Adrenal corticosteroids: Central nervous system targets, mechanisms of action, and glucocorticoid regulation of preproenkephalin-gene expression
Description
Adrenal corticosteroids have diverse effects on central nervous system (CNS) function. These include regulation of the activity of neurotransmitters-modulators, neuro- and gliogenesis, learning and behavior and neuronal and glial survival. Many of these actions are thought to be mediated at least in part, by intracellular corticosteroid receptors. A Type I receptor, which acts as a mineralocorticoid receptor in the peripheral tissues, is selective for endogenous glucocorticoids in most regions of the CNS. A Type II receptor, also known as the classical glucocorticoid receptor has a low affinity and high capacity for endogenous glucocorticoids in the CNS. We mapped corticosteroid targets in the rat CNS using immunocytochemical detection of corticosteroid receptors. Contrary to previous reports of a restricted distribution of Type I receptors, we found that both types of corticosteroid receptors show widespread expression in neurons, and may indeed be coexpressed by some neurons. However, most glia expressed only Type II receptors. The intracellular location of corticosteroid receptors was regulated by corticosterone and aldosterone, the principle glucocorticoid and mineralocorticoid in rats. In the presence of these steroids, both Type I and II receptors showed a predominantly nuclear location, although cytoplasmic receptor was often present. This suggests a largely genomic role for these receptors in the CNS. We also demonstrated regulation of nuclear Type II receptor immunoreactivity (ir) by progesterone and androgenic-anabolic steroids. Our findings corroborated recent reports on cross-regulation of the Type II receptor by these steroids, based largely on binding studies Using double-labeling immunocytochemical techniques, we demonstrated for the first time, colocalization of Type II receptors by subpopulations of GABA-ir cerebellar Purkinje cells and LHRH-neurons. These cells regulate motor and neuroendocrine processes which are affected by circulating glucocorticoids. Most investigators have suggested that effects of glucocorticoids on these systems are largely indirect. By showing that some Purkinje and LHRH cells are potential direct targets for glucocorticoids, we have broadened the scope of possible mechanisms underlying the effects of glucocorticoids. Finally we examined the regulation expression of preproenkephalin (PPE) gene in the forebrain by glucocorticoids. PPE gene has been used as model, especially in vitro, to study direct regulation by glucocorticoids (i.e. corticosteroid receptor-mediated). We extended this concept in vivo, by examining glucocorticoid regulation of PPE gene expression in forebrain regions, which show an overlap in the distribution of PPE and corticosteroid receptors. In all regions analyzed, we found that circulating glucocorticoids were required for basal expression of PPE. Chronically elevated levels increased expression in selected regions, notably the striatum. We suggest that as in in vitro systems, PPE expression in vivo is regulated directly, at least in part, by glucocorticoids