Risk assessment behaviors associated with corticosterone trigger the defense reaction to social isolation in rats: role of the anterior cingulate cortex

The extent to which the hypothalamic-pituitary-adrenal axis is activated by short-term and long-term consequences of stress is still open to investigation. This study aimed to determine (i) the correlation between plasma corticosterone and exploratory behavior exhibited by rats subjected to the elevated plus maze (EPM) following different periods of social isolation, (ii) the effects of the corticosterone synthesis blocker, metyrapone, on the behavioral consequences of isolation, and (iii) whether corticosterone produces its effects through an action on the anterior cingulate cortex, area 1 (Cg1). Rats were subjected to 30-min, 2-h, 24-h, or 7-day isolation periods before EPM exposure and plasma corticosterone assessments. Isolation for longer periods of time produced greater anxiogenic-like effects on the EPM. However, stretched attend posture (SAP) and plasma corticosterone concentrations were increased significantly after 30?min of isolation. Among all of the behavioral categories measured in the EPM, only SAP positively correlated with plasma corticosterone. Metyrapone injected prior to the 24?h isolation period reversed the anxiogenic effects of isolation. Moreover, corticosterone injected into the Cg1 produced a selective increase in SAP. These findings indicate that risk assessment behavior induced by the action of corticosterone on Cg1 neurons initiates a cascade of defensive responses during exposure to stressors.     

Individual differences in chronically defeated male mice: behavioral, endocrine, immune, and neurotrophic changes as markers of vulnerability to the effects of stress

This study aimed to analyze different behavioral profiles in response to chronic social defeat using the sensorial contact model. We hypothesized that a passive profile, unlike an active one, would be associated with behavioral and physiological characteristics related to depression. Six-week-old OF1 male mice were subjected to defeat for 21 consecutive days. A combination of cluster and discriminant analyses of the behavior exhibited during confrontation on Day 21 established two behavioral profiles: active (n?=?22) and passive (n?=?34). Passive mice, with a high level of immobility and low non-social exploration, had higher plasma corticosterone concentrations than active mice after 21 days of defeat. Three days after the last defeat, passive mice had lower corticosterone levels than manipulated-control mice (n?=?11). Higher levels of interleukin-6 and tumor necrosis factor-α (TNF-α) in the spleen and lower hippocampal brain-derived neurotrophic factor levels were observed in passive mice in comparison with those in active mice and the manipulated controls. The only differences observed in active mice in relation to the manipulated control were higher plasma corticosterone (Day 21) and TNF-α levels. The results show that different behavioral profiles in response to chronic defeat are associated with different physiological profiles, and that the passive profile presents physiological characteristics previously associated with depression.     

Establishment of a schizophrenic animal model through chronic administration of MK-801 in infancy and social isolation in childhood

BackgroundAlthough an increasing amount of evidence supports a “two-hit” hypothesis for the neurodevelopmental model of schizophrenia, there has been no development in animal models to test this hypothesis.MethodsAn animal model was established by chronic administration of 0.1, 0.3, and 0.5 mg/kg MK-801 in P7-P21 rats followed by four weeks of social isolation in childhood and then five days of social housing. Animal behaviors were measured by the open field (OF) test, the novel object recognition (NOR) test, the prepulse inhibition (PPI) test, and the elevated plus maze (EPM) test.ResultsWe found a significant decrease in the NOR index in adolescent rats compared to saline control rats when administering 0.5 mg/kg of MK-801 (P = 0.02). We found that social isolation had no significant effect on NOR index, though social isolation significantly increased the total distance traveled and significantly decreased the resting time in adolescent rats in the OF test (P < 0.001 and P = 0.003, respectively). In contrast, we observed that MK-801 administration showed no significant effects on either total distance traveled or resting time. Both MK-801 administration and social isolation had no significant effect on the percent of PPI and startle amplitudes in adolescent rats. Social isolation significantly reduced the open arm entries in adolescent rats in the EPM test (P = 0.023), but it did not reduce the ratio to enter the open arms and the stay time in open arm. Administration of MK-801 showed no significant effect on the indexes of entering the open arms in the EPM test on adolescent rats.ConclusionMK-801 intervention in infancy is associated with the damage of long-term visual memory, whereas social isolation in childhood is associated with the increased spontaneous activity and anxiety levels. Administration of MK-801 in infancy and social isolation in childhood are two independent factors on the neurodevelopmental defects.     

Acute exposure to a novel stressor further reduces the habituated corticosterone response to restraint in rats

The present study sought to identify dishabituation of the hypothalamic-pituitary-adrenal(HPA) axis response to different psychological stressors. Young adult male Sprague Dawley rats were exposed to five, 1 h sessions of restraint stress on five consecutive days. On the sixth day, and 2 h before additional exposure to restraint, animals were subjected to 30 min of a small (27cm square), elevated open field stressor (pedestal), which served as the dishabituating stimulus. We predicted HPA axis response dishabituation in chronically restrained rats exposed to the novel pedestal. Rats which underwent five days of restraint stress showed significantly blunted plasma corticosterone levels to restraint (habituation) as compared to restraint-nai've rats. However, rats which underwent five sessions of restraint responded with an enhanced habituation response when confronted with restraint shortly after exposure to the novel pedestal. Instead of HPA axis response dishabituation, we observed enhanced habituation. Subsequent experiments determined that a 1.25 mgkg corticosterone injection could substitute for pedestal exposure to produce enhanced restraint habituation.Combined treatment with both the glucocorticoid receptor antagonist RU40555 (30 mgkg)and the mineralocorticoid receptor antagonist RU283 18 (50 mgkg) blocked the expression of enhanced habituation after pedestal exposure. Thus, the delayed corticosterone negative feedback produced by novel stress led to enhanced expression of corticosterone response habituation.     

Estradiol decreases anxiety behavior and enhances inhibitory avoidance and gestational stress produces opposite effects

Although there is evidence that estradiol has effects in women and in animal models to reduce anxiety and depressive behavior and enhance performance in some cognitive tasks, this is not seen among all individuals. Given the interaction between estradiol and hypothalamic-pituitary-adrenal function, we hypothesized that an individual's prior exposure to stress may mitigate some of the subsequent effects of estradiol. To address this, rats were exposed to gestational stress, or not, to determine if stress exposure during development alters behavioral responses to estradiol in adulthood. If estradiol's effects on anxiety and cognitive behavior are modulated by prior stress experience, then gestationally-stressed rats administered estradiol should have decreased anti-anxiety (open field, elevated plus maze) behavior and cognitive performance in the inhibitory avoidance task. Offspring of dams that were exposed to restraint stress daily on gestational days 14-20, or no such manipulation, were used as adults either intact in behavioral estrus (high estradiol) or diestrus (low estradiol), or ovariectomized (OVX) with empty or estradiol-containing silastic implants. Rats were used for blood collection to determine plasma corticosterone and estradiol concentrations, or were used for behavioral testing. Compared with rats in diestrus or OVX and vehicle-replaced, rats in behavioral estrus and OVX rats with estradiol implants had higher estradiol concentrations, entered more central squares in an open field, spent more time on the open arms of the plus maze, and had a longer latency to crossover to the dark, shock-associated side of the inhibitory avoidance chamber. Gestational stress increased plasma corticosterone but not estradiol levels, decreased plus maze open arm time in cycling rats, and decreased inhibitory avoidance performance. Thus, estradiol and gestational stress can have opposite effects on anxiety and inhibitory avoidance performance.     

Dietary ethyl-eicosapentaenoic acid but not soybean oil reverses central interleukin-1-induced changes in behavior, corticosterone and immune response in rats

Omega (n)-3 and n-6 fatty acids are important membrane components of neurons and immune cells, and related to psychiatric and inflammatory diseases. Increased ratio of n-6/n-3 in the blood has been reported in depressed patients and in students following stress exposure. The n-3 fatty acid, eicosapentaenoic acid (ethyl-EPA) suppresses inflammation and has antidepressant properties. Interleukin (IL)-1beta can stimulate corticosterone secretion, induce anxiety and stress-like behavior and inflammatory responses. This study was to evaluate the effect of diets enriched with coconut oil, ethyl-EPA and soybean oil on central IL-1beta induced stress and anxiety-like behavior, induced changes in the concentration of prostaglandin (PG) E2 and corticosterone and the release of IL-10. Groups of rats were fed with either 5% coconut oil (as control diet), 0.2% EPA with 4.8% coconut oil or 1% EPA with 4% coconut oil and 5% soybean oil for 7 weeks. The central administration of IL-1beta induced sickness, stress and anxiety-like behavior as indicated by a reduction in body weight, decreased time spent, and the number of entries, into the open arms of the elevated plus maze and decreased exploration and entry into the central zone of the "open field" apparatus. IL-1beta also increased PGE2 and corticosterone concentrations and decreased the release of IL-10 from leucocytes. Food enriched with ethyl-EPA but not soybean oil, significantly attenuated most of these changes. These results demonstrate that ethyl-EPA has anti-inflammatory, anti-stress and anti-anxiety effects in rats.     

Proactive sensitizing effects of acute stress on acoustic startle responses and experimentally induced colitis in rats: relationship to corticosterone

In humans, some individuals develop a syndrome after trauma (post-traumatic stress disorder, PTSD) characterized by increased startle responses and lower than normal cortisol secretion. We explored a rat model using the acoustic startle response (ASR) as a behavioral indicator of the effect of a short series of shocks. Because gastrointestinal disorders have been associated with prior stress, we also studied the rats' vulnerability to a chemically-induced colitis. After initial blood sampling, 12 rats were exposed to ten 1 mA 5 s foot-shocks while 12 rats served as controls. Nineteen days later the rats were tested for ASR. Thirty trials (10 trials at each of 95, 105, and 115 dB, pseudo-randomized) were given. After exposure for 6 days to dextran sulphate sodium in their drinking water, the rats were killed and the colons examined for erosions. Shocked rats showed greater startle responses and more colonic erosion than unshocked rats, but the shock effects were significant only for animals with low initial plasma corticosterone levels. Shocked rats also showed higher levels of granulocyte marker protein (GMP) in their faeces. These results suggest that low corticosterone secretion may represent a marker for vulnerability to long term effects of shocks as indicated by increased startle responses and colonic pathology.     

Chronic stress, but not hypercaloric diet, impairs vascular function in rats

The aim of this study was to evaluate vascular and metabolic effects of chronic mild unpredictable stress (CMS) and hypercaloric diet (HD) without carbohydrate supplementation in rats. Male Sprague-Dawley rats were randomly assigned to four groups: Control, HD, CMS, and HD plus CMS. CMS consisted of the application of different stressors for 3 weeks. The rats were killed 15 days after CMS exposure. The HD group presented higher plasma lipid concentrations, without changes in fasting glucose concentration, glucose tolerance test, and vascular function and morphology, in comparison with the control group. Stressed rats presented higher fasting blood concentration of insulin, higher homeostasis model assessment index values and area under the curve in an oral glucose tolerance test, in comparison with non-stressed rats. CMS increased the plasma concentrations of corticosterone and lipids, and the atherogenic index values, without change in high-density lipoprotein level. CMS increased intima-media thickness and induced endothelium-dependent supersensitivity to phenylephrine, and lowered the relaxation response to acetylcholine in the thoracic aorta isolated from rats fed with control or HD, in comparison with non-stressed groups. CMS effects were independent of diet. In non-stressed rats, the HD induced dyslipidemia, but did not change glucose metabolism, vascular function, or morphology. The data from this study indicate that CMS promotes a set of events which together can contribute to impair function of the thoracic aorta.     

Neurotoxicity of Kainate to the Hippocampus is not Accrued by Aging, Stress and Exogenous Corticosterone in Wistar Kyoto and Spontaneously Hypertensive Rats

It has been reported that a high corticosterone milieu can exacerbate various experimental insults to the nervous system, in particular to the hippocampus. However, in many of these studies the above milieu was attained by injecting corticosterone in doses (e.g. 10 mg/rat) producing supraphysiological concentrations. In the present study we have investigated whether high plasma corticosterone levels, such as those associated with aging or stress, potentiate a hippocampal excitotoxic insult. Male Wistar Kyoto (WKY) and Spontaneously Hypertensive Rats (SHR) at the age of 6, 12, 18 and 24 months (only WKY for the oldest age) were used. As in other strains, aging in these rats was marked by an increase in basal plasma corticosterone levels. Rats were infused in the dorsal hippocampus with kainic acid (0.035 μg/hippocampus) and the neuronal injury was evaluated within the areas CA3 and CA4. Results indicated that neither aging nor the hypertensive condition affected kainic acid neurotoxicity. In order to study the effect of stress, rats were stressed twice a day, with alternate types of stressors to avoid possible habituation, 3 days prior to and 3 days following the kainic acid infusion. Using this experimental paradigm the hippocampal damage in stressed rats was of the same degree as in non-stressed controls. In a complementary set of experiments, 6 month old WKY and SHR rats were injected with corticosterone (10 mg/rat s.c.). Four hours after administration plasma corticosterone levels in the range of 60-70 μg/100 ml were found. Moreover, a time-course study showed a plasma corticosterone peak in the range of 240 μg/100 ml. Daily corticosterone administration for 3 days before and 3 days after kainic acid infusion potentiated the hippocampal damage in 6 months old SHR but not in the WKY. These results demonstrate that elevation of corticosterone levels within physiological range does not exacerbate hippocampal kainate neurotoxicity and that pharmacological doses of glucocorticoid hormone, which produces plasma levels well above those observable in any physiopathological condition, might, with some strain dependency, potentiate a hippocampal neurotoxic insult.     

Differing effects of acute and chronic stressors on plasma osteocalcin and leptin in rats

Stressor activation of the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis can have profound effects on bone and also appetite and metabolism. We tested in rats the response of plasma osteocalcin (pOC, a bone biomarker that is acutely stress responsive), corticosterone, and leptin to (1) ethanol consumption (5% w/v) in a liquid diet (compared with ad libitum and pair-fed rats), (2) acute restraint, and (3) acute (once, 1 h) and (4) chronic (1 h/day for 7 weeks) social aggression. Basal pOC concentration did not differ with ethanol diet or social interaction, but was elevated by both foot restraint immobilization (Imo) and restraint in wire mesh cylinders (WMR). As previously reported for chronic Imo, ingestion of ethanol blunted the pOC response to Imo. Plasma corticosterone concentration was increased by acute WMR and acute social interaction but was unaltered by chronic social interaction. Plasma leptin concentration was markedly increased by Imo in ad libitum fed, but only slightly in ethanol or pair-fed rats. In contrast, the data reflect significant differences between acute and chronic stressor effects since chronic social stress had little effect on pOC or plasma corticosterone, but tended to decrease leptin level in relation to dominance. Lack of significant impact of prolonged ethanol intake or social aggression suggests physiological adaptation.     

Diazepam-stress interactions in the rat: effects on autoanalgesia and a plus-maze model of anxiety

On six occasions spaced at least a week apart, two groups of rats were subjected to a variety of stressful conditions consisting of a restraint/bright light complex, either alone or in combination with a tail pinch, whole-body inversion, or partial immersion in cold water. One of these groups was injected with diazepam (2.0 mg/kg) 30 min prior to the stressors, while the other group experienced the drug in their home cages the following day. A third group also received the diazepam but was not exposed to the stressors. In three test sessions all animals were injected with either diazepam or saline and were then exposed to a novel stressor: a plus-maze used as a screening device for anxiolytic drugs. This was immediately followed by a tail-flick measure of analgesia. The longest tail-flick latencies, indicating stress-induced analgesia ("autoanalgesia"), were observed in the group that had not been exposed to stress prior to testing. The other two groups exhibited substantially shorter latencies but did not differ from one another, thus showing a "stress inoculation" effect that was uninfluenced by diazepam. In the plus-maze, diazepam tends to increase the amount of time rats will spend in the two exposed arms of the maze relative to the two enclosed arms. This effect was significantly attenuated in the group that had previously experienced the variety of stressors after a diazepam injection, suggesting a learned association between drug and stress that resulted in a diminution of the drug's anxiolytic property.     

Social isolation-induced changes in the hypothalamic-pituitary-adrenal axis in the rat

Social isolation of rats both reduces the cerebrocortical and plasma concentrations of 3a-hydroxy-5a-pregnan-20-one (3a,5a-TH PROG) and 3a,5a-tetrahydrodeoxycorticosterone and potentiates the positive effects of acute stress and ethanol on the concentrations of these neuroactive steroids. We now show that social isolation decreased the plasma level of adrenocorticotropin (ACTH), moreover, intracerebroventricular administration of corticotropin releasing factor (CRF) induced a marked increase in the plasma corticosterone level in both isolated and group-housed rats, but this effect was significantly greater in the isolated rats (+121%) than in the group-housed rats (+86%). In addition, in isolated rats, a low dose of dexamethasone had no effect on the plasma corticosterone concentration, whereas, a high dose significantly reduced it; both doses of dexamethasone reduced plasma corticosterone in group-housed rats. Furthermore, the corticosterone level after injection of dexamethasone at the high dose was significantly greater in the isolated animals than in the group-housed rats. These results suggest that social isolation increased sensitivity of the pituitary to CRF and impaired negative feedback regulation of the hypothalamic-pituitary-adrenal (HPA) axis.     

Plasma corticosterone and immune reactivity in restrained female C3H mice

Psychological stressors are known to stimulate the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system resulting in the release of corticosterone and catecholamines respectively. They have also been reported to induce cytokine production. All these molecules affect various immune parameters and can alter overall immune competence of the individual. The purpose of this investigation was to study the regulation of the production of corticosterone during stress and its possible effects on immune reactivity. In a first series of experiments, the possible regulation of corticosterone production by interleukin (IL)-1beta and peripheral catecholamines during restraint was assessed using a pharmacological approach in mice. Plasma IL-1beta concentrations remained at basal after 1-h restraint and the stress-induced increase of plasma corticosterone was not modified by a peripheral injection of an IL-1 receptor antagonist (IL-1ra). By contrast, chemical sympathectomy potentiated the restraint-induced increase in plasma corticosterone concentration, this potentiation being reversed by IL-1ra. In a second series of experiments, the role of corticosterone in stress-immune relationships was studied in adrenalectomized mice subjected to restraint and immunized with sheep erythrocytes. Non-specific immunity, i.e. proliferation of splenocytes and thymocytes and plasma levels of IL-1beta, as well as specific immunity, i.e. antibody production and delayed hypersensitivity, were not altered after 2-h restraint. Adrenalectomy failed to induce immune effects in stressed animals, except that delayed hypersensitivity was stronger in adrenalectomized animals, revealing that the high levels of corticosterone produced during stress have an anti-inflammatory activity. The present data show that the stress-induced production of corticosterone was modulated by both peripheral catecholamines and IL-1beta. However, this production of corticosterone was unable to modulate immune reactivity except delayed hypersensitivity.     

Persistent neuroendocrine changes in multiple hormonal axes after a single or repeated stressor exposures

Many researchers have studied acute responses to stress in animals and how they are modified by prior stressor exposure, but relatively few have examined whether responses to stressors might last for prolonged periods of time. We have previously demonstrated that trough plasma corticosterone levels in rats are elevated for three to five days after single or repeated exposures to mild restraint and inescapable tailshock. The current study measured other aspects of the adrenal axis, and activity in other neuroendocrine systems, 24 hours after one or three consecutive exposures to the same stress paradigm. The data indicated persistent activation of the adrenal axis and prolactin levels, whereas the thyroid and reproductive hormone axes were inhibited after either one or three stress sessions. These changes are remarkable in that one would have expected acute responses to even intense stressors to have ended within hours after the end of the stressor. It will be important to understand the interactions among these responding neuroendocrine systems and to know how long such persistent changes last. Finally, it will be critical to understand the relative contributions of neuroendocrine and psychological factors in maintaining these persistent neuroendocrine changes after exposure to intense stressors.     

Influence of housing on the consequences of chronic mild stress in female rats

The chronic mild stress (CMS) paradigm was developed to model anhedonia in animals. The repeated administration of a series of unpredictable, mild stressors attempts to mimic the daily stress associated with the onset of clinical depression in humans. Male animals are predominantly used in these investigations despite significant, well-documented sex differences in human depression. In this study, the CMS procedure was modified to be more ecologically relevant to female animals. The effects of stress on sucrose preference, social interaction, rate of weight gain, and regularity of the estrous cycle in female Sprague-Dawley (SD) rats were evaluated in both single- and paired-housed rats, during 3 weeks each of baseline, CMS, and post-CMS phases. The results indicate that only single-housed rats exposed to stressors have a reduced rate of weight gain, significantly attenuated sucrose preference levels, and increased social interaction scores during the CMS phase of the study. Housing condition more than exposure to stress appeared to contribute to the disruption of estrous cycling in some animals. These data suggest that housing affords some protection from the negative consequences of CMS, at least in female rats, and that lack of social interaction in the single-housing condition may render females more vulnerable to stress-related illnesses. The development of paradigms that model human depression should emphasize sex-specific differences.     

The effects of acute stress and pubertal development on metabolic hormones in the rat

A dramatic change in stress responsiveness occurs during pubertal development such that stress-induced corticosterone secretion in prepubertal animals takes 45-60 min longer to return to baseline compared to adults. Though corticosterone is known to influence energy mobilization, it is presently unknown whether stressors affect other hormones important in energy utilization and metabolism differentially in animals before and after pubertal development. Therefore, we exposed prepubertal (28 days of age) and adult (77 days of age) male rats to a single 30 min session of restraint stress in either the light or dark phase of the animals' light-dark (LD) cycle and measured plasma glucose, insulin and thyroid hormones (thyroxine (T4) and triiodothyronine (T3)). We found similar stress-induced increases in plasma glucose levels in prepubertal and adult animals in the LD phase of the LD cycle. We also found that prepubertal animals have lower circulating insulin and total and free T4 levels, but higher total and free T3 levels compared to adults in both the light and dark phases (LD). Interestingly, insulin and thyroid hormone levels were unaffected by acute stress at either age or time of day. These data indicate that, despite prepubertal animals showing an extended glucocorticoid stress response after a single acute exposure to stress, glucose levels are similarly affected by acute stress in prepubertal and adult animals. Furthermore, though stage of development significantly affects the levels of peripheral metabolic hormones such as insulin, T4 and T3, acute stress does not appreciably influence their secretion before or after puberty.     

Effects of Stress on Nonassociative Learning Processes in Male and Female Rats

In this study we assessed habituation and sensitization of the acoustic startle response (ASR) to discern whether intense, inescapable stress affects nonassociative learning differently in male and female rats. Rats were inescapably stressed 2 hours per day over 3 consecutive days. ASR magnitudes were measured at several times post-stress (1, 4, 8, and 15 days after cessation). Females generally showed greater ASR magnitudes (compared to males), but both sexes exhibited short and long-term habituation across the testing days. ASR magnitudes were only affected by stress in male subjects. The effect in males was an increase in short-term sensitization of the ASR on post-stress day-4. The results suggest that stressed males and females react differently to ASR testing, in that stress males appear to develop an exaggerated ASR response over repeated test sessions due to short-term sensitization. The source of the short-term sensitization is discussed with regards to possible stress-induced enhanced contextual learning during ASR testing on post-stress day-1.     

Effects of stress on nonassociative learning processes in male and female rats

In this study we assessed habituation and sensitization of the acoustic startle response (ASR) to discern whether intense, inescapable stress affects nonassociative learning differently in male and female rats. Rats were inescapably stressed 2 hours per day over 3 consecutive days. ASR magnitudes were measured at several times post-stress (1, 4, 8, and 15 days after cessation). Females generally showed greater ASR magnitudes (compared to males), but both sexes exhibited short and long-term habituation across the testing days. ASR magnitudes were only affected by stress in male subjects. The effect in males was an increase in short-term sensitization of the ASR on post-stress day-4. The results suggest that stressed males and females react differently to ASR testing, in that stress males appear to develop an exaggerated ASR response over repeated test sessions due to short-term sensitization. The source of the short-term sensitization is discussed with regards to possible stress-induced enhanced contextual learning during ASR testing on post-stress day-1.     

The role of the anterodorsal thalami nuclei in the regulation of adrenal medullary function, beta-adrenergic cardiac receptors and anxiety responses in maternally deprived rats under stressful conditions

Maternal separation can interfere with growth and development of the brain and represents a significant risk factor for adult psychopathology. In rodents, prolonged separation from the mother affects the behavioral and endocrine responses to stress for the lifetime of the animal. Limbic structures such as the anterodorsal thalamic nuclei (ADTN) play an important role in the control of neuroendocrine and sympathetic-adrenal function. In view of these findings we hypothesized that the function of the ADTN may be affected in an animal model of maternal deprivation. To test this hypothesis female rats were isolated 4.5 h daily, during the first 3 weeks of life and tested as adults. We evaluated plasma epinephrine (E) and norepinephrine (NE), cardiac adrenoreceptors and anxiety responses after maternal deprivation and variable chronic stress (VCS) in ADTN-lesioned rats. Thirty days after ADTN lesion, in non-maternally deprived rats basal plasma NE concentration was greater and cardiac beta-adrenoreceptor density was lower than that in the sham-lesioned group. Maternal deprivation induced a significant increase in basal plasma NE concentration, which was greater in lesioned rats, and cardiac beta-adrenoreceptor density was decreased in lesioned rats. After VCS plasma catecholamine concentration was much greater in non-maternally deprived rats than in maternally-deprived rats; cardiac beta-adrenoreceptor density was decreased by VCS in both maternally-deprived and non-deprived rats, but more so in non-deprived rats, and further decreased by the ADTN lesion. In the plus maze test, the number of open arm entries was greater in the maternally deprived and in the stressed rats. Thus, sympathetic-adrenal medullary activation produced by VCS was much greater in non-deprived rats, and was linked to a down regulation of myocardial beta-adrenoceptors. The ADTN are not responsible for the reduced catecholamine responses to stress in maternally-deprived rats. Maternal deprivation or chronic stress also induced a long term anxiolytic effect, which was also not affected by ADTN lesion.     

Maternal separation in early life impairs tumor immunity in adulthood in the F344 rat

Neonatal stress alters the hypothalamic-pituitary-adrenal (HPA) axis in rodents, such that, when these animals are exposed to stress as adults they hypersecrete corticosterone. Given that glucocorticoids are immunosuppressive, we examined the impact of maternal separation on HPA axis reactivity, natural killer (NK) cytotoxicity, and tumor growth in Fischer 344 rats following chronic restraint stress in adulthood. Pups underwent a chronic stress protocol whereby they were separated from their dams for 3 h on postnatal days 1-21. In adulthood, corticosterone responses were assessed following exposure to chronic (6 days for 10 h) restraint stress. Rats allocated to the chronic stress condition were inoculated with MADB106 tumor cells on day 4 of the restraint protocol. Blood was assessed for NK cytotoxicity on the final day of the chronic restraint protocol, and tumor colonization was assessed 3 weeks thereafter. Maternal separation impaired developmental weight gain (P < 0.05), depressed NK cytotoxicity (P < 0.05), and increased tumor colonization in the presence of chronic restraint stress in adulthood (P < 0.00 l). These findings occurred independently of circulating plasma corticosterone as only adult stress exposure potentiated corticosterone responses (P < 0.05). Our findings indicate that maternal separation and chronic stress can impair NK cytotoxicity and hence tumor immunity, but these effects are not directly mediated by perturbations in HPA axis function.