Postnatal behavioral effects in mice after prenatal exposure to methylmercury

CFW mice were injected with methylmercury hydroxide (1, 2, 3, 5 or 10 mg/kg as mercury) on Day 8 of gestation. Mice treated with 3, 5 or 10 mg/kg averaged $\text{1}\text{3}$ fewer pups than controls. Pups from these treated animals weighed less than controls and the weight differences persisted through weaning but were no longer significant at 56 days of age. Mice exposed to methylmercury in utero showed significant differences from controls in their behavior in a 2-way active avoidance shuttle box and in a punishment situation but not when tested in an open field, a water escape runway or a conditioned suppression paradigm. Neither the mothers nor progency of the mice exposed prenatally to methylmercury showed behavioral deficits.     

Effects of prenatal cocaine on behavioral adaptation to chronic stress in adult rats

Prenatal exposure to cocaine in rats has previously been shown to alter the behavioral and hormonal responses to acute stressors, although no work has yet examined stress adaptation in these animals in adulthood, a possibility examined in this experiment. Male and female offspring of Sprague–Dawley rat dams given 40 mg/kg/3 ml subcutaneously daily from gestational days 8–20 (C40), saline injected and pair-fed dams (PF), and non-treated dams (NT) were tested in adulthood (90–120 days). Offspring were given a 5-min open field test 24 h following the last of 1 (Acute), 9 (Chronic) or 0 (control) daily 15-min intermittent footshock sessions. Substantially more behavioral adaptation was evident in NT offspring than in C40 and PF animals. The attenuated stress adaptation seen in C40 offspring extends prior work showing altered stress responsiveness in these animals, although the PF data caution against the conclusion that this lack of stress adaptation necessarily reflects gestational exposure to cocaine per se.     

Parachlorophenylalanine exacerbates oxidative stress induced by gentamicin in rats

The present work studies the effect of parachlorophenylalanine (PCPA, 200 mg/kg intraperitoneally/48 hr for 7 days) on the oxidative stress and nephropathy induced by gentamicin (80 mg/kg intraperitoneally/daily for 7 days) in Wistar rats. The effect of PCPA on lipid peroxidation products and reduced glutathione content in renal and brain tissue, as well as on 5HT content in brain was assessed. Catalase and superoxide dismutase activities were determined in brain tissue. Blood urea nitrogen and creatinine in plasma and total protein content in urine were also measured. Gentamicin caused significant increases in proteinuria, non-protein nitrogen compounds and lipid peroxidation markers, together with decreases in both reduced glutathione content in renal and brain tissue and enzymatic activities in brain homogenates. PCPA harnessed the effect of gentamicin in the brain and the kidney, while PCPA alone induced brain oxidative stress. These results support the prooxidant action of PCPA in brain tissue and its capacity to exacerbate the oxidative stress and renal dysfunction induced by gentamicin, as well as the possible antioxidant property of serotonin.     

Postnatal function following prenatal reserpine exposure in rats: neurobehavioral toxicity

Behavioral and neurochemical analyses were conducted on preweanling CD rats prenatally exposed to either 0, 0.375 or 0.750 mg/kg/day reserpine SC on gestation days 12-15. Offspring body weights were taken on test days, and pups were tested for negative geotaxis responding on postnatal day 8, developmental activity on days 12, 16 and 20, and auditory startle habituation on day 19 or 20. In addition, brains were removed from culled pups on day 1, 1 male and 1 female/litter on day 8, and animals tested for activity on day 21. Neurochemical assays were performed on whole brains from 1- and 8-day-old pups, and on caudate nucleus, frontal cortex and hippocampus of day 21 rats. Treatment resulted in dose-related decreases in maternal weight gain over gestation and mean pup weight at birth. Changes in the normal developmental activity pattern were both sex and dose dependent in treated rats. In auditory startle habituation experiments, rats exhibited a dose-related decrease in response amplitude and rate of habituation. In the day 21 females, caudate nucleus dopamine (DA) and serotonin (5-HT) concentrations and DA-receptor binding were decreased in a dose-dependent manner. Males showed less dramatic, but similar trends in caudate changes. However, hippocampal 5-HT and 5-HT receptor binding were significantly reduced only in females. Thus, sex-related behavioral alterations were accompanied by sex-related neurochemical changes, and females generally were more affected than males by prenatal reserpine treatment. The significant decrease in activity and auditory startle amplitude in the females is consistent with the suggested down regulation of the DA system in regional brain areas.     

Exposure to juvenile stress exacerbates the behavioural consequences of exposure to stress in the adult rat

To examine the effects of exposure to post-weaning pre-puberty (juvenile) stress on the emotional and cognitive abilities in response to exposure to stress in adulthood, we first exposed rats to a platform stress at the age of 28 d. Two months later the rats were exposed to acute swim stress. Rats exposed to both stressors showed a higher level of anxiety (as measured both in open-field and startle response tests) than controls or rats exposed to either the juvenile or the adulthood stressor. In the Morris water-maze, rats that were exposed to both juvenile and adulthood stress performed better than the other groups. In a second experiment we verified that the effect of the juvenile stress was indeed age-dependent. One group was exposed at the age of 26-28 d and again at the age of 60 d (juvenile + adulthood stress); the other group was exposed to the first stressor at the age of 60-62 d and to the second at the age of 90 d [adulthood (60) + adulthood (90) stress]. Juvenile + adulthood stress had a significantly greater effect than exposure to stress twice in adulthood, on anxiety level and on the performance in the water-maze. Finally, in a third experiment we found that the juvenile+adulthood stress group swam faster and tended to explore the central area more than the other groups--a finding that could explain their better performance on the first trial of the spatial task. These results indicate that an exposure to a relatively brief juvenile stressful experience has profound and long-lasting effects on the ability to cope with stress in adulthood.     

Postnatal development and behaviour of Wistar rats after prenatal toluene exposure

Pregnant Wistar rats were treated with different concentrations of toluene by inhalation (300, 600, 1000 and 1200 ppm) from day 9 to day 21 of pregnancy for 6 h a day in a whole-body inhalation chamber (controls inhaled fresh air only). From day 22, rats were kept single-caged and were allowed to deliver. Besides a detailed evaluation of the physical development of the offspring we performed the following tests: forelimb-grasp reflex, righting reflex, cliff-drop aversion reflex, maintainance of balance on a rotating rod, measurement of locomotor activity and learning ability in a discrimination learning test. A toluene exposure of 1200 ppm resulted in a reduced body weight of rat dams and offspring and a higher mortality until weaning. The physical development (incisor eruption, eye opening and vaginal opening) was retarded in this group. There were no clear-cut and concentration-dependent differences in the development of reflexes, rota rod performance and locomotor activity between the offspring of animals exposed to toluene and the controls. Likewise, no effects were found on learning ability in the operant conditioning task. Compared to the controls there were no differences in mating, fertility and pregnancy indexes in the F₁-generation. The tests performed have provided no evidence that toluene exposures ≤ 1200 ppm induce adverse effects on the behaviour of rat offspring exposed during late embryonic and fetal development. Received: 17 July 1996 / Accepted: 20 September 1996     

Persisting behavioral consequences of prenatal domoic acid exposure in rats

To investigate the behavioral effects of prenatal exposure to the marine toxin domoic acid, pregnant female rats were injected subcutaneously with 0, 0.3, 0.6, or 1.2 mg/kg of domoic acid on gestational day 13. The offspring were then run through a behavioral testing battery to determine the developmental effects of the toxin on spontaneous alternation in the T-maze, on locomotor activity in the Figure-8 maze, and on working memory in the 8-arm radial maze. In the T-maze, no significant domoic acid induced differences were seen on spontaneous alternation, but there were significant domoic acid effects on latency. Prenatal domoic acid exposure caused a dose-related increase in response latency in the second spontaneous alternation test. There was also a significant domoic acid effect seen in the 1-h long Figure-8 maze test. Locomotor activity measured in the Figure-8 maze detected a persisting effect of the 1.2 mg/kg domoic acid dose, which significantly increased the rate of habituation over the activity test session. This was characterized by higher initial activity followed by greater decline in activity. In the radial-arm maze the control vehicle treated rats showed the normal sex-related difference in spatial learning and memory with males outperforming females. Developmental domoic acid exposure decreased this effect such that the normal sex difference in spatial memory was not seen with the 1.2 mg/kg domoic acid dose. The rats of both sexes with a history of prenatal domoic acid exposure showed increased susceptibility to the amnestic effects of the muscarinic acetylcholine scopolamine, suggesting that they had less functional reserve with which to solve the radial-arm maze memory task. This study demonstrates persisting neurobehavioral effects of acute prenatal exposure to domoic acid at doses that do not cause overt clinical signs of toxicity.     

Effect of prenatal haloperidol exposure on behavioral alterations in rats

Pregnant Charles-Foster rats were exposed to haloperidol (HAL), a neuroleptic drug that binds to and blocks dopamine (DA) receptor subtypes at a dose of 2.5 mg/kg body weight (intraperitoneally) from Gestation Day (GD) 12 to 20. The animals from both treated as well as vehicle control groups were allowed to deliver on GD 21. The offspring culled at birth on the basis of sex and weight were subjected to behavioral tests at the age of 8 weeks. The HAL-treated rat offspring showed a significant increase in anxiogenic behavior on the open field, elevated plus-maze and elevated zero-maze tests when compared with the vehicle-treated (control) rat offspring of the same age group. These findings suggest that prenatal exposure to HAL during a critical period of brain development leaves a lasting imprint on the brain, resulting in abnormal anxiety states, possibly through dopaminergic neurotransmission mechanisms.     

Chronic agomelatine treatment corrects behavioral, cellular, and biochemical abnormalities induced by prenatal stress in rats

Rationale and objectives

The rat model of prenatal restraint stress (PRS) replicates factors that are implicated in the etiology of anxious/depressive disorders. We used this model to test the therapeutic efficacy of agomelatine, a novel antidepressant that behaves as a mixed MT1/MT2 melatonin receptor agonist/5-HT_2c serotonin receptor antagonist.

Results

Adult PRS rats showed behavioral, cellular, and biochemical abnormalities that were consistent with an anxious/depressive phenotype. These included an increased immobility in the forced swim test, an anxiety-like behavior in the elevated plus maze, reduced hippocampal levels of phosphorylated cAMP-responsive element binding protein (p-CREB), reduced hippocampal levels of mGlu2/3 and mGlu5 metabotropic glutamate receptors, and reduced neurogenesis in the ventral hippocampus, the specific portion of the hippocampus that encodes memories related to stress and emotions. All of these changes were reversed by a 3- or 6-week treatment with agomelatine (40?C50?mg/kg, i.p., once a day). Remarkably, agomelatine had no effect in age-matched control rats, thereby behaving as a ??disease-dependent?? drug.

Conclusions

These data indicate that agomelatine did not act on individual symptoms but corrected all aspects of the pathological epigenetic programming triggered by PRS. Our findings strongly support the antidepressant activity of agomelatine and suggest that the drug impacts mechanisms that lie at the core of anxious/depressive disorders.     

Behavioral changes in juvenile rats after prenatal exposure to ethosuximide

Juvenile rats 4-6 weeks old exposed prenatally at days 5-20 of gestation to ethosuximide at 10 mg/kg/dams' body weights per day were examined for behavioral abnormalities. Pinning behavior in the pups aged 4-5 weeks was significantly more frequent than that in age-matched controls. However, basal activity of open-field behavior and activity inhibited by diazepam administration in the pups aged 5-6 weeks showed no difference from the controls. The intensity of stereotyped behavior induced by apomorphine (1 mg/kg, SC) was significantly greater in the pups aged 5-6 weeks than in the controls. These results indicate that prenatal exposure to ethosuximide may cause changes in the dopaminergic neurons in the central nervous system.     

Alterations in behavioral and striatal dopamine asymmetries induced by prenatal stress

We investigated the effects of maternal noise and light stress, randomly applied throughout pregnancy, on the development of behavioral and neurochemical asymmetries in the rat offspring. This form of maternal stress resulted in a rightward positioning of the tail of both sexes soon after birth as opposed to the leftward bias in controls. At adulthood, prenatally stressed offspring showed a change in directional bias compared to controls with a preponderance of left turns after amphetamine. In the males, this was expressed as a reduction in directional preference, while in females a reversal occurred of their dominant turning direction from right (controls) to left. We also observed a reduction in dopamine turnover rates in the left corpora striata of stressed offspring of both sexes. Again, in the females, this change was particularly marked and resulted in a reversal towards the right hemisphere. The findings from this study are consistent with the possibility that the alterations in cerebral asymmetries induced by prenatal stress may underly the decrease in the ability of the offspring to cope with anxiety provoking situations.     

Postnatal behavior in hatano high- and low-avoidance rats following prenatal exposure to low-dose methylazoxymethanol

The hypothesis that genetic factors influence behavioral effects was tested in rats exposed prenatally to methylazoxymethanol (MAM). We examined whether baseline behavior is an important factor influencing behavioral effects, and whether a behaviorally selected strain was useful for study of neurobehavioral teratology. Pregnant high- and low-avoidance animals (HAAs and LAAs) of the Hatano strain, selectively bred for high and low shuttlebox avoidance responses, respectively, were given an IP injection of a low dose of MAM (15 mg/kg) on day 14 of gestation. The offspring of these animals were subjected to behavioral tests for locomotor activity (running-wheel and open-field tests) and learning ability (Biel maze and shuttlebox avoidance tests). There were no significant effects of MAM on running-wheel activity or shuttlebox avoidance learning, whereas the number of errors in the Biel maze was increased in the MAM offspring of both strains. Interestingly, open-field activity of the MAM offspring was markedly decreased in LAAs but not in HAAs. Therefore, an additional experiment was performed to determine plasma levels of ACTH and corticosterone following open-field exposure. When compared to control offspring of the respective strains, plasma levels of ACTH and corticosterone were not altered by prenatal MAM treatment in LAAs. Instead, the MAM offspring in HAAs exhibited decreased ACTH levels in absence of behavioral alterations. These results demonstrated that prenatal exposure to low doses of MAM may alter postnatal behavior and endocrine response of the offspring, although to a differing degree in HAAs and LAAs. Our observations suggested that behaviorally selected strains are sensitive to neurobehavioral teratogens such as MAM.     

Physical and behavioral development in rats after late prenatal exposure to diazepam

The effect of late prenatal exposure to diazepam (DZP) on physical and behavioral development of rat pups was investigated. Prenatal exposure to DZP (20 mg/kg, sc, in last week of pregnancy) did not alter litter size and no gross malformations were noted at birth. Body weight at birth and subsequent weight gain was significantly less in these animals. The development of reflexes and neuromuscular maturation was normal. Open field locomotor activity and rearing scores were significantly decreased. Test of social play in juvenile rats revealed normal pattern of sexual dimorphism with increased masculinized behavior. Acquisition and retention of passive avoidance task was not affected by DZP exposure, however, retention of brightness discrimination task was significantly decreased. The hypnotic effect of a challenge dose of DZP and convulsive effect of pentylene tetrazole remained unaltered. Open field activity test in adult animals revealed increased ambulation. Probe dose of amphetamine in these animals caused paradoxical decrease in activity. It is concluded that exposure to high dose of DZP during late prenatal period may not manifest in physical or neuromuscular impairment during early development period, except for weight loss, however, it may have long term effects on behavior becoming manifest in adolescence and at maturity.     

Loss of nicotine-induced effects on locomotor activity in fetal alcohol-exposed rats

Previous evidence from our laboratory showed that systemic injection of nicotine enhanced attention and memory in control rats, but not fetal alcohol–exposed (FAE) rats. The present study examined the effects of nicotine on two measures of locomotor activity in FAE rats. Subjects were 2-month-old male offspring of Sprague–Dawley rats fed a 35% ethanol-derived caloric diet, a pair-fed sucrose diet, or a chow-fed diet during the last 2 weeks of gestation. The two experiments examined the effects of intraperitoneal injection of saline or nicotine (0.25 or 0.75 mg/kg) on rearing in an operant chamber and locomotor activity in an open field for 60 min. The high dose of nicotine produced a decrease in rearing in the first 10-min period, followed by a later increase in rearing in the pair-fed and chow-fed groups, but not the FAE group. Nicotine also produced an elevation of locomotor activity in the open field in only the two control groups. These findings provide additional evidence that FAE rats show less behavioral responsiveness to nicotine.     

Magnetic resonance and spectroscopic imaging in prenatal alcohol-exposed children: preliminary findings in the caudate nucleus

Magnetic resonance imaging (MRI) and magnetic resonance spectroscopic imaging (MRSI) offer unique, noninvasive methods of measuring, respectively, in vivo quantitative neuroanatomy and neurochemistry. The main purpose of the present study was to identify and compare the neuroanatomical and neurochemical abnormalities that are associated with prenatal exposure to alcohol in both fetal alcohol syndrome (FAS)-diagnosed children and those diagnosed with fetal alcohol effects (FAE). MR data of three age-, gender- and race-balanced groups of children, FAS-diagnosed, FAE-diagnosed and non-exposed controls, were compared. Effects of prenatal alcohol exposure, regardless of diagnosis, were found in the caudate nucleus. Specifically, a significantly smaller caudate nucleus was found for the FAS and FAE participants compared to the controls. In addition, the metabolite ratio of N-acetyl-aspartate to creatine (NAA/Cr), an indicator of neuronal function, in left caudate nucleus of both the FAS and FAE participants was elevated compared to the control group. Analysis of absolute concentrations revealed that the increase in the ratio of NAA/Cr was due to an increase in NAA alone. Although its exact function in the CNS is unknown, NAA is believed to be a neuronal marker due to its exclusive localization to neurons. Some also speculate a role for NAA in myelination. Elevated NAA in the prenatal alcohol-exposed participants could indicate a lack of normal program cell death, dendritic pruning and/or myelination during development. The present study demonstrates that prenatal alcohol-exposed children, with or without facial dysmorphology, have abnormal brain anatomy and chemistry.     

Effect of prenatal administration of NSAIDs on the immune response in juvenile and adult rats

In order to investigate the effect of non-steroidal anti-inflammatory drugs (NSAIDs) on the development of rat immunity, indomethacin (IND; 0.25, 0.5, or 1.0 mg/kg/day), acetyl salicylic acid (ASA; 90, 180, or 360 mg/kg/day), or diclofenac sodium salt (DSS; 0.5, 1.0, or 2.0 mg/kg/day) suspended in 0.5% methylcellulose aqueous solution, was orally administered once daily to five pregnant Sprague-Dawley (IGS) rats per group on days 18-21 of gestation. After parturition, the serum IgM and IgG levels, the spleen weight, and the number of spleen cells were measured in 3- and 8-week-old pups. Afterwards, immunophenotyping analysis of splenocytes or peripheral blood lymphocytes and T-dependent antibody response were performed. The number of spleen cells in 3-week-olds increased when 1.0 mg/kg of IND and 180 mg/kg of ASA were administered. Immunophenotyping analysis using flow cytometry (FCM) indicated that the proportion and number of CD45RA(+) cells increased, and the proportion of CD3(-) NKR-P1A(+) cells decreased in males when dosed with IND at 1.0 mg/kg or ASA at 180 mg/kg. The serum anti-KLH IgG antibody titer decreased in the males of the IND 1.0 mg/kg dosing group, the serum levels of anti-KLH IgM, total IgM, and IgG were not changed at all. These changes disappeared in 8-week-old pups. There were no effects on any of the parameters in the 3- and 8-week-olds of the DSS treatment group. These results suggest that IND or ASA administration to dams during late gestation either causes a change in the lymphocyte subsets, or that they suppress the T-dependent antibody response in juvenile males. Both of these changes eventually recover to intact levels later on during development. These results will contribute to the development of a technique for the assessment of developmental immunotoxicity and generate data on the effect of prenatal administration of NSAIDs on the developmental immune system in pups.     

Effects of prenatal exposure to chronic mild stress and toluene in rats

The aim of the present study was to elucidate whether prenatal chronic stress, in combination with exposure to a developmental neurotoxicant, would increase effects in the offspring compared with the effects of either exposure alone. Development and neurobehavioral effects were investigated in female offspring of pregnant rats (Mol:WIST) exposed to chronic mild stress (CMS) during gestational days (GD) 9-20, or 1500 ppm toluene, 6 h/day during gestational days 7-20, or a combination of the two. Prenatal CMS was associated with decreased thymic weight and increased auditory startle response. The corticosterone response to restraint seemed modified by prenatal exposure to toluene. Lactational body weight was decreased in offsprings subjected to CMS, primarily due to effects in the combined exposure group. Cognitive function was investigated in the Morris water maze, and some indications of improved function due to CMS were observed. In the present experimental setting, there was no indication of the two exposures potentiating each other with respect to adverse effects on the nervous system. However, the effects of prenatal CMS indicate that stress during fetal life may interfere with the development of the thymus and increase the reactivity (startle reflex) of the offspring.