No abstract

The hippocampus is the principal target site in the brain for adrenocortical steroids, as it has the highest concentration of receptor sites for glucocorticoids. The aged rat has a specific deficit in hippocampal glucocorticoid receptors, owing in large part to a loss of corticoid-sensitive neurons. This deficit may be the cause for the failure of aged rats to terminate corticosterone secretion at the end of stress, because extensive lesion and electrical stimulation studies have shown that the hippocampus exerts an inhibitory influence over adrenocortical activity and participates in glucocorticoid feedback. We have studied whether it is the loss of hippocampal neurons or of hippocampal glucocorticoid receptors in the aged rat that contributes most to this syndrome of corticosterone hypersecretion. To do this, we used two model systems for producing reversible glucocorticoid receptor depletion in the hippocampus, and we found that depletion of receptors without inducing cell loss results in corticosterone hypersecretion. Furthermore, correction of the receptor deficit results in normalization of corticosterone secretion. These results focus attention on the hippocampus as an important glucocorticoid sensor in relation to the stress response. They also provide important new physiological correlates for the remarkable plasticity of the hippocampal glucocorticoid receptor system, which is under independent control by corticosterone and by vasopressin.In the mammalian brain, the hippocampus contains the highest concentration of glucocorticoid receptors and retains the highest concentration of [3H]corticosterone after in vivo injection (1). This phenomenon was initially reported in 1968 (2), and considerable speculation still remains regarding the physiological and behavioral significance of the hippocampal uptake system (1, 3). However, the hippocampus has been persistently implicated as an inhibitory influence on the hypothalamic-pituitary-adrenocortical (HPA) axis. Destruction of the hippocampus, for example, leads to hypersecretion of glucocorticoids under basal and stressed conditions (4-9). Furthermore, stimulation of most parts of the structure inhibits stress-induced HPA activation (10-13). At least some of this inhibitory influence of the hippocampus represents mediation of feedback inhibition by glucocorticoids. For example, hippocampectomized subjects are less sensitive to the suppressive effects of exogenous glucocorticoids on HPA secretion (6). Moreover, corticotropin (ACTH) is increased after hippocampectomy and the difference in corticotropin levels between lesioned and sham-lesioned animals is abolished by adrenalectomy, suggesting that the relative increase in corticotropin due to the lesion resulted from lesion-induced disinhibition from corticoid-feedback suppression (5). This evidence that circulating glucocorticoids exert some of their feedback effects via the hippocampus suggests that such actions are mediated by the hippocampal glucocorticoid receptor. Thus, one can postulate that decr...

We have examined whether corticosterone receptor number within the brain can be regulated by its own ligand and whether such autoregulation reduces receptor number after the sustained secretion of corticosterone during repeated stress. Glucocorticoid receptors were measured in cytosolic preparations from acutely adrenalectomized rats using [1,2,6,7-3H] dexamethasone; maximal binding and receptor affinity parameters were determined by Scatchard analysis. Sustained elevations of circulating corticosterone, whether by repeated stress or exogenous corticosterone administration, did not change receptor affinity for [3H]dexamethasone, but significantly reduced cytosolic corticosterone receptor number. This reduction in total receptor number could not be attributed to residual tissue contamination with endogenous corticosterone after adrenalectomy or to translocation of cytosolic receptors to cell nuclei. The receptor reductions were anatomically specific, occurring in the hippocampus and amygdala, but not in the hypothalamus or pituitary, and were limited, in that exogenous corticosterone plus stress reduced receptor number no more than did stress alone. Further, 3 weeks of daily administration of 5 mg corticosterone caused reductions similar to those seen after only 4 days of treatment. Finally, the declines in glucocorticoid receptor number were reversible; receptor concentrations returned to normal levels within 1 week after the cessation of treatment with exogenous corticosterone. Thus, this study presents evidence that glucocorticoid down-regulation may constitute a physiological phenomenon.

Daytime restriction of food and water availability in nocturnal animals phase shifts the circadian periodicity of plasma corticosteroid concentrations and body temperature. These shifted rhythms persist in animals with lesions of the suprachiasmatic nuclei who are arrhythmic under normal conditions. These findings suggest the existence of an additional "clock" that may be involved in the generation of the rhythm.