Strain, age, but not gender, influence ulcer severity induced by water-restraint stress

Two ulcerogenic procedures, supine restraint (SR) and water restraint (WR) were compared. In Experiment 1, Fischer-344 (F344), Sprague-Dawley (S-D), Wistar, Long-Evans (L-E), Spontaneously Hypertensive rats (SHR) and Wistar Kyoto normotensive (WKY) rats were exposed to SR and WR. WR produced more ulcers than SR. There was no difference in ulcer scores between WKY, F344 and L-E but these rats had significantly more ulcers as compared to SHR, Wistar and S-D rats. In Experiment 2, 4- and 16-month-old SHR, WKY and F344 rats were exposed to SR and WR. The older WKY rats had more ulcers than all other treatment groups. Experiment 3 revealed no significant differences between male and female rats exposed to either SR or WR. Body temperature (BT) scores obtained after restraint and after 2-hr postrestraint rest were only marginally related to ulcer severity. Rats exposed to WR had lower BT scores but the strain and age ulcer differences did not have corresponding BT differences. These studies revealed the following: the ulcer susceptibility of WKY rats; the WR technique is a useful ulcerogenic procedure; and hypothermia is a weak covariant to restraint-induced stress ulcer.     

"Behavioral despair" test predicts stress ulcer in WKY rats

Spontaneously hypertensive rats (SHR), Wistar Kyoto (WKY) and Wistar rats were exposed to Porsolt's forced-swimming test of "behavioral despair." In addition to floating time, which was the measure of despair, headshakes, bobbing, diving and struggling time were also recorded. Rats were subsequently exposed to the activity stress (A-S) ulcer procedure. Wistar rats had the highest struggling time scores and the fewest A-S ulcers. WKY rats were judged as more depressed and their ulcer severity scores were significantly greater as compared to SHR and Wistar rats. In addition, a within strains analysis revealed that WKY rats with high despair scores also had the most severe stress-ulcer scores. These data suggested that stress-ulcer disease may be more prevalent in animals which are prone to depression as defined by the Porsolt test. The value of WKY rats as an animal model to study the relationship between depression and stress ulcer is discussed.     

Lineage is an Epigenetic Modifier of QTL Influencing Behavioral Coping with Stress

A genome-wide scan was carried out on a segregating F2 population of rats derived from reciprocal intercrosses between two inbred strains of rats, Fisher 344 (F344) and Wistar Kyoto (WKY) that differ significantly in their behavioral coping responses to stress measured by the defensive burying (DB) test. The DB test measures differences in coping strategies by assaying an animals behavioral response to an immediate threat. We have previously identified three X-linked loci contributing to the phenotypic variance in behavioral coping. Here we report on six significant autosomal quantitative trait loci (QTL) related to different behaviors in the DB test:one for the number of shocks received, three for number of prod approaches, one for latency to bury, and one pleiotropic locus affecting both approach and latency. These QTL contributing to different aspects of coping behaviors show that the effect of genotype on phenotype is highly dependent on lineage. The WKY lineage was particularly influential, with five out of the six QTL affecting coping behavior only in rats of the WKY lineage, and one locus affecting only those in the F344 lineage. Thus, epigenetic factors, primarily of WKY origin, may significantly modulate the genetic contribution to variance in behavioral responses to stress in the DB test.     

Stress ulcer susceptibility and depression in Wistar Kyoto (WKY) rats

In a series of studies, Wistar Kyoto (WKY) normotensive rats were more susceptible to water-restraint-induced stress ulcer as compared to spontaneously hypertensive rats (SHR) Fisher-344 (F344) and Wistar rats. In these same studies, WKY rats were also deficient in several behavioral tasks. The four strains were observed in the open-field test of emotionality and WKYs were judged more emotional. In a study on "learned helplessness" WKYs were more deficient in the acquisition of a shuttlebox escape response following unavoidable shock the day before. The prevalence of freezing behavior in the shuttlebox task and the low ambulation scores in the open-field test suggested depressive behavior as a WKY behavior characteristic. WKY rats were judged more depressed in the Porsolt forced-swim test as compared to the other strains. A possible depression-ulcer relationship may exist in WKY rats. This strain may represent a good model for studying possible relationships between depression and stress-induced disease.     

The delayed effects of chronic unpredictable stress on anxiety measures

Previous research has found that exposure to unpredictable stress can augment anxiety in humans and animals. The appearance of anxiety symptoms in humans frequently develop after stress exposure has terminated, but few rodent studies have systematically examined the delayed anxiogenic effects of unpredictable stress. Therefore, the current study investigated whether anxiety-like behaviors in rats would increase at several time intervals following exposure to chronic unpredictable stress (CUS). Unconditioned and conditioned response tasks were used to assess anxiety in male rats 1, 7 or 14 days following exposure to 10 days of a variety of stressors. Rats exposed to CUS showed increased burying behaviors and immobility during the defensive burying test, a conditioned anxiety test. The effects on burying behavior were apparent 7 and 14 days after the termination of the unpredictable stress procedure, but not when tested 1 day after CUS. Total time immobile in the defensive burying test also increased 14 days after termination of the last stressor. In contrast, there were no significant effects of CUS on behavioral measures in the unconditioned response tasks, the elevated plus-maze or light-dark box, at any time point following exposure to CUS. The current findings suggest that CUS may be a useful model of human conditioned anxiety that develops subsequent to chronic stress exposure.     

Prenatal stress effects on emotion regulation differ by genotype and sex in prepubertal rats

Behavioral effects of different prenatal stress (PNS) schedules were examined in prepubertal “depressive/anxious‐like” WKY and control Wistar rats. Pregnant dams received 1 hr daily restraint stress on gestational days 14–20 or on 7 randomly scheduled days, or remained undisturbed. Offspring were tested during postnatal days 29–35 in social play, forced swim‐test, open field, and novelty tests. PNS induced an increase in anxiety‐like behaviors in WKY, particularly in females, while seemingly reducing depressive‐like behavior in the swim test. However, very high post‐stress corticosterone levels were found, suggesting that the reductions in swim‐test immobility reflect an extremely over‐responsive HPA axis, rather than normalization in stress reactivity leading to a less depressive‐like profile. In Wistar, PNS produced weight loss, hyperactivity and risk taking behavior, especially in males. The results support the importance of the environment during gestation and its interaction with sex and genetics on long‐term anxiety and depressive like behaviors. © 2012 Wiley Periodicals, Inc. Dev Psychobiol 55: 176–192, 2013     

Conditioned neuroendocrine and cardiovascular stress responsiveness accompanying behavioral passivity and activity in aged and in young rats.

Mean arterial pressure (MAP), heart rate (HR), plasma epinephrine (E), plasma norepinephrine (NE), and plasma corticosterone (CORT) were measured in 3-month- and 24-month-old male Wistar rats exposed to a conditioned emotional stress response (CER) paradigm and a conditioned defensive burying (CDB) paradigm. In the CER situation blood samples were taken during reexposure to the training environment one day after a single inescapable footshock (0.6 mA, AC for 3 s) had been administered. In the CER paradigm the young rats displayed passive behavior (immobility) accompanied by an increase in plasma levels of CORT and E, whereas both the control and conditioned animals showed increased NE responses. Previously shocked aged rats exhibited an attenuated plasma NE response, whereas levels of E remained elevated to a greater extent. Aged animals showed elevated basal levels of CORT one day after footshock administration. Stress-induced immobility was preserved in the aged rats. These animals had an increase in basal MAP values and a decrease in basal HR values compared to young ones. In the CDB paradigm, rats were exposed to a nonelectrified probe 1 day after the repeated shock (2 mA/contact) procedure. Young rats displayed defensive burying accompanied by increments in MAP, HR, CORT, and NE. The aged animals showed similar hormonal, autonomic, and behavioral stress responses. Thus, the age-related alterations in neuroendocrine and autonomic response patterns are apparent in stressed animals during behavioral passivity in absence of control (CER) rather than during active control (defensive burying).     

Sexual experience of male rats influences anxiety-like behavior and androgen levels

There is a wide body of literature to suggest that sexual experience may influence androgen secretion in various species, in turn, androgens may also influence anxiety. We hypothesized that sexual experience may alter anxiety behavior and secretion of endogenous androgens. Experiment 1: anxiety behavior of rats with a history of sexual experience was compared to that of sexually-inexperienced, na?ve male rats. Sexually-experienced rats showed less anxiety-like behavior in the open field and elevated plus maze, and exhibited increased plasma and hippocampal testosterone (T) levels. Experiment 2: the effects of recent sexual experience on anxiety behavior of sexually-experienced male rats, sexually-responsive but inexperienced male rats, and sexually-unresponsive, inexperienced male rats exposed to a receptive female immediately prior to testing was examined. Recent sexual experience significantly decreased anxiety-like behavior in the open field, elevated plus maze, and the elevated zero maze tasks, and tended to decrease anxiety-like behavior in the light-dark task. Rats with recent sexual experience exhibited increased plasma and hippocampal T levels. Experiment 3: to examine the effect of recent sexual experience, anxiety behavior of rats with a history of sexual experience that received sexual experience with a stimulus female immediately prior to testing was compared to that of rats with a history of sexual experience that did not receive sexual experience immediately prior to behavioral testing. Experienced rats that were exposed to a female prior to testing showed decreased anxiety-like behavior in the open field, elevated plus maze, and light-dark transition tasks, and showed increased plasma and hypothalamic, T and 3alpha-diol, and increased hippocampal T. Thus, sexual experience is associated with lower levels of anxiety-like behavior and higher levels of androgen secretion.     

Depression- and anxiety-like behaviors of a rat model with absence epileptic discharges

Depression and/or anxiety are major comorbidities of epilepsy. However, the contribution of absence epileptic discharges in psychiatric syndromes is inconclusive. This study aimed to clarify the influence of absence seizure in anxiety- and depression-like behaviors using normal Wistar rats and Long-Evans rats with spontaneous spike-wave discharges (SWDs). Anxiety-like behaviors were evaluated by the open field (OF) and elevated plus maze (EPM) tests, and depression-like behaviors by the forced swimming (FS) and sucrose consumption (SC) tests. Long-Evans rats displayed significantly higher frequency and longer duration in the open arms of the EPM and in the center zone of the OF than did Wistar rats. Normalized behavioral indexes by movement also were significantly higher in Long-Evans rats. An excess of SWD numbers was associated with lower indexes and worse movement in the two behavioral tests. Ethosuximide eliminated the seizure frequency-dependent relationship and also significantly increased all indexes of the EPM test. Additionally, Long-Evans rats revealed significantly longer immobility in the FS test and lower consumption of sucrose solution in the SC test than did Wistar rats. Meanwhile, no relationship was found between immobility of the FS test and SWD number. Ethosuximide ameliorated depression-like behavior of Long-Evans rats that was equal to that of Wistar rats. Thus, Long-Evans rats showed seizure frequency–related exacerbation in anxiety-like behavior; and they displayed a depressive propensity. Our data suggest that generalized SWDs may have distinct influences in anxious and depressive behaviors.     

Central amygdala lesions affect behavioral and autonomic balance during stress in rats.

The effects of a bilateral electrolytical lesion of the CEA on the behavioral and sympathetically induced cardiac response in the shock-probe/defensive-burying test have been analyzed in male Wistar rats. Lesions in the CEA failed to affect defensive burying and accompanying tachycardiac response as compared to sham-lesioned controls during the presentation of the electrified shock probe (unconditioned test). However, CEA lesioning attenuated the bradycardiac response and the immobility behavior during the late part of the test. Retention of this behavior one day after the exposure to the probe (conditioned test) was attenuated by the lesion. However, when the lesion was placed after the unconditioned test situation, retention of the burying was not affected, but the animals failed to show immobility behavior. These results, in agreement with former studies, suggest that the CEA is involved particularly in the organization and/or expression of the passive component of the behavior and the parasympathetic outflow during stress. The active component, i.e., burying behavior, and the accompanying tachycardiac response remains unaffected unless the acquisition of the stress response took place with damaged CEA.     

Selective Effects of Dehydroepiandrosterone Sulfate on Corticoliberin-Induced Anxiety

The effects of dehydroepiandrosterone sulfate (DHEA-S) on changes in the levels of anxiety induced by administration of the stress neurohormone corticoliberin were studied. A T maze was used to select Wistar rats with active and passive strategies of adaptive behavior. Testing of the active group in an elevated plus maze was used to select low- and high-anxiety individuals. Intranasal administration of corticoliberin to low-anxiety active rats resulted in decreases in total activity and increases in the level of anxiety, while high-anxiety animals had low sensitivity to this neurohormone. Prior administration of DHEA-S at a dose of 3 mg/100 g had antistress effects in low-anxiety rats and anxiolytic effects in high-anxiety rats. In passive animals, which were characterized by initially high levels of anxiety and were resistant to corticoliberin, administration of DHEA-S also had antistress actions. These results led to the conclusion that the effects of DHEA-S depended on the initial psychoemotional state and behavioral sensitivity to corticoliberin.     

Effects of prenatal stress on motor performance and anxiety behavior in Swiss mice

Stressor presence during the last weeks of gestation has been associated with behavioral disorders in later life. In this study we support further research on the long term effects of prenatal stress on Swiss mice descendant's behavior. Prenatal stress procedure consisted on restraining the dams under bright light for 45 min, three times per day from the 15th day of pregnancy, until birth. After weaning, offspring's motor performance and spontaneous exploratory behavior were measured by the tight-rope and T-maze tests, respectively. We also evaluated anxiety behavior using elevated plus maze test. We found that maternal stress improves the performance of the animals in the tight rope test and that this effect was sex and age dependent: prenatal stressed males obtained the best scores during the first month of life, while in females the same was achieved at the second month. Spontaneous exploratory behavior analysis revealed that it was elevated in prenatal stressed males and that this effect persisted on time. However, we did not find significant differences on this behavioral response among both females groups. Finally, differences on anxiety behavior were found only in females: prenatally stressed animals showed a higher proportion of entries into the open arms of a plus maze (reduced anxiety) compared to the control group. Our results show that prenatal stress modifies the normal behavior of the progeny: prenatal stressed animals have a better performance in the carried out test. These notably results suggest the existence of an adaptive response to prenatal stress.     

Assessment of antidepressant and anxiolytic properties of NK1 antagonists and substance P in Wistar Kyoto rats

In an attempt to explore the involvement of substance P in depression and anxiety and its' potential therapeutic effects, we measured basal plasma and hypothalamic levels of substance P in a well-studied animal model of depression--adult male Wistar Kyoto (WKY) rats and their controls, Wistar rats. We also studied the influence of a substance P receptor (NK1) antagonist (SPA) on "anxiety-like" and "depressive-like" behaviors exhibited by the WKY rats in the open field and swim test paradigms, compared to controls. WKY rats exhibited lower levels of substance P compared to controls in the hypothalamus. Though the WKY strain exhibited less rearing behavior in the open field compared to controls, SPA did not influence this pattern of behavior. In contrast, SPA had a significant effect on a depressive-like behavior exhibited by the WKY strain--it reduced significantly the immobility duration of WKY rats in the swim test. Thus it seems that depression involves alterations in levels of substance P, and that NK1 antagonists may be effective in the relief of depressive, but not anxiety symptoms.     

单次延长应激导致的创伤后应激障碍行为伴随乳头体神经元活化

目的:探讨创伤后应激障碍(PTSD)模型大鼠的焦虑抑郁行为改变以及乳头体神经元的活化情况。方法:采用单次延长应激(SPS)建立大鼠PTSD模型,采用自发活动、高架十字迷宫方法评价大鼠的自发活动能力和焦虑或抑郁行为;同时利用Fos蛋白免疫荧光染色方法观察乳头体神经元的活化情况。结果:SPS大鼠自发活动明显减少,焦虑样行为明显增多,乳头体内Fos免疫反应阳性神经元数量较正常大鼠显著增加。结论:SPS大鼠乳头体神经元显著激活,可能参与SPS所造成的PTSD反应。     

Effects of neonatal administration of vasopressin on cardiac and behavioral responses to emotional stress in adult male rats.

Arginine-8-vasopressin (AVP) was administered subcutaneously on postnatal days 3-7 in a high (10 micrograms/100 g b.wt.) or a low dose (1 microgram/100 g b.wt.) to male Wistar rats. Control pups were untreated or saline injected. Behavioral observations in a complex maze after maturation indicated that neonatal administration of AVP increases exploratory behavior in this novel environment in a dose-dependent way. Cardiac monitoring during the conditioned emotional stress of fear of inescapable electric footshock showed that only the high dose of AVP attenuates the bradycardiac stress response. The analysis of cardiac responses also suggested an adult hyposensitivity to AVP in rats treated neonatally with AVP. In addition, the low dose of neonatal AVP was impairing the retention of a passive avoidance behavior. The data indicate that the neonatal administration of AVP exerts long-term effects upon the behavioral adaptation to novelty and memory processes related to emotional stress. That neonatal AVP is less effective in influencing adult vagally mediated cardiac stress responses suggests differences in the developmental sensitivity ("critical periods") of the central vasopressinergic systems involved in the regulation of behavior and autonomic functioning.     

Behavioral and Neurochemical Differences Between Fischer 344 and Harlan–Wistar Rats Raised Identically

Inbred Fisher 344 and outbred Harlan–Wistar rats were compared in the elevated plus maze, the black-and-white box, the social interaction test, and a modified open-field test, to assess the contribution of genetic factors to aversion-motivated behavior. All animals used were born and raised under identical conditions. Compared to the Wistar rats, the Fischer rats displayed a more pronounced fearful behavior in all tests. In a separate microdialysis study, the relationship between behavioral variations to biochemical differences was assessed, with serotonin (5-HT) release in the ventral hippocampus being measured during the elevated plus-maze test. Exposure to the elevated plus-maze induced an increase in hippocampal 5-HT in the (more anxious) Fischer rats but not in the (less anxious) Wistar rats. The results confirm the influence of genetic factors on emotionality in rats and demonstrate a close, although not simple, relationship between the serotonergic system and anxiety-related behavior.     

D2-subtype of dopaminergic receptors is involved in anxiety behavior in ovariectomized rats

To compare the role of D2-subtype dopaminergic receptors in mechanisms of anxiety behavior in adult intact female rats during ovary cycle and ovariectomized (OVX) female rats, influence of chronic administration of D2-dopaminergic receptors agonist--quinperole (0.1 mg/kg) and D2-dopaminergic receptors antagonist--sulpiride (10.0 mg/kg) injected separately or in combination with 17beta-es-tradiol (0.5 mcg for each animal) within 14 days on behavioral status of adult intact and ovariectomized (OVX) female rats was investigated. The level of anxiety was assessed in the elevated plus maze, behavior of the animals was estimated in the open field test. It was established that chronic administration of sulpiride to intact rats resulted in anxiogenic behavior in the elevated plus maze in all phases of ovary cycle except proestrous. Quinperole administration to the intact rats had an anxiolytic action on behavior in the elevated plus maze in the metestrous, diestrous and proestrous. Chronic quinperole administration alone or in combination with 17beta-estradiol in OVX rats resulted in an anxiolytic effect on behavior in the elevated plus maze. On the contrary, sulpiride administration alone in OVX rats failed to modify an anxiety level, while in its combination with 17beta-estradiol an anxiolytic effect of the hormone drug was com-pletely blocked. In the open field test quinperole administration to OVX rats increased horizontal locomotor activity, exploratory and grooming behavior. Thus, the results obtained suggest a modulating role of D2-subtype dopaminergic receptors in the mechanisms of anxiety behavior in imbalance of estrogen.     

Lactation and weaning effects on physiological and behavioral response to stressors

Two experiments tested the effects of lactation and weaning on heart rate (HR), corticosterone, and behavioral responses to stress in Wistar rats. In Experiment 1, HRs in lactating, weaning, and control animals were recorded for 10-min periods before, during, and after immobilization stress. Compared with control animals, lactating and weaning animals showed a diminished initial HR response. In addition, HRs of weaning animals failed to habituate and showed a delayed decline after stress termination. In Experiment 2, behaviors, HRs, and corticosterone levels in the elevated plus maze (EPM) were compared among lactating, weaning, and control animals. Compared with control animals, weaning animals exhibited more anxiety behaviors. Contrary to expectation, compared to the other two groups, lactating animals exhibited more closed-arm entries, although they may have been motivated by maternal behavior, rather than anxiety. Initial HR responses to the plus maze were attenuated in lactating animals. Corticosterone levels after the plus maze were lowest in the lactating dams and highest in the control animals. The results from these two experiments are consistent with effects of breast-feeding and weaning observed in humans. In general, lactation is associated with an attenuated initial HR response to stress, while weaning is associated with exacerbated response to stressors.     

Repeated exposure to stress across the childhood-adolescent period alters rats' anxiety- and depression-like behaviors in adulthood: The importance of stressor type and gender

This research tests the hypothesis that specific forms of adversity in early life map onto behavioral signs analogous to depression versus anxiety in later life. Male and female rats were exposed to either severe sporadic stress or chronic mild stress during the childhood-adolescent period, and their behavior was tested in adulthood. Males in the severe sporadic stress group showed exaggerated anxiety-related behaviors, as indicated by increases in shock-probe burying and escape-like responses (jumps) from the open arms of the elevated plus-maze. Females exposed to severe sporadic stress displayed no change in burying behavior but did display increases in escape behavior. These same females also exhibited behaviors analogous to depression that manifested as decreased sucrose consumption. The chronic mild stress regime produced effects only in females, including reduced burying, decreased sucrose consumption, and an exaggerated corticosterone response to cold-water immersion stress. Findings reiterate the importance of early life experience to the development of adult psychopathologies and emphasize the need to consider both the type of early experience and gender differences in these analyses.     

Environmental enrichment delays pup-induced maternal behavior in rats

Adult, virgin rats do not spontaneously display maternal behavior when exposed to foster pups. However, continuous daily exposure of the female to foster pups for about 5-7 days can induce a set of maternal behaviors similar to those shown by postpartum dams. Induction latencies depend upon a number of factors, including the stress and anxiety levels of the female. The goal of this study was to attempt to mitigate the likely stressfulness of being singly housed during testing by enriching the rat's home cage environment and to determine if the concomitant environmental change would alter the latency to express maternal behavior. In addition, the effect of varying the number of test pups used for testing was examined. Two groups of virgin Sprague-Dawley rats were first tested on the elevated plus maze after 1 week of exposure to either control (standard housing) or enriched conditions. One week later, maternal behavior testing began using one or three pups. Upon completion of maternal behavior testing, plasma corticosterone concentrations were determined following a mild stressor. The data indicate that enrichment tends to increase anxiety-like behaviors in the elevated plus maze. In addition, enrichment delayed the onset of maternal behavior irrespective of the number of test pups. There were no effects of environmental enrichment on plasma corticosterone levels following exposure to a stressor. These results indicate that what is considered a modestly enriched environment delays the expression of pup-oriented responses and does not apparently reduce stress or improve performance on all behavioral tasks.