Robert M. Sapolsky

Glucocorticoid toxicity in the hippocampus. Temporal aspects of synergy with kainic acid.

Excessive exposure to glucocorticoids can damage neurons of the hippocampus, the principal neural target tissue for the steroid. Glucocorticoids, which are broadly catabolic throughout the body, appear to damage the hippocampus by inducing a metabolic vulnerability in its neurons, impairing their capacity to survive varied neuropathologic challenges which would normally be sublethal. As such, a number of interventions which damage the hippocampus--infusion of an excitotoxin or of an antimetabolite or induction of global ischemia--have their toxicity enhanced in rats with high circulating corticosterone concentrations and attenuated in adrenalectomized animals. The present report examines the temporal parameters with which corticosterone modulates the toxicity of the excitotoxin kainic acid (KA). Rats adrenalectomized and maintained corticosterone-free for 1 week prior to and following microinfusion of KA had minimal volumes of hippocampal damage. Administration of 10 mg/day of corticosterone (which produces circulating concentrations in the upper physiological range for the majority of a day) for as little as 1 day prior to and following KA infusion significantly potentiated damage; increasing periods of exposure to corticosterone bracketing the infusion of the toxin progressively increased damage. Both exposure to corticosterone only during the period prior to KA infusion or only in the aftermath of infusion potentiated damage. Thus, glucocorticoids appear to compromise the capacity of hippocampal neurons to survive KA via both rapid effects (manifest within as little as 24 h) as well as through more persistent actions.

Thyroid Hormones Influence the Development of Hippocampal Glucocorticoid Receptors in the Rat: A Mechanism for the Effects of Postnatal Handling on the Development of the Adrenocortical Stress Response

The role of thyroid hormones on the development of intracellular glucocorticoid receptor concentrations was examined in the hippocampus, hypothalamus, and pituitary of the rat. Adult animals, administered triiodothyronine (T3; 1.0 micrograms/g body weight) on days 1, 2, and 4 of life or thyroxine (T4; 2.5 micrograms/g body weight) on days 1 and 2 of life, had significantly elevated glucocorticoid receptor concentrations in the hippocampus, but not in hypothalamus or pituitary. Adult animals treated with propylthiouracil (PTU; 0.2% in the mothers food), a thyroid hormone synthesis inhibitor, for the first 2 weeks of life showed decreased glucocorticoid receptor concentrations in hippocampus, but not in hypothalamus or pituitary. We then examined whether thyroid hormones might mediate the effects of early stimulation on the development of hippocampal glucocorticoid receptor concentrations. Animals that were handled for 15 min daily (Ha) for the first 2 weeks of life showed increased hippocampal glucocorticoid receptor concentrations as adults compared to nonhandled (NHa) controls. PTU administration blocked the effects of handling, such that Ha/PTU animals showed hippocampal glucocorticoid receptor concentrations that were indistinguishable from those of NHa animals. In contrast, corticosterone administration over the first 2 weeks of life had no effect on adult hippocampal glucocorticoid receptor concentrations. These data suggest that thyroid hormones mediate, in part at least, the development of glucocorticoid receptor concentrations in the hippocampus and that this effect occurs independently of their effects on corticosterone titers.

The adrenocortical axis in the aged rat: Impaired sensitivity to both fast and delayed feedback inhibition ☆

Aged rats secrete excessive amounts of the species-typical glucocorticoid, corticosterone, under basal conditions, following the end of stress and during habituation to mild stressors. Furthermore, the aged rat is resistant to the inhibitory effects of the synthetic glucocorticoid dexamethasone upon subsequent corticosterone secretion. These observations have led to the hypothesis that the aged adrenocortical axis is desensitized to the inhibitory effects of glucocorticoids. In the present study, we have defined this negative-feedback deficit more precisely. The aged adrenocortical axis is subject to both rate-sensitive fast feedback regulation by corticosterone and to level-sensitive delayed feedback. Moreover, there is no age difference in the maximal extent of feedback inhibition which can be attained. However, the sensitivity to both forms of feedback regulation is diminished in aged rats, in that the aged adrenocortical axes are responsive under feedback conditions which completely inhibit corticosterone secretion in young animals. Such insensitivity is likely to underlie the incidences of hyperadrenocorticism apparent in the aged rat; we speculate that progressive degeneration in the aged hippocampus might be the cause of this dampened sensitivity to feedback inhibition.

The effects of postnatal handling on the development of the glucocorticoid receptor systems and stress recovery in the rat

We have examined the effects of postnatal handling of rat pups from Days 1 to 21 on the development of the intracellular, glucocorticoid receptor in the hippocampus, and pituitary transcortin, and corticoid binding globulin in plasma. All animals were sacrificed 10-14h following adrenalectomy and the in vitro receptor assays were performed using 3H dexamethasone (intracellular receptors) or [3H] corticosterone (transcortin and corticoid binding globulin). Early handling resulted in a 30-40% increase in 3H dexamethasone binding (increase in Bmax with no change in Kd) in the hippocampus. In the pituitary handling was associated with a decrease in transcortin binding. There was no effect on plasma corticoid binding globulin. When tested as adults, nonhandled animals hypersecreted corticosterone following the termination of a stressor. This suggests a more efficient adrenocortical negative-feedback system in the handled animals and these data are consistent with previous work on the relationship between hippocampal glucocorticoid receptors and adrenocortical stress recovery.