Endogenous vasopressin contributes to hypothalamic– pituitary–adrenocortical alterations in aged rats M Hatzinger, C T Wotjak, T Naruo, R Simchen, M E Keck, R Landgraf, F Holsboer and I D Neumann Max Planck Institute of Psychiatry, 80804 Munich, Germany (Requests for offprints should be addressed to I D Neumann, Max Planck Institute of Psychiatry, Kraepelinstrasse 2, 80804 Munich, Germany; Email: ineu@mpipsykl.mpg.de) Abstract The ageing process in animals and humans is thought to be accompanied by a gradual impairment of corticosteroid receptor function, which is reflected by increased pituitary–adrenocortical hormone secretion at baseline and a number of aberrant neuroendocrine function test results. The latter include the ACTH and corticosteroid responses to a combined dexamethasone (DEX)/corticotropin- releasing hormone (CRH) challenge. The excessive hormonal response to this test among aged individuals has been taken as indirect evidence of enhanced endogenous arginine vasopressin (AVP) release, which – together with peripherally administered CRH – is capable of overriding DEX-induced ACTH suppression. The cur- rent study was designed to explore the role of endogenous AVP in mediating excessive hypothalamic–pituitary– adrenocortical (HPA) activity in ageing. The combined DEX/CRH test was administered to aged (22–24 months old) Wistar rats and the effect of the AVP type 1 (V1) receptor antagonist, d(CH 2 ) 5 Tyr(Me)AVP, on ACTH release was studied. Infusion of the V1 receptor antagonist after DEX pretreatment and before CRH administration prevented the CRH-induced rise in ACTH secretion in comparison with vehicle-treated aged rats (area under the concentration–time curve: 699 479 versus 2896 759; P < 0·01). This difference was absent in young (3 months old) control rats. In situ hybridization showed an increased number of AVP mRNA-expressing neurons in the parvocellular but not the magnocellular, portion of the hypothalamic paraventricular nucleus in DEX-pretreated aged rats. The number and synthetic activity of parvocellular neurons expressing CRH mRNA was also increased. We have concluded that the increased HPA activity in aged rats involves enhanced synthesis and release of AVP from parvocellular neurons, possibly secondary to impaired corticosteroid receptor function. Journal of Endocrinology (2000) 164, 197–205 Introduction Increased activity of the hypothalamic–pituitary– adrenocortical (HPA) system is a frequent concomitant of ageing. This led to the hypothesis that the neuroendocrine changes seen are causally involved in the development of both age-associated cognitive decline and stress-related psychiatric disorders, such as depression (for reviews see Holsboer & Barden 1996, Lupien & McEwen 1997). It has been postulated that these age- or disease-associated changes are induced by a synergistic action of corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) at pituitary corticotropic cells (von Bardeleben et al. 1985, von Bardeleben & Holsboer 1991), but only indirect evidence exists so far for a functional synergism between CRH and AVP as a crucial mechanism underlying excessive adrenocorticotropin (ACTH) and corticosteroid release in dexamethasone (DEX)-pretreated aged humans and animals (von Bardeleben & Holsboer 1991, Hatzinger et al. 1996). The current study was designed to elucidate the role of endogenous AVP in age-related alterations of the HPA system in rats. The combined DEX/CRH challenge was used as a paradigm because this test is an extremely sensitive measure for changes in the HPA system regulation in both humans and rats (Heuser et al. 1994a, Hatzinger et al. 1996). The mechanisms underlying the excessive secretion of ACTH and corticosteroids in aged individuals are believed to involve impaired corticosteroid receptor function in the limbic system (Sapolsky et al. 1986, Reul et al. 1991, Rothuizen et al. 1993). Since DEX, which suppresses ACTH, is rapidly exported from the brain by a transporter system of the blood–brain barrier (Schinkel et al. 1995), it has very limited access to brain tissues and, thus, should rather exert a pituitary than a central 197 Journal of Endocrinology (2000) 164, 197–205 0022–0795/00/0164–197  2000 Society for Endocrinology Printed in Great Britain Online version via http://www.endocrinology.org