NEUROENDOCRINE CONTROL OF THE STRESS RESPONSE

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Previous studies of this laboratory demonstrated that stress induces CRH receptors in the hypothalamic paraventricular nucleus (PVN), parallel to increases in CRH peptide expression. To test the hypothesis that CRH has an autoregulatory effect in the CRH neuron, the effect of central blockade of CRH receptors on stress-induced activation of the HPA axis was studied in the rat. Icv injection of a CRH antagonist, reduced the elevation in plasma catecholamines and the increases in CRH mRNA in the PVN, normally observed after stress, suggesting that central CRH exerts a positive feedback on CRH expression. The role of receptors in the PVN mediating these effect of CRH is under current investigation. The role of glucocorticoids regulating the HPA axis was studied in a partial glucocorticoid receptor knock out mouse. In contrast to the expected stimulation of hypothalamic-pituitary corticotroph function, glucocorticoid receptor knockout mice showed decreased CRH expression in the PVN and normal POMC expression in the pituitary under basal or stimulated conditions. These findings suggest that low expression levels of glucocorticoid receptors is sufficient for the negative feedback at the pituitary and hypothalamic level. On the other hand, high glucocorticoid receptor levels may be permissive for positive inputs to CRH neurons in the PVN. Regulation of CRH and VP receptors in the pituitary is important determining the responsiveness of the corticotroph during stress. Studies on the regulation of the pituitary CRH receptor showed that while acute injection of CRH or glucocorticoids in rats decreases CRH receptor mRNA, their simultaneous administration markedly reduces this effect. This indicates that interaction between CRH and glucocorticoids counteracts individual inhibitory effects of these regulators alone. Such an effect is likely to account for the stimulatory effect of stress on pituitary CRH receptor mRNA. Long term glucocorticoid administration increases V1b receptor mRNA but decreases VP binding indicating that V1b receptor mRNA levels are not a primary determinant of receptor number. In spite of the decrease in binding, glucocorticoids potentiate VP-stimulated inositol phosphate formation, probably trough an increase in the coupling protein, Gq. Post- receptor regulation of VP receptor activity may contribute to low inhibitory activity of glucocorticoids on VP-stimulated ACTH secretion.