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Studies of the Secretion of Corticotropin-Releasing Factor and Arginine Vasopressin Into the Hypophysial-Portal Circulation of the Conscious Sheep

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Studies of the Secretion of Corticotropin-Releasing Factor and Arginine Vasopressin Into the Hypophysial-Portal Circulation of the Conscious Sheep Studies of the secretion of corticotropin-releasing factor and arginine vasopressin into the hypophysial-portal circulation of the conscious sheep. II. The central noradrenergic and neuropeptide Y pathways cause immediate and prolonged hypothalamic-pituitary-adrenal activation. Potential involvement in the pseudo-Cushing's syndrome of endogenous depression and anorexia nervosa. J P Liu, … , J W Funder, D Engler J Clin Invest. 1994;93(4):1439-1450. https://doi.org/10.1172/JCI117121. Research Article Studies were performed to determine the effects of intracerebroventricular norepinephrine (NE) or neuropeptide Y (NPY) on the ovine hypothalamic-pituitary-adrenal (HPA) axis. NE (50 micrograms) increased mean hypophysial-portal corticotropin-releasing factor (CRF) and arginine vasopressin (AVP) levels (1 h, 1.3- and 2.9-fold; 4 h, 2.2- and 5.7-fold) and caused acute and sustained increases in mean plasma ACTH and cortisol. NPY (50 microgram) also increased mean CRF and AVP levels (1 h, 1.4- and 4.2-fold; 4 h, 1.1- and 1.9-fold), increased pituitary-adrenal activity at 1 h, and caused ACTH hypersecretion at 4 h. When added to cultured ovine anterior pituitary cells, NPY neither increased basal ACTH release nor augmented CRF- or AVP-induced ACTH release. We conclude that: (a) activation of either the central noradrenergic or NPY pathways causes an acute and sustained stimulation of the ovine HPA axis; (b) such activation increases the AVP/CRF ratio, suggesting a dominant role for AVP in the ovine stress response; and (c) the central noradrenergic or NPY systems may cause sustained HPA activation by attenuating or disrupting the glucocorticoid negative feedback on those brain areas concerned with regulation of the HPA axis. The possible roles of the central noradrenergic and NPY systems in the etiology of the hypercortisolemia of endogenous depression and anorexia nervosa are discussed. Find the latest version: https://jci.me/117121/pdf Studies of the Secretion of Corticotropin-releasing Factor and Arginine Vasopressin into the Hypophysial-Portal Circulation of the Conscious Sheep II. The Central Noradrenergic and Neuropeptide Y Pathways Cause Immediate and Prolonged Hypothalamic-Pituitary-Adrenal Activation. Potential Involvement in the Pseudo-Cushing's Syndrome of Endogenous Depression and Anorexia Nervosa Jun-Ping Liu,* lain J. Clarke,* John W. Funder,* and Dennis Engler* *Prince Henry's Institute ofMedical Research, Clayton, Victoria 3168; and the *Baker Medical Research Institute, Prahran, Victoria 3181, Australia Abstract hypophysial-portal circulation ( 1, 2). In the rat, corticotropin- releasing factor (CRF)' is the most potent ACTH secretagogue Studies were performed to determine the effects of intracere- and the only neuropeptide known to augment pro-opiomelan- broventricular norepinephrine (NE) or neuropeptide Y (NPY) ocortin (POMC) biosynthesis (3, 4). The effect of CRF on on the ovine hypothalamic-pituitary-adrenal (HPA) axis. NE ACTH release is potentiated by arginine vasopressin (AVP), (50 gg) increased mean hypophysial-portal corticotropin-re- oxytocin, angiotensin II, and the catecholamines norepineph- leasing factor (CRF) and arginine vasopressin (AVP) levels (1 rine and epinephrine (5, 6). However, it is now apparent that h, 13- and 2.9-fold; 4 h, 2.2- and 5.7-fold) and caused acute and CRF is not the most potent ACTH secretagogue in all species sustained increases in mean plasma ACTH and cortisol. NPY since CRF and AVP are equipotent in their ability to release (50 ,ug) also increased mean CRF and AVP levels (1 h, 1.4- and ACTH from bovine anterior pituitary cells (7), and in the 4.2-fold; 4 h, 1.1- and 1.9-fold), increased pituitary-adrenal ovine species, AVP is a more potent ACTH secretagogue than activity at 1 h, and caused ACI7H hypersecretion at 4 h. When is CRF in vivo and in vitro (8-10). In addition, AVP also added to cultured ovine anterior pituitary cells, NPY neither increases total ACTH accumulation in cultured ovine anterior increased basal ACTH release nor augmented CRF- or AVP- pituitary cells, a finding that has been interpreted to reflect an induced ACIJ7 release. We conclude that: (a) activation of effect of AVP on POMC biosynthesis (10). either the central noradrenergic or NPY pathways causes an The CRF and AVP neurons that project to the median acute and sustained stimulation of the ovine HPA axis; (b) eminence and secrete into the hypophysial-portal circulation such activation increases the AVP/CRF ratio, suggesting a are mainly located in the medial parvocellular subdivision of dominant role for AVP in the ovine stress response; and (c) the the paraventricular hypothalamus (PVHmp) ( 11 ). Recent im- central noradrenergic or NPY systems may cause sustained munohistochemical studies performed in the rat indicate that HPA activation by attenuating or disrupting the glucocorticoid pro-AVP expressing and pro-AVP-deficient CRF perikarya negative feedback on those brain areas concerned with regula- are found in almost equal proportions in the PVH ( 12). Al- tion of the HPA axis. The possible roles ofthe central noradren- though comparative studies have yet to be performed, it is prob- ergic and NPY systems in the etiology of the hypercortisolemia able that similar findings may be obtained in other species. In of endogenous depression and anorexia nervosa are discussed. the rat, the CRF+/AVP+ subpopulation is preferentially con- (J. Clin. Invest. 1994. 93:1439-1450.) Key words: hypotha- centrated in the dorsolateral aspect of the PVHmp (12), and lamic-pituitary-adrenal axis * central facilitation * brain cate- this area is densely innervated by dopamine-,B-hydroxylase cholaminergic pathways * brain neuropeptide Y pathways * psy- (DBH) and phenylethanolamine-N-methyltransferase (PNMT) chiatric illness nerve terminals ( 13). The DBH-immunoreactive (ir) axon ter- minals in the PVH are derived from noradrenergic cell bodies Introduction located in the nucleus ofthe tractus solitarius (NTS, A2 area), the ventrolateral medulla (Al area), and the locus ceruleus It is currently believed that the secretion of ACTH by the ante- (A6 area), whereas the PNMT-ir fibers originate from the C1, rior pituitary is regulated in a unidirectional manner by the C2, and C3 brainstem adrenergic cell groups. The adrenergic hypothalamus. This control is stimulatory in nature and is ef- cell groups are found rostral to the noradrenergic perikarya and fected by a number of neuropeptides that are secreted into the the Cl group appears to be absent from the ovine brain ( 13, 14). There are direct synaptic contacts between these DBH- Address correspondence to Dr. Dennis Engler, Prince Henry's Institute and PNMT-ir nerve fibers and the CRF-stained neurons in the of Medical Research, P.O. Box 152, Clayton, Victoria 3168, Australia. PVH, suggesting that the ascending noradrenergic and adren- Jun-Ping Liu's present address is the Department of Endocrinology, John Hunter Hospital, Newcastle, New South Wales 2310, Australia. ergic pathways are strategically placed to regulate CRF and There was a preliminary report of this work at the 74th Annual AVP secretion and/or biosynthesis ( 15 ). Meeting of the Endocrine Society, San Antonio, TX, June 24-26, 1992. Receivedfor publication 28 August 1993 and in revisedform 2 No- 1. Abbreviations used in this paper: AVP, arginine vasopressin; CRF, vember 1993. corticotropin-releasing factor; DBH, dopamine-fl-hydroxylase; icv, intracerebroventricular; EPI, epinephrine; ir, immunoreactive; LC, J. Clin. Invest. locus ceruleus; NE, norepinephrine; NPY, neuropeptide Y; NTS, nu- © The American Society for Clinical Investigation, Inc. cleus of the tractus solitarius; PNMT, phenylethanolamine-N-methyl- 0021-9738/94/03/1439/12 $2.00 transferase; POMC, pro-opiomelanocortin; PVHmp, paraventricular Volume 93, April 1994, 1439-1450 hypothalamus. Stimulation ofthe Ovine Hypothalamic-Pituitary-Adrenal Axis 1439 Neuropeptide Y (NPY) is a highly conserved 36-residue conscious sheep (36). In those studies, we noted that NE and peptide that was isolated from porcine brain and subsequently EPI caused both an acute and sustained increase in ACTH and found to be widely distributed in the mammalian central and cortisol secretion, and that NE appeared to be the more potent peripheral nervous system ( 16). The concentrations ofNPY in agonist in vivo. Since NE and EPI released only very modest the mammalian brain are higher than those of any previously amounts of ACTH from the anterior pituitary, we concluded discovered neuropeptide and the hypothalamus contains partic- that both catecholamines were acting mainly at suprahypophy- ularly high concentrations of the peptide ( 17-19). Studies us- sial brain sites to increase CRF and AVP secretion. In the stud- ing immunohistochemistry and in situ hybridization histo- ies described below, we have directly measured the effects of chemistry have determined the distribution of NPY-ir peri- intracerebroventricular (icv) NE on the secretion of CRF and karya and fibers throughout the brain ( 17-22). The AVP into the hypophysial-portal circulation as well as ACTH hypothalamic arcuate nucleus contains the highest concentra- and cortisol into the systemic circulation of the conscious tion of NPY-ir perikarya of any brain region, and from this sheep. Since the distribution of NPY-stained varicosities in the nucleus there arises a prominent projection that proceeds ros- parvocellular PVH encompasses the PNMT-ir and DBH-ir in- trally to innervate the PVH (19, 23). NPY is not colocalized put (21 ), we have also assessed the effect of icv NPY on the with either norepinephrine (NE) or epinephrine (EPI) within activity of the entire hypothalamic-pituitary-adrenal axis. A the arcuate nucleus (23), but in the brainstem, NPY is exten- preliminary account of these observations has appeared in ab- sively colocalized within the adrenergic neurons of the C1, C2, stract form (37). and C3 groups, while its correspondence within the noradrener- gic cell groups is less complete (2 1). The NPY-ir axon termi- nals within the PVH are therefore derived from two sources, Methods the arcuate nucleus and the brainstem, and of these two the arcuato-paraventricular projection is the more important.
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