INCREASED BASAL ACTIVITY OF THE HPA AXIS AND RENIN- ANGIOTENSIN SYSTEM IN CONGENITAL LEARNED HELPLESS RATS EXPOSED TO STRESS EARLY IN DEVELOPMENT E. EDWARDS,$* J.A. KING% and J.C.S. FRAY} $Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA; %Department of Psychiatry, University of Massachusetts Medical School, Worcester, MA 01655, USA; }Department of Physiology, University of Massachusetts Medical School, Worcester, MA 01655, USA (Received 26 March 1999; received in revised form 14 June 1999; accepted 18 June 1999) AbstractÐLearned helpless behavior has been successfully bred in rats and designated as a genetic ani- mal model of human depression and/or anxiety. Since congenital learned helpless animals have an impaired stress response in adulthood, we examined the eects of early stressors (at postnatal day 7, 14 or 21) on the hypothalamic±pituitary±adrenal axis and the renin-angiotensin system. The functioning of the hypothalamic±pituitary±adrenal axis was monitored through changes in corticosterone plasma levels in the adult animals after acute exposure to cold stress and maternal deprivation early in development. Renin-angiotensin system functioning was assessed by plasma renin activity. Unstressed congenital learned helpless rats had corticosterone levels that were similar to control animals (congenital non- learned helpless rats not stressed during development), but unstressed plasma renin activity levels of congenital learned helpless rats were lower than congenital non-learned helpless rats. There was a step- wise increase in corticosterone plasma levels in the congenital learned helpless rats with age of acute presentation of either cold stress or maternal deprivation stress (day 7, 49%; day 14, 84%; and day 21, 543% for cold stress). However, these baseline corticosterone levels were signi®cantly lower in congeni- tal learned helpless rats compared to congenital non-learned helpless controls. Similarly, in response to early exposure to cold stress and maternal deprivation, there was an increase in plasma renin activity levels of congenital learned helpless rats with age of presentation to either stressors. However, this increase in plasma renin activity levels was not evident in congenital non-learned helpless controls. Taken together, these results suggest that exposure to stress early in development has long-term eects on both the hypothalamic±pituitary±adrenal axis and the renin-angiotensin system, two neuroendocrine indicators of stress responsivity. # 1999 ISDN. Published by Elsevier Science Ltd. All rights reserved. INTRODUCTION Following exposure to uncontrollable stress, a subset of animals exhibit a de®cit in learning to escape controllable stress. This ``learned helplessness'' phenomenon has been used as a valid model of depression. 11,22,35 After several generations of selective breeding, a strain of rats, termed congenital learned helpless (cLH), emerged that exhibit an increased vulnerability to helplessness even in the absence of prior exposure to uncontrollable stress. 10 In addition to the cLH strain, a control strain of rats was concurrently bred to exhibit a relative resistance to helpless behavior. Our laboratory has utilized these two rat strains as a unique model system to identify speci®c biological markers of clinical psychopathology and to gain further understanding of the etiology of aective disorders. The present experiments were designed to assess whether the cLH rat model of depression would present a congruent pro®le of HPA axis and cardiovascular system functioning in response to exposure to early stressors. With the increasing evidence of a major role for the stress hormones in the pathogenesis of aective disorders, we hypothesized that exposure to various stressors early in development would modify the regulation of hypothalamic and extrahypothalamic neurons resulting in an exaggerated and possibly harmful endocrine, Int. J. Devl Neuroscience, Vol. 17, No. 8, pp. 805±812, 1999 # 1999 ISDN. Published by Elsevier Science Ltd All rights reserved. Printed in Great Britain 0736-5748/99 $20.00 + 0.00 PII: S0736-5748(99)00062-3 www.elsevier.com/locate/ijdevneu *To whom all correspondence should be addressed. Tel.: +1-410-706-7510; Fax: +1-410-706-0346; E-mail: edwards @pharmacy.ab.umd.edu Abbreviations: HPA axis, hypothalamic-pituitary-adrenal axis; RAS, renin-angiotensin system; CORT, corticosterone; cLH, congenital learned helpless; cNLH, congenital non-learned helpless; PRA, plasma renin activity; CS, cold stress; MD, maternal deprivation. 805