Increased basal activity of the HPA axis and renin-angiotensin system in congenital learned helpless rats exposed to stress early in development

Abstract

Learned helpless behavior has been successfully bred in rats and designated as a genetic animal model of human depression and/or anxiety. Since congenital learned helpless animals have an impaired stress response in adulthood, we examined the effects 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 significantly lower in congenital 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 effects on both the hypothalamic pituitary-adrenal axis and the renin-angiotensin system, two neuroendocrine indicators of stress responsivity.