1. The responsiveness of the rat hypothalamo-pituitary-adrenal (HPA) axis and hypothalamo-neurohypophysial system (HNS) to emotional (elevated plus-maze) and physical (forced swimming) stressors and to administration of synthetic corticotrophinreleasing hormone (CRH) was investigated during pregnancy and lactation. In addition to pregnancy-related adaptations at the adenohypophysial level, behavioural responses accompanying the neuroendocrine changes were studied. 2. Whereas basal (a.m.) plasma corticosterone, but not corticotrophin (adrenocorticotrophic hormone; ACTH), levels were increased on the last day (i.e. on day 22) of pregnancy, the stress-induced rise in both plasma hormone concentrations was increasingly attenuated with the progression of pregnancy beginning on day 15 and reaching a minimum on day 21 compared with virgin control rats. A similar attenuation of responses to both emotional and physical stressors was found in lactating rats. 3. Although the basal plasma oxytocin concentration was elevated in late pregnancy, the stressinduced rise in oxytocin secretion was slightly lower in day 21 pregnant rats. In contrast to vasopressin, oxytocin secretion was increased by forced swimming in virgin and early pregnant rats indicating a differential stress response of these neurohypophysial hormones. 4. The blunted HPA response to stressful stimuli is partly due to alterations at the level of corticotrophs in the adenohypophysis, as ACTH secretion in response to CRH in vivo (40 ng kg¢, i.v.) was reduced with the progression of pregnancy and during lactation. In vitro measurement of cAMP levels in pituitary segments demonstrated reduced basal levels of cAMP and a lower increase after CRH stimulation (10 nÒ, 10 min) in day 21 pregnant compared with virgin rats, further indicating reduced corticotroph responsiveness to CRH in pregnancy. 5. The reduced pituitary response to CRH in late pregnancy is likely to be a consequence of a reduction in CRH receptor binding as revealed by receptor autoradiography.[ÁÂÇI]CRH binding in the anterior pituitary was significantly reduced in day 11, 17 and 22 pregnant rats compared with virgin controls. 6. Anxiety-related behaviour of the animals as revealed by the time on and entries into the open arms of the elevated plus-maze was different between virgin and pregnant rats with decreased number of entries indicating increased anxiety with the progression of pregnancy (except on pregnancy day 18). The emotional behaviour, however, was not correlated with the neuroendocrine responses. 7. The results indicate that the reduced response of the HPA axis to stressors described previously during lactation is already manifested around day 15 of pregnancy in the rat and involves physiological adaptations at the adenohypophysial level. However, alterations in stressor perception at higher brain levels with the progression of pregnancy may also be involved.

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The effects of emotional stressors on the release of arginine vasopressin (AVP) and oxytocin (OXT) within the rat hypothalamus and the origin and physiological significance of AVP released within the hypothalamic paraventricular nucleus (PVN) were investigated. First, adult male Wistar rats with a microdialysis probe aimed at the PVN or the supraoptic nucleus were exposed to either a dominant male rat (social defeat) or a novel cage. Release of AVP within the PVN was significantly increased in response to social defeat but not to novelty. In contrast to an activation of the hypothalamic-pituitary-adrenal (HPA) system, neither stressor stimulated the hypothalamic-neurohypophysial system (unchanged plasma AVP and OXT and unchanged release within the supraoptic nucleus [AVP] and the PVN [OXT]). Next, we demonstrated by simultaneous microdialysis of the suprachiasmatic nucleus and the PVN that AVP measured in PVN dialysates during social defeat was probably of intranuclear origin. Finally, a mixture of a V1 AVP and the alpha-helical corticotropin-releasing hormone (CRH) receptor antagonists administered via inverse microdialysis into the PVN caused a significant increase in the plasma adrenocorticotropic hormone (ACTH) concentration compared with vehicle-treated controls both under basal conditions and during social defeat, indicating inhibitory effects of intra-PVN-released AVP and/or CRH on HPA system activity. The antagonists failed to affect anxiety-related behavior of the animals as assessed with the elevated plus-maze. Taken together, our results show for the first time that AVP is released within the PVN in response to an emotional stressor. We hypothesize that this intranuclear release provides a negative tonus on ACTH secretion.

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Two Wistar rat lines, selectively bred for high-anxietyrelated behavior (HAB) and low-anxiety-related behavior (LAB) in the elevated plus-maze test, were tested for the susceptibility of their behavioral characteristics to anxiolytic treatment and for their endocrine and physiological reactivity to different stressors. Injection of 1mg/kg diazepam failed to affect line differences in coping strategy but resulted in a marked (20-fold) Genetic factors contribute to the high interindividual variability in type and/or intensity of the behavioral, neuroendocrine, and physiological stress responses observed in various species, including humans and laboratory rats (Boissy 1995;Clément et al. 1997;Cools et al. 1990;Curé and Rolinat 1992;Prasad et al. 1996;Spanagel et al. 1995;Tesser 1993;Zuckerman 1993). This fact has been used as the basis for selective bidirectional breeding programs from which strains and lines differing in their behavioral and/or neuroendocrine reFrom the Max Planck Institute of Psychiatry, Munich, Germany. Address correspondence to: Dr. R. Landgraf, Max Planck Institute of Psychiatry, Kraepelinstr. 2, 80804 Munich, Germany.Received January 15, 1997; revised March 25, 1998; accepted April 16, 1998. 382 G. Liebsch et al. N EUROPSYCHOPHARMACOLOGY 1998 -VOL . 19 , NO . 5 sponses to environmental challenges have emerged (Brush 1991;Castanon and Mormède 1994;Cools et al. 1993;Gentsch et al. 1988;Walker et al. 1992). Recently, we reported the establishment of two Wistar rat lines selectively bred for differing behavioral performances in the elevated plus-maze test, now termed high-anxiety-related behavior (HAB) and low-anxiety-related behavior (LAB) lines, respectively ). This animal model of inborn anxiety provides the advantage of avoiding conditioned stimuli that by themselves are likely to trigger behavioral, neuroendocrine, and physiological alterations. Interestingly, the HAB and LAB animals also prefer different coping strategies in a forced swim test ), pointing toward a link between anxiety and coping with stressful situations.The elevated plus-maze test is based on the creation of a conflict between the exploratory drive of a rat and its innate fear of open, exposed areas. It is one of the most widely used nonconditioned animal models of anxiety and has been extensively validated pharmacologically and ethologically (Dawson and Tricklebank 1995;Pellow 1986;Pich et al. 1993). However, various clinically effective anxiolytic substances often yield contradictory results when administered to "normal" unstressed rats in this test (Griebel 1995;Rodgers et al. 1997), indicating that-in parallel to the situation in humans (Green and Hodges 1991; Lader 1991)-the efficacy of an anxiolytic may depend upon the animal's basal level of anxiety. To test this prediction and to characterize further our breeding lines, in the first experiment, male rats from the HAB and LAB lines were injected with a classical anxiolytic, diazepam, and submitted to a plus-maze test and a forced swim test to assess the e...