The proposed studies are designed to clarify the neurochemical mechanisms by which afferent inputs are transformed into hypophysiotropic signals mediating ACTH secretion. Previous studies have demonstrated the multifactorial, stimulus specific nature of hypophysiotropic regulation of ACTH secretion by a constellation of substances including corticotropin releasing factor (CRF), arginine vasopressin (AVP), epinephrine (EPI), and possibly oxytocin and angiotensin II. However, little is presently known of central neurochemical regulation of these factors. The first question to be addressed will be: What are the actions of neurotransmitter agonists and antagonists on secretion of irCRF, irAVP and EPI into the hypophysical-portal circulation? Because the parvocellular division of the paraventricular nucleus (pPVN) receives abundant aminergic input, electrical and chemical activation of discrete aminergic regions (A1, A2, A6 noradrenergic; C1-3 adrenergic; raphe serotonergic) will be used to probe the activity of endogenous amines on secretion of individual hypophysiotropic factors into the portal circulation. The receptor specificity of the observed actions will be evaluated by microinjection of receptor antagonists into the pPVN prior to stimulation of ascending pathways. A major goal of the proposed studies is determination of the relative contributions of individual aminergic projections in mediation of stimulus-induced secretion of ACTH secretagogues. Discrete components of these ascending pathways, which provide visceral sensory information to the pPVN, will be inactivated by electrolytic and neurotoxin lesions prior to application of previously developed experimental paradigms and the hypophysiotropic/ACTH secretory responses assessed. Voltammetric monitoring of catecholamine flux in the pPVN will be performed in parallel with these experiments for validation prior to use in unanesthetized, unrestrained rats. This approach will be coupled with dialysis perfusion for measurement of irCRF and irAVP at the stalk-pituitary junction in unanesthetized rats as the technique evolves. During the interim period depletion of median eminence peptide content in colchicine-treated rats will be utilized as an index of secretion into the portal circulation. Finally, the plasticity of irCRF- and irAVP-secretory responses to specific neurochemical or more diverse stimuli will be assessed in the presence and absence of glucocorticoids using both in vitro and in vivo approaches. Information derived from these studies will augment our understanding of central regulation of this complex neuroendocrine axis.
| Sapolsky, R M; Plotsky, P M (1990) Hypercortisolism and its possible neural bases. Biol Psychiatry 27:937-52 |
