Ž . Brain Research 786 1998 11–17 Research report A role for brain glucocorticoid receptors in contextual fear conditioning: dependence upon training intensity M. Isabel Cordero, Carmen Sandi ) Department of Psychobiology, UniÕersidad Nacional de Educacion a Distancia, Ciudad UniÕersitaria s r n, 28040 Madrid, Spain Accepted 18 November 1997 Abstract We studied the possible involvement of corticosteroids in the establishment and long-term expression of contextual fear conditioning Ž. and questioned whether a corticosteroid action might be dependent upon stimulus intensity at training. Experiments included: i the intracerebroventricular administration of specific antagonists for the two types of intracellular corticosteroid receptors to rats trained at Ž. either 1 mA or 0.4 mA shock intensity at conditioning; and ii the administration of corticosterone after conditioning rats to 0.2 mA shocks. The results showed that the administration of a type II glucocorticoid, but not a type I mineralocorticoid, receptor antagonist before conditioning rats to the intermediate shock condition attenuated long-term expression of contextual fear conditioning. However, treatment with the antagonists before conditioning to the high shock intensity failed to influence the extent of fear conditioning. In addition, an intraperitoneal corticosterone injection, given immediately after training rats at the low shock intensity, enhanced long-term expression of the fear response. The results support the view that post-training levels of circulating corticosterone, through an interaction with central type II glucocorticoid receptors, modulate the strength to which memory for contextual fear conditioning is established and maintained. q 1998 Elsevier Science B.V. Keywords: RU28318; RU 38486; Corticosterone; Corticosteroid; Learning; Memory; Fear-conditioning; Rat 1. Introduction Adrenal steroid hormones play a key role in the physio- logical and behavioral responses developed by organisms to cope with stressful situations. In addition to their wide range of actions in many physiological systems, corticos- teroids can affect brain function through binding to spe- w w xx cific receptor sites for reviews, see Refs. 18,10 . Classic corticosteroid actions involve the modulation of gene tran- w x scription 1,3 through the binding to two types of intra- cellular receptors, the type I mineralocorticoid receptor and w x the type II or glucocorticoid receptor 35,45 . The intra- cellular receptors differ both in their distribution through- out the brain and the affinity with which endogenous and exogenous steroids bind to them. Thus, whereas mineralo- corticoid receptors are mainly confined to the limbic sys- tem, cerebellum, and certain brain stem neurons, glucocor- ticoid receptors are more widely distributed throughout the brain, although both receptor types are at their highest ) Corresponding author. Fax: q34-1-398-62-87; E-mail: csandi@cu.uned.es w x density in the hippocampus 10,18 . Corticosterone—the naturally occurring glucocorticoid in many animal species, including rats and chicks—binds with approximately 10- fold greater affinity to mineralocorticoid receptors than to glucocorticoid receptors. Thus, in vivo receptor activation w x is defined by the level of circulating corticosterone 10 . A role for corticosteroids in learning and memory pro- w cesses is being increasingly recognised for reviews, see w xx Refs. 16,17,25 . A number of experimental manipulations addressed to interfere either with circulating or cerebral w x corticosteroid levels 4,7,21,23,40,42 or with a cortico- w x steroid receptor action 5,8,23,36–39 , modulated memory formation, supporting the view that a corticosteroid action is required for the information processing and storage involved in certain types of memory. We have recently reported that the modulatory action of manipulating en- dogenous corticosteroid levels is experience-dependent; i.e., the ability of exogenously administered corticosterone to influence memory consolidation was dependent upon the intensity of the unconditional stimulus used in the w x learning situation in a spatial orientation task in rats 42 w x and a passive avoidance test in chicks 40,41 . 0006-8993r98r$19.00 q 1998 Elsevier Science B.V. All rights reserved.