Rapid central corticosteroid effects: evidence for membrane glucocorticoid receptors in the brain

Glucocorticoid secretion occurs in a circadian pattern and in response to stress. Among the broad array of glucocorticoid actions are multiple effects in the brain, including negative feedback regulation of hypothalamic hormone secretion. The negative feedback of glucocorticoids occurs on both rapid and delayed time scales, reflecting different regulatory mechanisms. While the slow glucocorticoid effects are widely held to involve regulation of gene transcription, the rapid effects are too fast to invoke genomic mechanisms. We provide a brief overview of multiple lines of evidence for membrane-associated glucocorticoid receptors in the brain, with an emphasis on our recent findings of a rapid, G protein-dependent glucocorticoid action in the rat hypothalamus. We have observed a novel mechanism of rapid glucocorticoid inhibition of parvocellular neuroendocrine cells of the hypothalamic paraventricular nucleus (PVN) mediated by the retrograde release of endocannabinoids and suppression of synaptic glutamate release. This acute glucocorticoid action may underlie the rapid inhibitory effect of glucocorticoids on hypothalamic neuroendocrine function, and provides a potential model for the rapid glucocorticoid effects that occur in several areas of the brain.