Gender-related differences in the effects of antidepressant imipramine on glucocorticoid receptor binding properties and association with heat shock proteins in the rat liver and kidney

Abstract

Gender-related differences in susceptibility to stress and stress-related disorders such as depression, and in response to treatment with antidepressants have been observed, but the underlying molecular mechanisms are still unknown. Considering the role of glucocorticoid hormones in the systemic reaction against stress and in pathogenesis of depression, the aim of the present work was to study gender-related differences in glucocorticoid signaling and in response of this system to a typical antidepressant drug, imipramine. Gender-related differences in glucocorticoid receptor functional properties were assessed using hepatic and renal whole cell extracts of female and male rats before and after long-term imipramine treatment. The receptor's hormone-binding parameters, B(max) and K(D), were determined by radioligand binding assay, the glucocorticoid receptor and heat shock proteins (Hsp70 and Hsp90) levels by quantitative immunoblotting, and the interaction of these proteins within glucocorticoid receptor heterocomplex by co-immunoprecipitation. Glucocorticoid receptor binding potency (B(max)/K(D) ratio) was significantly higher in males than females both before and after treatment with imipramine. Gender-specific changes in the glucocorticoid receptor binding parameters in the examined tissues were observed in response to imipramine, and were found to be associated with alterations in the receptor interaction with Hsp70 and Hsp90. The results of the study point to sexual dimorphism in the glucocorticoid signaling and imply that glucocorticoid receptor functional alterations contribute to gender-related differences in vulnerability to stress and stress-related disorders, and in response to antidepressant drugs.