoter construct. Furthermore, recruitment of the GR to the Cbg gene promoter increased in response to DEX.