Biphasic effects of adrenal steroids on learned helplessness behavior induced by inescapable shock.

Corticosterone (CS) has been shown to regulate behavior in the learned helplessness (LH) paradigm. Here we provide evidence for a U-shaped relationship between the increasing doses of CS administered and escape failures in the LH model. Replacement with CS (20-400 microg/ml in drinking water) in adrenalectomized (ADX) animals was utilized to examine how the selective activation of mineralocorticoid (MR) and glucocorticoid (GR) receptors is related to the behavioral impairments induced by inescapable shock (IS). Available MR and GR levels were determined in hippocampal cytosol by radioligand binding assays. Non-CS replaced ADX animals showed a high percentage of escape failures assessed 48 h after IS. A CS does of 100 microg/ml given to ADX animals markedly reduced escape failures and resulted in an almost total reduction of available MR associated with a partial reduction of GR. However, the administration of aldosterone (ALDO), a selective MR agonist, was not sufficient to restore normal coping behavior. Moreover, an important role for GR was further shown by means of the specific GR antagonist, RU 38486, which blocked the reduction of LH in ADX rats that were given 100 microg/ml CS. Higher doses of CS given to ADX rats reinstated the LH behavior, and SHAM rats that produced stress CS levels also produced LH behavior. The results indicate a U-shaped dose response function with both negligible and high CS levels being associated with LH behavior. Hence, along with a moderate reduction of available GR level in the cytosol, a large decrease in MR availability seems to be necessary to prevent the acquisition and expression of LH. However, very high reduction of available GR is associated with LH behavior.