Journal of Neuroendocrinology, zyxwvutsrqp 1994, Vol. 6, 341-345 zyxwvutsr Prenatal Stress Increases the Hypothalamo-Pituitary-Adrenal Axis Response in Young and Adult Rats zyxw Chantal Henry, Moharned Kabbaj, Herve Simon, Michel Le Moal and Stefania Maccari Psychobiologie des Cornportements Adaptatifs, lnstitut National de la Sante et de la Recherche Medicale U. 259, Universite de Bordeaux II, Domaine de Carreire-Rue Camille St Saens, 33077 Bordeaux Cedex, France. Key words: hyporesponsive period, hippocampus, plasma corticosterone, type I and type II corticosteroid receptors. Abstract Prenatal stress is considered as an early epigenetic factor able to induce long-lasting alterations in brain structures and functions. It is still unclear whether prenatal stress can induce long-lasting modifications in the hypothalamo-pituitary-adrenal axis. To test this possibility the effects of restraint stress in pregnant rats during the third week of gestation were investigated in the functional proper'ties of the hypothalamo-pituitary-adrenal axis and hippocampal type zyxwvuts I and type II corticosteroid receptors in the male offspring at 3, 21 and 90 days of age. Plasma corticosterone was significantly elevated in prenatally-stressed rats-at 3 and 21 days after exposure to novelty. At 90 days of age, prenatally-stressed rats showed a longer duration of corticosterone secretion after exposure to novelty. No change was observed for type I and type II receptor densities 3 days after birth, but both receptor subtypes were decreased in the hippocampus of prenatally-stressed offspring at 21 and 90 days of life. These findings suggest that prenatal stress produces long term changes in the hypothalamo-pituitary-adrenal axis in the offspring. The development of the central nervous system and of behavior is determined by genetic factors and by the postnatal environment, but also by the maternal environment during gestation (1). Clinical studies have shown a highly significant correlation between infant morbidity and maternal stress (2-4). However, these studies present methodological and interpretative difficulties. Thompson (S), conducted the first experiment to explore the manipulation of the prenatal environment in animals. Further animal studies have shown behavioral abnormalities in the off- spring of stressed dams, lasting until adulthood (6-7). Stress during pregnancy induces alterations in early motor development zyxwvut (S), increases emotionality in adulthood and disrupts the normal course of sexual differentiation (8-1 1 ). We have recently shown that prenatally-stressed animals exhibit a higher locomotion response to novelty and a higher level of amphetamine self- administration (12). It has also been found that prenatal stress reduces dopamine turnover rates in the left corpora striata (13-14) and induces changes in brain 5 hydroxytryptamine especially in the hypothal- amus at 60 days of age (15). The activity of the hypothalamo- pituitary-adrenal (HPA) axis may also play a critical role in the behavioral modifications observed in prenatally-stressed rats since, in the adult, the HPA axis is central for the control of the homeostatic disturbances induced by stress ( 16) and the hyperac- tivity of the HPA axis has already been associated with behavioral disorders (17-19). It has been shown that a maternal corticos- terone manipulation modifies the development of this axis (20). Thus, the development of the HPA axis of the fetus could be influenced by in-utero exposure to abnormal levels of maternal glucocorticoids during stress which are able to cross the placental and blood-brain barriers (21) and could result in long Iasting perturbations in the offspring. However, literature data show that a prenatal stress is able to increase HPA axis reactivity in the early stage of life (15, 22) but it is not clear if this manipulation modifies glucocorticoid feedback in the adult and, if so, by which mechanism (23, 24). Hippocampal type I and type 11 corticos- teroid receptors regulate at least in part the negative feedback of the HPA axis in adult animals (25, 26). Long-lasting alterations in these receptors are responsible for impaired stress responses, and aged rats which have less corticosteroid receptors in the hippocampus have a delayed stress-response (27). Given this evidence, we investigated the influence of restraint stress, during the third- week of pregnancy, on the development of the HPA axis and corticosteroid receptors of the offspring. Thus, we have measured basal and stress corticosterone levels in 3, 21, and 90 day-old male rats and hippocampal type I and type zyxwv I1 corticosteroid receptors at the same age. Results Data concerning circulating corticosterone levels in 3, 21, 90 day- old rats under basal conditions, at the end of a 30 min exposure to novelty and, for the adult subjects, also after 120 min of exposure to novelty, are shown in Figure 1. zyx Correspondence 20: Dr Stefania Maccari, INSERM U259-Universitt de Bordeaux 11, Rue Camille St Saens, 33077 Bordeaux Cedex, France.