Effects of prenatal stress on defensive withdrawal behavior and corticotropin releasing factor systems in rat brain

Exposure of pregnant rats to stress results in offspring that exhibit abnor mally fearful behavior and have elevated neuroendocrine responses to novelt y and aversive stimuli. This study examined the effects of prenatal stress on plasma corticosterone, adrenal weight, defensive withdrawal behavior, an d the density of receptors for corticotropin releasing factor (CRF) in the amygdala. Pregnant Sprague-Dawley rats were stressed by daily handling and saline injection (s.c., 0.9%, 0.1 mt) during the last week of gestation. Ma le offspring were studied at adulthood (60-120 days of age). Adrenal hypert rophy and increased plasma corticosterone were observed in the prenatally s tressed offspring. Defensive withdrawal, an ethological measure of the conf lict between exploratory behavior and retreat, was quantified in naive offs pring, and in offspring exposed to restraint stress (2 h). Restraint stress increased defensive withdrawal in both control and prenatally stressed off spring. Both naive and restraint-stressed prenatally stressed offspring exh ibited increased defensive withdrawal compared to control offspring. There was a significant interaction between prenatal stress and restraint stress, suggesting increased vulnerability of prenatally stressed offspring. The e ffects of restraint in the defensive withdrawal test were reduced by intrac erebroventricular administration of the CRF antagonists, alpha-helical CRF9 -41 (20 mu g every hour) or D-phe(12), Nle(21,38), C-alpha-MeLeu(37)]-CRF(1 2-41) (5 mu g every hour) during the restraint period. The difference betwe en control and prenatally stressed offspring was abolished by the CRF antag onists, suggesting that increased activation of CRF receptors may be a fact or in the behavioral abnormalities of prenatally stressed rats. Measurement of CRF receptors in amygdala revealed a 2.5-fold increase in binding in pr enatally stressed offspring. In light of previous work from this laboratory demonstrating increased content and release of CRF in amygdala from prenat ally stressed offspring, the present study suggests that the increased fear fulness of prenatally stressed rats may be a consequence of increased activ ity of CRFergic systems in the amygdala. (C) 2000 Elsevier Science Inc. All rights reserved.