Prenatal Restraint Stress Research Articles

Prenatal restraint stress: an in vivo microdialysis study on catecholamine release in the rat prefrontal cortex

There is substantial evidence that prenatal exposure to adverse environmental conditions might lead to the psychiatric disorders that can appear in adolescence or in adulthood; vulnerability to drug addiction may increase as well. It is currently accepted that the alteration of catecholamine transmission in the prefrontal cortex plays a prominent role in the etiology of psychiatric disorders. We assessed basal and stimulated dopamine and noradrenaline extracellular concentration in the medial prefrontal cortex by means of microdialysis in awake male adolescent and young adult offspring of rats exposed to restraint stress in the last week of pregnancy. Catecholamine stimulation was obtained by amphetamine or nicotine. We observed that prenatal stress (PNS) did not change dopamine but decreased noradrenaline basal output in both adolescents and adults. Moreover, it decreased amphetamine stimulated dopamine output and increased amphetamine stimulated noradrenaline output. PNS decreased nicotine stimulated noradrenaline (but not dopamine output) in adults, though not in adolescents. These data show that PNS stress modifies prefrontal cortex catecholamine transmission in a complex and age dependent manner. Our results support the view that prenatal stress may be a contributing factor for the development of psychiatric disorders and that its effect may augment drug addiction vulnerability.

Effect of prenatal stress on alcohol preference and sensitivity to chronic alcohol exposure in male rats

In rats, prenatal restraint stress (PRS) induces persistent behavioral and neurobiological alterations leading to a greater consumption of psychostimulants during adulthood. However, little is known about alcohol vulnerability in this animal model. We examined in adolescent and adult male Sprague Dawley rats the long-lasting impact of PRS exposure on alcohol consumption. PRS rats were subjected to a prenatal stress (three daily 45-min sessions of restraint stress to the mothers during the last 10 days of pregnancy). Alcohol preference was assessed in a two-bottle choice paradigm (alcohol 2.5%, 5%, or 10% versus water), in both naïve adolescent rats and adult rats previously exposed to a chronic alcohol treatment. Behavioral indices associated with incentive motivation for alcohol were investigated. Finally, plasma levels of transaminases (marker of hepatic damages) and ΔFosB levels in the nucleus accumbens (a potential molecular switch for addiction) were evaluated following the chronic alcohol exposure. Alcohol preference was not affected by PRS. Contrary to our expectations, stressed and unstressed rats did not display signs of compulsive alcohol consumption. The consequences of the alcohol exposure on locomotor reactivity and on transaminase levels were more prominent in PRS group. Similarly, PRS potentiated alcohol-induced ΔFosB levels in the nucleus accumbens. Our data suggest that negative events occurring in utero do not modulate alcohol preference in male rats but potentiate chronic alcohol-induced molecular neuroadaptation in the brain reward circuitry. Further studies are needed to determine whether the exacerbated ΔFosB upregulation in PRS rats could be extended to other reinforcing stimuli.

PW01-22 - Agomelatine treatment reverses changes in neuroplasticity induced by prenatal stress in rats

The rat model of prenatal restraint stress (PRS) is particularly valuable to study the mechanisms involved in the pathophysiology of anxiety/depression since adult PRS rats show endocrine and behavioral abnormalities that are corrected by antidepressant medication. We have previously shown that agomelatine chronic treatment reversed the anxiety behaviour and decreased hippocampal neurogenesis observed in PRS. Here, we investigated the mechanisms that may contribute to the antidepressant activity of agomelatine, by assessing the effects of a chronic treatment with agomelatine on neurobiological markers of neuroplasticity in the rat hippocampus such as BDNF and its receptor, TrkB, the transcription factor pCREB and metabotrophic glutamate receptors (mGluRs). Adult SD control and PRS rats were treated chronically with agomelatine (40mg/kg ip) or vehicle. 16h after last drug administration, animals were sacrificed and hippocampus dissected for biochemical analysis.PRS animals showed reduced levels of pCREB in the hippocampus and increased hippocampal BDNF, and TrkB receptor levels. Agomelatine reversed changes in pCREB and BDNF/TrkB levels in PRS rats, had no effect on pCREB in control rats, and, interestingly, increased BDNF and TrkB receptor levels in control rats. Moreover, agomelatine reversed the reduced expression (for mGluR5 and mGluR2/3 receptors) and function (for mgluR5 receptor) observed in the hippocampus of PRS rats.In conclusion, we have shown that agomelatine treatment reversed all biochemical and cellular changes induced by PRS in rats. These changes, independently of their direction, are the expression of an enduring maladaptive form of neuroplasticity that may contribute to the depressive/anxious phenotype of PRS rats.

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

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.

Influence of low level maternal Pb exposure and prenatal stress on offspring stress challenge responsivity

We previously demonstrated potentiated effects of maternal Pb exposure producing blood Pb(PbB) levels averaging 39 μg/dl combined with prenatal restraint stress (PS) on stress challenge responsivity of female offspring as adults. The present study sought to determine if: (1) such interactions occurred at lower PbBs, (2) exhibited gender specificity, and (3) corticosterone and neurochemical changes contributed to behavioral outcomes. Rat dams were exposed to 0, 50 or 150 ppm Pb acetate drinking water solutions from 2 mos prior to breeding through lactation (pup exposure ended at weaning; mean PbBs of dams at weaning were <1, 11 and 31 μg/dl, respectively); a subset in each Pb group underwent prenatal restraint stress (PS) on gestational days 16–17. The effects of variable intermittent stress challenge (restraint, cold, novelty) on Fixed Interval (FI) schedule controlled behavior and corticosterone were examined in offspring when they were adults. Corticosterone changes were also measured in non-behaviorally tested (NFI) littermates. PS alone was associated with FI rate suppression in females and FI rate enhancement in males; Pb exposure blunted these effects in both genders, particularly following restraint stress. PS alone produced modest corticosterone elevation following restraint stress in adult females, but robust enhancements in males following all challenges. Pb exposure blunted these corticosterone changes in females, but further enhanced levels in males. Pb-associated changes showed linear concentration dependence in females, but non-linearity in males, with stronger or selective changes at 50 ppm. Statistically, FI performance was associated with corticosterone changes in females, but with frontal cortical dopaminergic and serotonergic changes in males. Corticosterone changes differed markedly in FI vs. NFI groups in both genders, demonstrating a critical role for behavioral history and raising caution about extrapolating biochemical markers across such conditions. These findings demonstrate that maternal Pb interacts with prenatal stress to further modify both behavioral and corticosterone responses to stress challenge, thereby suggesting that studies of Pb in isolation from other disease risk factors will not reveal the extent of its adverse effects. These findings also underscore the critical need to extend screening programs for elevated Pb exposure, now restricted to young children, to pregnant, at risk, women.

Prenatal restraint stress differentially modifies basal and stimulated dopamine and noradrenaline release in the nucleus accumbens shell: an ‘in vivo’ microdialysis study in adolescent and young adult rats

Gestational stress [prenatal stress (PNS)] has been associated with low birth weight, preterm delivery, and higher vulnerability to psychiatric disorders such as schizophrenia, depression or attention deficit with hyperactivity disorder. The alteration of catecholamine transmission has been attributed a major role in the etiology of psychiatric disturbances. We investigated the effect of PNS on basal and stimulated dopamine and noradrenaline output in the nucleus accumbens of freely moving adolescent and young adult rats (30-35 and 60-70 postnatal days respectively) because of the importance of this area in drug dependence and possibly in psychiatric disorders that are treated with drugs that act on dopamine and noradrenaline transmission. Stimulation was obtained with intraperitoneal amphetamine (0.25 mg/kg) or subcutaneous nicotine (0.4 mg/kg). The results showed the following: (i) basal and amphetamine-stimulated dopamine output in adolescent and adult PNS rats is higher than in controls; (ii) nicotine-stimulated dopamine output is lower than in controls in adolescent but not in adult PNS rats; (iii) basal noradrenaline output is lower than in controls in adolescent but not in adult PNS rats; (iv) amphetamine-stimulated noradrenaline output is higher than in controls in adult but not in adolescent PNS rats; (v) nicotine-stimulated noradrenaline output in PNS rats is higher than in controls, although only in adults. These results show that PNS may produce a complex change in accumbal dopamine and noradrenaline transmission. We discuss the possibility that these changes might be correlated with the development of psychiatric disorders or with an increased vulnerability to drug addiction.

The effects of prenatal stress on expression of p38 MAPK in offspring hippocampus

The hippocampus, which has the highest density of GC receptors in the brain, is involved in the regulation of the HPA and the behavioral responses to stress. Overexposure to corticosteroid hormones is harmful to hippocampal neuron integrity. Our purpose is to investigate the effects of prenatal stress (PNS) on expression of p38 mitogen-activated protein kinase (p38 MAPK) in offspring hippocampal neurons using Western blotting and Immunohistochemistry. The prenatal restraint stress induces significant increase in the expression of p-p38 MAPK and total p38 MAPK in female offspring hippocampus. The level of p-p38 MAPK in PNS female offspring rats was significantly increased (126.41±3.937, n=6) compared with that in the control female offspring rats (101.35±3.468, n=6, P<0.01). Immunoblot analysis revealed there was significant difference in the level of total p38 MAPK between the female control and prenatal restraint stress offspring rats (101.70±3.162 vs. 128.111±2.724, respectively, P<0.01). Immunodensity of p38 MAPK was significantly increased above female control in PNS female offspring hippocampal CA3 and CA4 fields (P<0.001 vs. control group, CON). The data suggest that exposure of animals to a period of stressful experience during a critical phase could impose lasting effects on the offspring hippocampal neurons cellular signalling of offspring hippocampus.

Prenatal Restraint Stress Generates Two Distinct Behavioral and Neurochemical Profiles in Male and Female Rats

Prenatal Restraint Stress (PRS) in rats is a validated model of early stress resulting in permanent behavioral and neurobiological outcomes. Although sexual dimorphism in the effects of PRS has been hypothesized for more than 30 years, few studies in this long period have directly addressed the issue. Our group has uncovered a pronounced gender difference in the effects of PRS (stress delivered to the mothers 3 times per day during the last 10 days of pregnancy) on anxiety, spatial learning, and a series of neurobiological parameters classically associated with hippocampus-dependent behaviors. Adult male rats subjected to PRS (“PRS rats”) showed increased anxiety-like behavior in the elevated plus maze (EPM), a reduction in the survival of newborn cells in the dentate gyrus, a reduction in the activity of mGlu1/5 metabotropic glutamate receptors in the ventral hippocampus, and an increase in the levels of brain-derived neurotrophic factor (BDNF) and pro-BDNF in the hippocampus. In contrast, female PRS rats displayed reduced anxiety in the EPM, improved learning in the Morris water maze, an increase in the activity of mGlu1/5 receptors in the ventral and dorsal hippocampus, and no changes in hippocampal neurogenesis or BDNF levels. The direction of the changes in neurogenesis, BDNF levels and mGlu receptor function in PRS animals was not consistent with the behavioral changes, suggesting that PRS perturbs the interdependency of these particular parameters and their relation to hippocampus-dependent behavior. Our data suggest that the epigenetic changes in hippocampal neuroplasticity induced by early environmental challenges are critically sex-dependent and that the behavioral outcome may diverge in males and females.

Effects of Prenatal Stress and Restraint Stress on Amygdala Complex of the Rat: II. Effects on the Astrocytic Cell Processes

Effects of Prenatal Stress and Restraint Stress on Amygdala Complex of the Rat: II. Effects on the Astrocytic Cell Processes

Impact of an acute exposure to ethanol on the oxidative stress status in the hippocampus of prenatal restraint stress adolescent male rats

Prenatal restraint stress (PRS) in rats is associated with hippocampal dysfunctions and several behavioural and endocrine disorders related to this brain area. Recently, we have reported that the PRS modifies the hypothalamic–pituitary–adrenal (HPA) response to an ethanol challenge in adolescent animals. Since hippocampus is particularly sensitive to the deleterious effects of ethanol during adolescence, we investigated in this study the combined effects of PRS and ethanol administration on the oxidative status in the hippocampus of 28-day-old male rats. Thirty minutes after an intraperitoneal (i.p.) injection of ethanol (1.5 g/kg), the activities of several antioxidant enzymes (superoxide dismutase, catalase and glutathione peroxidase) but also non-enzymatic antioxidant (reduced glutathione) were assayed. Thiobarbituric acid reactive substances (TBARS) levels were also measured as a marker of lipid peroxidation. Ethanol enhanced superoxide dismutase activity in control rats but not in PRS rats. At basal level, catalase activity was lower in PRS rats than in control rats, indicating a potentially higher sensitivity to oxidative damages after this early stress. However, the hippocampal TBARS levels were not significantly affected by the ethanol administration, showing that an acute ethanol exposure does not induce oxidative damage in adolescent male rats. In conclusion, our data suggest that PRS affects both basal antioxidant status in the hippocampus and antioxidant response after an acute ethanol exposure. These findings extend previous works showing that PRS leads to hippocampal dysfunctions and raise the question of the potential increase of the hippocampal oxidative damage in PRS rats after repeated exposure to ethanol.

Effects of prenatal restraint stress on the hypothalamus–pituitary–adrenal axis and related behavioural and neurobiological alterations

Chronic hyper-activation of the hypothalamus-pituitary axis is associated with the suppression of reproductive, growth, thyroid and immune functions that may lead to various pathological states. Although many individuals experiencing stressful events do not develop pathologies, stress seems to be a provoking factor in those individuals with particular vulnerability, determined by genetic factors or earlier experience. Exposure of the developing brain to severe and/or prolonged stress may result in hyper-activity of the stress system, defective glucocorticoids-negative feedback, altered cognition, novelty seeking, increased vulnerability to addictive behaviour, and mood-related disorders. Therefore, stress-related events that occur in the perinatal period can permanently change brain and behaviour of the developing individual. Prenatal restraint stress (PRS) in rats is a well-documented model of early stress known to induce long-lasting neurobiological and behavioural alterations including impaired feedback mechanisms of the HPA axis, disruption of circadian rhythms and altered neuroplasticity. Chronic treatments with antidepressants at adulthood have proven high predictive validity of the PRS rat as animal model of depression and, reinforce the idea of the usefulness of the PRS rat as an interesting animal model for the design and testing of new pharmacologic strategies in the treatment of stress-related disorders.

Prenatal restraint stress and motherless rearing disrupts expression of plasticity markers and stress-induced corticosterone release in adult female Sprague–Dawley rats

This study investigated the effects of prenatal stress and complete maternal deprivation, using the artificial rearing (AR) paradigm, on the expression of neural plasticity markers and hypothalamic–pituitary–adrenal (HPA) axis responsivity to stress. Rats were exposed to stress during gestation (day 10–21) and postnatally were either artificially reared (AR) or mother reared (MR). AR involves complete separation of the pup from both the dam and the litter throughout the pre-weaning period. In adulthood, we measured levels of corticosterone (CORT) in response to restraint stress. Also, we examined the expression of synaptophysin (SYN) and brain-derived neurotrophic factor (BDNF) in the medial prefrontal cortex (MPFC) and the nucleus accumbens (Nacc), areas of the brain that mediate behavioral activation and attention, among other behaviors. Earlier work on the same rats indicated that these behavioral endpoints, such as locomotor activity and sensorimotor gating, are affected by our prenatal and postnatal manipulations. Prenatal stress decreased CORT at 20 and 90 min post-stressor in MR, but not in AR, animals. Also, in comparison to MR groups, AR decreased SYN and BDNF expression in the MPFC and Nacc. Additional somatosensory ‘licking-like’ stroking stimulation partially reversed the effects of AR. Prenatal stress did not have a robust main effect but affected the impact of the postnatal rearing condition on SYN expression and stress-induced CORT. These results suggest that both prenatal and postnatal adversities have an influence on HPA axis responsivity and alter the expression of plasticity related neuronal proteins.

Concurrent Exposure to Perfluorooctane Sulfonate and Restraint Stress during Pregnancy in Mice: Effects on Postnatal Development and Behavior of the Offspring

The combined effects of maternal restraint stress and perfluorooctane sulfonate (PFOS) on postnatal development and behavior of the offspring were assessed in mice. Thirty-four plug positive females were randomly divided into two groups. Animals were given by gavage 0 and 6 mg PFOS/kg/day on gestation days 12-18. One-half of the animals in each group was subjected to restraint stress (30 min per session, three sessions per day) during the same period. Neither restraint nor PFOS exposure significantly modified maternal food or water consumption. Pups of dams exposed to 6 mg/kg of PFOS showed a reduced body weight on postnatal days 4 and 8. Moreover, PFOS exposure induced some delay in developmental landmarks and neuromotor maturation. Maternal restraint stress reduced activity in an open-field when combined with 6 mg PFOS/kg/day. In addition, in males prenatal restraint stress impaired motor coordination in a rotarod. The current results indicate that concurrent exposure to PFOS and restraint stress during pregnancy induces opposite effects on developmental parameters in the pups. These effects consist in a general delayed maturation trend induced by PFOS exposure, and a general accelerated maturation pattern induced by prenatal stress. Interactive effects between PFOS and maternal stress were observed in young adult mice. These effects consisted mainly in a diminished activity in an open-field test.

Sex and region difference of the expression of ERK in prenatal stress offspring hippocampus

Prenatal stress is known to cause neuronal loss and oxidative damage in the hippocampus of offspring rats. The underlying molecular mechanism has not been fully understood. The extracellularsignal-regulated kinase (ERK1/2) is recruited when the brain undergoes synaptic plasticity and remodeling. In the present study, we used Western blotting and immunohistochemistry techniques to examine the effects of prenatal restraint stress (PNS) on the expression of phosphorylated ERK (p-ERK) and total ERK. Pregnant rats in the PNS group were exposed to restraint stress on day 14–20 of pregnancy three times daily for 45min. One-month-old offspring rats were used in this experiment. PNS treatment increased the expression of p-ERK2 compared to that in the control female offspring rats and total ERK2 in female offspring hippocampus compared with that of control group. No significant changes in the amounts of total ERK1 of prenatally offspring hippocampus were observed in both genders compared with control animals. ERK immunodensity was significantly increased in PNS groups in CA3 field in male offspring hippocampus compared with control animals. ERK optical density was significantly increased in PNS female offspring hippocampus CA1, CA3 and CA4 region. However, ERK optical density was not significantly different between male control and PNS groups in CA1, CA4 fields and DG in offspring hippocampus. These findings suggest the sex and region-dependent effects of prenatal stress on the expression of ERK in offspring hippocampus. ERK expression changes induced by prenatal stress may contribute to hippocampus synaptic plasticity changes of the offspring.

Prenatal restraint stress impairs learning and memory and hippocampal PKCbeta1 expression and translocation in offspring rats

Prenatal stress results in various learning, behavioral and emotional alterations observed in later life. However, the mechanisms underlying these effects of prenatal stress are not fully understood. In the present study we examined the impact of prenatal stress (an unpredictable restraint stress) during gestational days 13 to 20 on the performance in Morris water maze and passive avoidance training in 1- and 3-month-old rat offspring. The expression and translocation/activation of protein kinase C (PKC) beta1 in the hippocampus of prenatally stressed offspring were also investigated. One-month-old female and male and 3-month-old female prenatally stressed offspring showed longer latency to find the platform and used the inefficient search strategy in the water maze task and showed lower memory score in the passive avoidance training compared with controls. The expression of PKCbeta1 protein and mRNA in the hippocampus of prenatally stressed offspring was dramatically weakened. In the control offspring hippocampus, passive avoidance training induced the PKCbeta1 translocation from the cytosol to the membrane, which, however, was not observed in prenatally stressed offspring. Our results suggest that deficient signal transduction of PKCbeta1 in the hippocampus resulting from prenatal restraint stress may play an important role in the impairment of learning and memory abilities of offspring.

Prenatal stress and early adoption effects on benzodiazepine receptors and anxiogenic behavior in the adult rat brain

Chronic maternal stress during pregnancy has been associated with behavioral alterations that persist into adulthood. Moreover, adoption procedures performed immediately after birth can reverse these alterations. In this study, we examined the effects of prenatal restraint stress and adoption at birth (cross-fostering) on the behavioral response to an anxiety-provoking situation and on the adult male offspring expression of benzodiazepine (BDZ) receptors in selected brain areas. Adult offspring of rats stressed during the last week of pregnancy exhibited higher levels of anxiety than control rats. The anxiogenic behavior found at the elevated plus maze (EPM) has been related to the reduced levels of BDZ receptor levels in specific brain areas. Adult offspring of rats stressed during pregnancy exhibited a decrease in the number of BDZ receptors binding sites in the central amygdaloid nucleus (Ce), CA1, CA3, and the dentate gyrus regions of the hippocampus when compared to controls. Regarding the adoption procedure, control pups raised by a foster gestationally stressed mother showed similar levels of anxiety as stressed groups. Stressed offspring raised by a foster control mother showed reduced anxiety levels compared to that of the control groups. Adoption per se showed no difference in time spent, neither in the open arms of the plus maze nor in BDZ receptor levels, when compared to the corresponding control and stressed groups. Stressed offspring raised by a foster control mother reverted BDZ receptor levels to control values. However, control pups raised by a gestationally stressed foster mother showed similar values compared to the control offspring in hippocampus, in spite of showing an anxiogenic behavior in the EPM. We found a significant increase of Ce BDZ receptor levels in control offspring raised by a foster stressed mother that could be explained as a compensatory effect to a GABA receptor desensitization. In summary, the behavioral outcome of the adult offspring is vulnerable both to the stress experience during the late prenatal period as well as to possible variations in care during lactation by mothers subjected to chronic stress during gestation. There seems to be a direct correlation between anxiety state and BDZ receptor levels in the adult offspring raised by their biological mothers. However, the mechanism of BDZ regulation leading to an anxious behavior might be different if the insult is received only postnatally as opposed to both pre and postnatally.

Aluminum, restraint stress and aging: Behavioral effects in rats after 1 and 2 years of aluminum exposure

Both aluminum (Al) and aging have been associated with neurobehavioral changes in mammals. In this study, the long-lasting neurobehavioral effects of prenatal restraint stress and oral Al exposure from conception to sacrifice were assessed in adult (1 year) and old (2 years) rats. Pregnant females were orally exposed to 0, 50, and 100 mg Al/kg/day. Each Al-exposed group was divided into two subgroups. One of this was subjected to restraint stress (2 h/day on gestation days 6–20). The offspring of the treated females were maintained with the same Al treatment until sacrifice at 1 or 2 years of age. Activity in an open-field and learning in a water maze were evaluated. Although no significant differences were observed in motor activity, a biphasic effect of Al on learning could be observed. Thus, exposure to 100 mg Al/kg decreased performance of the task in both adult and old rats when compared to animals exposed to 50 mg Al/kg. An age-related effect on water maze performance, as well as an accumulation of Al in brain of rats exposed to 100 mg Al/kg at 2 years of age was found. Interestingly, while prenatal restraint stress did not modify behavioral parameters, Al accumulation was prevented by prenatal restraint.

Prenatal Restraint Stress and Long-Term Affective Consequences

Chronic or repeated stress during critical periods of human fetal brain development has been associated with various learning, behavioral and/or mood disorders in later life. In this investigation, pregnant Fischer 344 rats was individually restrained three times a day for 45 min during the last week of gestation in transparent plastic cylinders while at the same time being exposed to bright light. Control pregnant females were left undisturbed in their home cages. Anxiety and depressive-like behavior was measured in the offspring at an age of 6 months using the open field test, the home cage emergence test and the forced swim test. Prenatally stressed rats spent more time in the corners and less time along the walls of an open field, while no difference in total distance moved was observed. In addition, prenatally stressed rats took more time to leave their home cage in the home cage emergence test. On the other hand, no differences in immobility were observed in the forced swim test. Moreover, prenatally stressed rats showed lower stress-induced plasma corticosterone levels compared with control rats. Prenatal stress (PS) had no effect on the number of 5-bromo-2-deoxyuridine-positive cells – used as a measure for cell proliferation – in the dentate gyrus of these rats. These data further support the idea that PS may perturb normal anxiety-related development. However, the present data also suggest that an adaptive or protective effect of PS should not be ignored. Genetic factors are likely to play a role in this respect.

Attenuation by a sigma1 (σ1) receptor agonist of the learning and memory deficits induced by a prenatal restraint stress in juvenile rats

1. Stress during pregnancy results in complex neurochemical and behavioral alterations throughout the offspring lifetime. We here examined the impact of prenatal stress (PS) on memory functions in male and female offspring and report the efficacy of a selective sigma(1) (sigma(1)) receptor agonist, igmesine, in alleviating the observed deficits. 2. Dams received an unpredictable 90-min duration restraint stress from gestational day E17 to E20. Learning was examined in offspring between day P24 and P36 using spontaneous alternation in the Y-maze, delayed alternation in the T-maze, water-maze learning and passive avoidance. 3. Both male and female PS rats showed impairments of spontaneous and delayed alternation performances. Acquisition of a fixed platform position in the water-maze was unchanged in PS rats, but the probe test revealed a diminution of time spent in the training quadrant. Acquisition of a daily changing platform position demonstrated impaired working memory for male and female PS rats. Finally, passive avoidance deficits were observed. 4. Pretreatment with the selective sigma(1) agonist igmesine (1-10 mg x kg(-1) i.p.) reversed the PS-induced learning deficits in offspring rats for each test. The sigma(1) antagonist BD1063 failed to affect performances alone but blocked the igmesine effect, confirming the involvement of the sigma(1) receptor. 5. PS thus induces delayed memory deficits, affecting spatial and nonspatial, short- and long-term memories in juvenile male and female offspring rats. Activation of the sigma(1) neuromodulatory receptor allows a significant recovery of the memory functions in PS rats.

Persistent behavioral and autonomic supersensitivity to stress following prenatal stress exposure in rats

Prenatal restraint stress (PS) has been suggested as an attractive chronic model of anxiety. Here, we characterized the behavioral and autonomic responsivity to acute stress exposure in adult PS subjects. In Wistar rats, locomotor activity, as well as spontaneous behavior in an established animal model of anxiety, the elevated plus-maze, was unaffected by PS. However, the anxiogenic-like response normally seen on the plus-maze following a restraint stress was markedly potentiated in adult PS subjects, despite indistinguishable corticosterone responses. In addition, we assessed the tail skin temperature response to a mild social stressor, transient social mixing. The diazepam-sensitive, late phase of the temperature response was markedly potentiated in adult PS subjects. In summary, PS induces a persistent phenotype of increased behavioral and autonomic sensitivity to stress. This paradigm might serve as an attractive screening model for anti-anxiety compounds.