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Prenatal stress exacerbates the impact of an aversive procedure on the corticosterone response to stress in female rats

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Summary

Post-traumatic stress disorder (PTSD) is associated with marked alterations in hypothalamic-pituitary adrenal (HPA) function. In rats, prenatal restraint stress (stress applied to pregnant mothers, PRS) is known to impact behavioral and neuroendocrine sensitivity to several kinds of mild stress in adulthood. We have recently shown that PRS also modifies behavioral responses after exposure to an intense footshock in a potential animal model of PTSD. The aim of the present study was to evaluate the long-term effects of an aversive procedure (footshock followed by 3 weekly situational reminders) on the corticosterone response to a novel stress (restraint stress, 140 days after the footshock) in adult female PRS rats. Our data extend previous results showing that PRS leads to a long-lasting increase in plasma corticosterone after restraint stress in adult male rats. Moreover, we demonstrate that 140 days after the intense footshock, female PRS rats have lower corticosterone levels 60 min after restraint stress, suggesting an increase in the negative feedback of the HPA axis. These results indicate that early stress may favor long-lasting modifications of the HPA axis subsequent to exposure to an intense stress in adulthood.

Introduction

Several lines of evidence demonstrate that certain psychiatric disorders are associated with alterations in hypothalamic-pituitary adrenal (HPA) function (de Kloet, 2008). Many depressed patients exhibit cortisol non-suppression in response to dexamethasone administration, suggesting an inhibition of negative feedback, while post-traumatic stress disorder (PTSD) patients, on the other hand, typically show enhanced cortisol suppression (Gillespie and Nemeroff, 2005, Yehuda et al., 2004). These two psychiatric disorders share common risk factors, such as being a woman (Gavranidou and Rosner, 2003) and exposure to stressful events in childhood (Heim and Nemeroff, 2001).

In animals, as in humans, HPA function is affected by gender and by early exposure to adverse events (Darnaudéry and Maccari, 2008, Kapoor et al., 2006, Louvart et al., 2006, Weinstock et al., 1992). The corticosterone response of female rats after an acute stress is of higher magnitude and duration than that of males (Louvart et al., 2006). However, 42 days after a traumatic procedure (an intense inescapable footshock followed by situational reminders), female rats exhibit increased negative feedback of the HPA axis whereas no effect is seen in male animals (Louvart et al., 2006). Prenatal restraint stress (PRS) induced by chronic restraint stress in pregnant rats is associated with HPA axis alterations in the offspring. Indeed, PRS animals display reduced levels of both mineralocorticoid and glucocorticoid receptors in the hippocampus, as well as prolonged stress-induced corticosterone secretion after restraint stress or exposure to novelty (Darnaudéry and Maccari, 2008). Moreover, PRS provokes depressive-like disturbances such as an increase in paradoxical sleep episodes and high levels of immobility in the forced swim test (Maccari and Morley-Fletcher, 2007). Recent studies suggest that the early environment could play a major role in the development of PTSD-like behaviors in animal models (Imanaka et al., 2006, Louvart et al., 2005a). Indeed, neonatal isolation significantly increases the contextual freezing observed in animals exposed to a single prolonged stress in adulthood (Imanaka et al., 2006). In the same way, after exposure to an intense footshock, female rats stressed in utero exhibit increased immobility in an aversive context, fail to habituate to a novel environment (Louvart et al., 2005a), and show a high preference for alcohol (Darnaudéry et al., 2007). Taken together, these results suggest that stress in early life can predispose animals to vulnerability to the negative effects of intense stress during adulthood.

Therefore, the aim of this study was to assess the long-term effects of a traumatic procedure on the corticosterone response to stress in female PRS rats. The corticosterone response to restraint stress was assessed 140 days post-shock in control and female PRS rats.

Section snippets

Methods

Animals were maintained on a 12 h light/dark cycle, with free access to food and water. Manipulation of the animals was carried out following the principles of laboratory animal care published by the French Ethical Committee and European Union norms (86/609/EEC). Nulliparous female Sprague–Dawley rats (Harlan, France) weighing 250 g were group-housed for 7 days after arrival to coordinate their estrus cycle. Females were then individually housed with a sexually experienced male rat for a complete

Results

As shown in Fig. 1A–C, corticosterone levels increased after 30 min of restraint stress in all experimental groups (time effect, F(3, 117) = 191.56, p < 0.001; post hoc Newman–Keul test, p < 0.001, 30 min vs. other time points). As expected, among No Shock groups (Fig. 1A), PRS rats exhibited higher plasma corticosterone levels (21.5 ± 3.0 μg/dl) than control females (12.1 ± 3.0 μg/dl), 120 min after the stress (group effect, F(1, 39) = 4.32, p < 0.05).

The aversive procedure affected the corticosterone response

Discussion

The present study aimed to evaluate the effects of the interaction between stress in early life and exposure to an intense footshock stress in adulthood, a proposed animal model of PTSD (Louvart et al., 2005b, Pynoos et al., 1996, Rasmussen et al., 2008), on the corticosterone response to stress in female rats. Our result reveals that in female rats, a traumatic procedure can induce a reversal of the prolongation of corticosterone secretion, a classic phenomenon described in PRS rats (

Conflict of interest

None declared.

Acknowledgements

We thank D. Deschamps and S. Lefèvre for animal care and F. Paquet, A. Bous and Dr. H. Bouwalerh for the technical help. English editing assistance was provided by Gap Junction (www.gap-junction.com).

Role of the funding sources: Funding for this study was provided by the CNRS (programme Sciences biomédicales, Santé et Société) and the University of Lille 1. Hélène Louvart was supported by a Fondation pour la Recherche Médicale fellowship program (Action dynamique en Psychiatrie). These funding

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