Regulation of corticosteroid receptor gene expression in depression and antidepressant action

Objective: Major alterations of the hypothalamic-pituitary-adrenocortical ( HPA) system are often seen in patients with depression, and can be reversed by successful antidepressant therapy. Persuasive evidence points to the in volvement of a dysfunctional glucocorticoid receptor system in these change s. The authors developed a transgenic mouse to determine the mechanism for these changes. Design: In vivo and in vitro animal experiments. Animals: Tr ansgenic mice expressing glucocorticoid receptor antisense RNA and control mice. Interventions: In vivo: hormone assays and dexamethasone suppression tests; in vitro: cell transfection, chloramphenicol acetyl transferase assa y, Northern blot analysis, binding assays of cytosolic receptor. Outcome me asures: indicators of depressive disorder in transgenic mice, effect of ant idepressant therapy on dexamethasone binding in transgenic mouse hippocampu s, mouse behaviour, and glucocorticoid receptor activity. Results: Transgen ic mice showed no suppression of corticosterone with a dose of 2 mg per 100 g body weight dexamethasone. Treatment with amitriptyline reduced levels o f corticotropin and corticosterone, increased glucocorticoid receptor mRNA concentrations and glucocorticoid binding capacity of several brain areas, and reversed behavioural changes. In vitro experiments also showed that des ipramine increased glucocorticoid receptor mRNA. Conclusion: These transgen ic mice have numerous neuroendocrine characteristics of human depression as well as altered behaviour. Many of these neuroendocrinologic and behaviour al characteristics are reversed by antidepressants. The antidepressant-indu ced increase in glucocorticoid receptor activity may render the HPA axis mo re sensitive to glucocorticoid feedback. This new insight into antidepressa nt drug action suggests a novel approach to the development of new antidepr essant drugs.