Prenatal stress and long-term consequences: implications of glucocorticoid hormones

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Abstract

We have shown that prenatal restraint stress (PNRS) induces higher levels of anxiety, greater vulnerability to drugs, a phase advance in the circadian rhythm of locomotor activity and an increase in the paradoxical sleep in adult rats. These behavioral effects result from permanent modifications to the functioning of the brain, particularly in the feedback mechanisms of the hypothalamic-pituitary–adrenal (HPA) axis: the secretion of corticosterone is prolonged after stress and the number of the central glucocorticoid receptors is reduced. These abnormalities are associated with modifications in the synthesis and/or release of certain neurotransmitters. Dysfunction of the HPA axis is due, in part, to stress-induced maternal increase of glucocorticoids, which influences fetal brain development. Some biological abnormalities in depression can be related to those found in PNRS rats reinforcing the idea of the usefulness of PNRS rats as an appropriate animal model to study new pharmacological approaches.

Section snippets

Perinatal events in humans

There is increasing evidence that variations in prenatal environment can influence the responses of the new-born. Barker [1] has emphasized how adult vulnerability to cardiovascular disease may be programmed during the fetal period. Indeed, non-genetic factors that could act early in life to organize or imprint permanently physiological systems are known as perinatal programming [2], [3]. It can be speculated that prenatal plasticity of physiological systems allows environmental factors, acting

An animal model characterization

In order to better understand mechanisms involved in the long-term effects of such early experiences and considering the obvious difficulties inherent to human research in this particular field, different kind of prenatal stress animal models have been developed. Pregnant rats have been subjected to various types of stressors: conditioned avoidance training [15], tail suspension [16], crowding [17], repeated electric shocks [18], noise [19] or saline injections [20]. During the last years we

Parallel between prenatal stress effects and biological abnormalities found in depression

Taken together, our results indicate that prenatal stress induces an increased stress response and abnormal circadian and sleep function in adult rats, suggesting an underlying dysfunction of their circadian clock and a global bad adaptation to challenges. These biological alterations indicate that PNRS adult rats have similar biological correlates of depressed patients [63], [64]. Thus, like depressed patients, PNRS rats do escape from the feedback inhibition responsible for returning

Predictive validity

The PNRS seems to be an interesting animal model because of the permanent disturbances it produces in the long-term. We determined whether PNRS rats are sensitive to a chronic treatment with antidepressants. There is one single report showing efficacy of tricyclic antidepressants in prenatally stressed female rats [80].

We investigated the behavioral response of PNRS rats in the forced swimming test (Porsolt test), a behavioral test classically used to study antidepressant efficacy. The

Role of maternal factors

In order to understand the pathophysiological mechanisms by which stress in the mother reaches the fetus and influences its development, we studied the effects of blocking maternal corticosterone secretion during PNRS on stress-induced corticosterone secretion and hippocampal corticosteroid receptors in adult offspring [82]. Dams were adrenalectomized, at 13 days of pregnancy to block the increased in corticosterone secretion induced by restraint stress. Adrenalectomized dams were implanted

Acknowledgements

This work was supported by the Fondation de la Recherche Medicale, the University of Lille 1, the Belgian FNRS and FRSM, SERVIER.

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