Adult rats handled (H) daily for the first 3 weeks of life show a dramatically altered adrenocortical response to stress. We found that H animals secreted less ACTH and corticosterone (B) during and following the termination of stress than did nonhandled (NH) controls. In contrast, H and NH animals did not differ in basal B secretion at any point in the diurnal cycle, nor in adrenocortical responses to exogenously administered oCRF or ACTH. Moreover, the clearance rate for B was similar in H and NH animals. H animals were more sensitive than NH animals to the inhibitory effects of either B or dexamethasone on stress-induced adrenocortical activity. In a dose-response study, both glucocorticoids administered 3 h prior to testing suppressed the adrenocortical response to a 20-min restraint stress to a greater extent in the H animals. Handling increased type II, glucocorticoid receptor binding capacity in the hippocampus of adult animals (∼50% increase in capacity, with no change in affinity). There were no handling-induced changes in type II receptor binding capacity in the hypothalamus or pituitary, nor in type I receptor binding capacity in the hippocampus. Following chronic (5 mg/kg/day) treatment with B, hippocampal type II receptor binding capacity was significantly reduced in the B-treated H animals, compared with saline-treated H animals, and indistinguishable from saline-treated NH animals. Down-regulated H animals, like NH animals, hypersecreted B following the termination of stress in comparison to the saline-treated H animals. These data suggest that the increase in hippocampal type II glucocorticoid receptors is a critical feature for the handling effect on the adrenocortical stress response. The increase in receptors appears to render the H animals more sensitive to the negative feedback effects of the high levels of circulating glucocorticoids, exerting a greater inhibitory control over subsequent adrenocortical activity.

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The present study was aimed at simultaneously determining on the same subject, the effects of stress on retrieval of flexible (contextual or temporal) or stable (spatial) information. Three behavioral paradigms carried out in a four-hole board were designed as follows: (1) Simple Discrimination (SD), in which mice learned a single discrimination; (2) Contextual and Serial Discriminations (CSD), in which mice learned two successive discriminations on two different internal contexts; (3) Spatial Serial Discriminations (SSD), in which mice learned two successive discriminations on an identical internal context. The stressor (three inescapable electric footshocks) was delivered 5 min before retention, occurring 5 min or 24 h after acquisition. Results showed that this stressor increased plasmatic corticosterone levels and fear reactivity in an elevated-plus-maze, as compared with nonstressed mice. The stressor reversed the normal pattern of retrieval observed in nonstressed controls in the CSD task, this effect being context dependent, as it was not observed in the SSD task. Overall, our study shows that stress affected the retrieval of flexible and old information, but spared the retrieval of stable or recent ones. Therefore, these behavioral paradigms allow us to study simultaneously, on the same animal, the effects of stress on distinct forms of memory retrieval.Extensive evidence indicates that stress or pharmacologically induced modifications of the emotional state can influence cognitive function (Kirschbaum et al. 1996;Lupien and McEwen 1997;Belanoff et al. 2001;Wolf et al. 2001). It has been demonstrated that the stress-induced release of glucocorticoids is one of the main factors responsible for these effects. However, glucocorticoids have differential effects depending on the memory phase or the memory system concerned in animal and human subjects (Roozendaal 2002). Glucocorticoids enhance the consolidation of new memories for emotionally arousing experiences (Kovacs et al. 1977;Buchanan and Lovallo 2001), whereas glucocorticoids impair retrieval of long-term spatial memory in rats (De Quervain et al. 1998) and free recall of verbal material in humans (De Quervain et al. 2000;Wolf et al. 2001). Interestingly, even though the modification of the affective state can act on different memory and neurobiological systems (Packard and Cahill 2001), it has been shown that working and declarative memory retrieval are particularly sensitive to glucocorticoids' administration (Lupien et al. 1999;De Quervain et al. 2003).Animal studies have focused mainly on the effects of stress on acquisition, consolidation, and long-term storage of newly acquired information (Lupien and McEwen 1997). Only a few studies have been carried out in animals to determine the effects of stress on retrieval processes (De Quervain et al. 1998;Bats et al. 2001). More specifically, De Quervain et al. (1998) have shown that stress and glucocorticoids impaired retention performance in a water-maze spatial task, as a function of the time interval...