Intact Catecholamine Inputs to the Forebrain Are Required for Appropriate Regulation of CRH and Vasopressin Gene Expression by Corticosterone in the Rat Paraventricular Nucleus

摘要

CRH neuroendocrine neurones in the paraventricular nucleus of the hypothalamus (PVH) drive ACTH and thereby glucocorticoid release from pituitary corticotrophs and adrenal cortex respectively. Glucocorticoids suppress the ability of neuroendocrine CRH neurons to synthesise and release ACTH secretogogues. Despite the importance of glucocorticoids as regulatory signals to CRH neurones in the extended time domain, how and where they act in this capacity is still not fully understood. Ascending catecholamine projections encode important cardiovascular, metabolic, and other visceral information to the rat PVH and surrounding hypothalamus. These afferents have previously been implicated as targets for glucocorticoid action, including a role in the feedback regulation of PVH neuroendocrine neurones. To determine the contribution of these neurones to corticosterone’s long-term actions on CRH and vasopressin (AVP) gene expression in the PVH we used an immunocytotoxin (a conjugate of the cytotoxin saporin and an antibody against dopamine-β-hydroxylase) that specifically ablates adrenergic and noradrenergic neurones. Lesions were administered to intact animals and to adrenalectomized animals with either no corticosterone or corticosterone replacement that provided levels above those required to normalise Crh expression. The ability of elevated levels of corticosterone to suppress Crh expression was abolished in animals lacking catecholaminergic innervation of the PVH. No effect was seen in the absence of corticosterone or in animals with intact adrenals. Furthermore, Avp expression, which is increased in CRH neurons following adrenalectomy, was suppressed in adrenalectomized catecholaminergic lesioned animals. Interactions between corticosterone and catecholaminergic projections to the hypothalamus therefore make significant contributions to the regulation of Crh and Avp expression. However, the importance of catecholamine inputs is only apparent when circulating corticosterone concentrations are maintained either below or above those required to maintain the activity of the hypothalamo-pituitary-adrenal axis that is seen in intact animals.