Roles of steroid hormones and their receptors in structural organization in the nervous system

Paradoxical effects of adrenal steroids on the brain: Protection versus degeneration

The pituitary-adrenal axis participates in the diurnal response of the organism to the environment and in its response to stress. Circulating glucocorticoid and mineralocorticoid hormones act on cells in the brain via Type I and Type II receptors, which operate at the level of gene regulation, and mediate various feedback effects of adrenal steroids on brain chemistry and structure, including the operation of second-messenger generating systems, levels of structural proteins of glial cells, and the death and survival of neurons. The hippocampus is prominent in these effects, and it also displays the highest level of Type I receptors of any brain region. New concepts point to a special role of the hippocampus, a nexus of cognition and emotion, in the feedback actions of adrenal steroids during the diurnal rhythm, and in response to stress. The hippocampus is, therefore, a prime target area for investigation of the events which accompany stress, and which may be related to the maladaptive state that results in depressive illness. Initial studies are described which investigate the effects of tianeptine on pituitary-adrenal function, hippocampal morphology and Type I and Type II receptor levels.

The vulnerability of the hippocampus to protective and destructive effects of glucocorticoids in relation to stress.

Effects of acoustic prepulses on the startle reflex in rats: a parametric analysis

Diurnal Regulation of Glucocorticoid Receptor and Mineralocorticoid Receptor mRNAs in Rat Hippocampus

Neuromodulation: Associative and nonlinear adaptation

Calciam/calmodulin-dependent processes are altered by manipulations of the hypothalamic-pituitary-adrenal axis, and are associated with changes in synaptic efficacy in the hippocampus, such as long-term potentiation. Recent evidence indicates that there are diurnal variations in the threshold for long-term potentiation, as well as diverse effects of the adrenals and of adrenal steroids on electrical activity related to long-term potentiation. In order to probe possible mechanisms underlying these observations, we investigated the effects of the diurnal cycle, as well as adrenalectomy (ADX) and adrenal demedullation on adenylate cyclase activity. In hippocampal, but not cortical, membranes the adenylate cyclase response to calmodulin was higher during the beginning of the dark phase of the cycle, when endogenous corticosterone levels are high. Basal and forskolin-stimulated adenylate cyclase activity did not exhibit diurnal variation in either brain region. ADX (6 and 14 days) depressed the adenylate cyclase response to calmodulin in hippocampal membranes, and abolished the diurnal difference. ADX had smaller effects on this response in cortical membranes. ADX also attenuated basal and forskolin-stimulated adenylate cyclase activity, but these changes were less striking than effects on calmodulin-stimulated activity. Demedullation (14 days), generating corticosterone levels in the low physiological range, mirrored the effects of ADX on hippocampal adenylate cyclase activity. Corticosterone (20 to 25 mug/ml in the drinking water) did not consistently prevent ADX effects on adenylate cyclase activity. These results demonstrate that adrenal effects on adenylate case activity are regionally specific within the brain, and they suggest that other adrenal secretions besides glucocorticoids may be involved in the feedback of the diurnal rhythm on the hippocampus. Taken together with our recent finding that chronic stress or corticosterone injection selectively attenuated the adenylate cyclase response to calmodulin in cortical, but not hippocampal membranes our findings provide further support for a role of the pituitary-adrenal axis in modulating neural calmodulin-dependent adenylate cyclase activity.

Diurnal differences and adrenal involvement in calmodulin stimulation of hippocampal adenylate cyclase activity.

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Neuromodulation: Associative and nonlinear adaptation

Diurnal differences and adrenal involvement in calmodulin stimulation of hippocampal adenylate cyclase activity.