Chronic stress differentially regulates glucocorticoid negative feedback response in rats

Exposure to chronic stress is thought to play an important role in the etio logy of depression. In this disorder, a disrupted negative feedback respons e to exogenous glucocorticoids on cortisol secretion has been indicated. Ho wever, the regulation of glucocorticoid negative feedback by chronic stress is not fully understood. In the present study, we investigated the effects of chronic stress administered by water immersion and restraint (2 h/day) for four weeks on the glucocorticoid feedback in rats. In the acutely (one- time) stressed rats, the basal plasma corticosterone (CORT) level was marke dly elevated, remained at high levels for 5 h after the termination of stre ss, and then decreased. In the chronically stressed rats, the CORT level wa s initially elevated similarly, but rapidly decreased at 2 h. In the dexame thasone (DEX) suppression test, the peak CORT level in response to stress w as not suppressed by DEX in the acutely stressed rats, but was significantl y suppressed in the chronically stressed rats. In contrast, the suppressive effects of DEX on the basal CORT secretion in naive rats were attenuated i n the chronically stressed rats. In the chronically stressed hippocampus, w hich plays an important role in the regulation of the glucocorticoid feedba ck response, the binding of [H-3]DEX was decreased and the increased respon se of activator protein-1 induced by acute stress was abolished. These resu lts suggest that chronic stress induces a hypersuppressive state for induce d CORT secretion in response to acute stress, which is caused by partial ha bituation, coping, and adaptation to the stressor, whereas it induces a hyp osuppressive state for the basal CORT secretion, which is caused by glucoco rticoid receptor downregulation. These mechanisms may be involved in the st ress-induced neural abnormalities observed in depression. (C) 2001 Elsevier Science Ltd. All rights reserved.