Differential vascular adaptive response to stress exposure in male and female rats: role of gonadal hormones and endothelial cells

Although there are reports concerning a vascular adaptive response to stress in males, this is not yet defined in females. The aim of this study was to delineate functional gender differences in the rat vascular adaptive response to stress and to determine the ability of sex hormones to modulate the stress-induced vascular adaptive response. Responses to noradrenaline were evaluated in aortas, with and without endothelium, from intact, gonadectomized and gonadectomized-hormone-replaced males and females submitted or not to stress (2-h immobilization). Reactivity of the aorta of stressed and non-stressed intact males and females (n = 6-14 per group) was also examined in the presence of L-NAME or indomethacin. Stress decreased and gonadectomy increased maximal responses to noradrenaline in aortas with intact endothelium from both genders. Stress also reduced noradrenaline potency in males. In females, but not males, stress decreased the gonadectomy-induced noradrenaline hyper-reactivity to near that of intact non-stressed rats. Hormone replacement restored the gonadectomy-induced impaired vascular adaptive response to stress. L-NAME, but not indomethacin, abolished the stress-induced decrease in aorta reactivity of males and females. None of the procedures altered reactivity of aortas denuded of endothelium. CONCLUSION: Stress-induced vascular adaptive responses show gender differences. The magnitude of the adaptive response is dependent on testicular hormones and involves endothelial nitric oxide-system hyperactivity.     

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.     

Repeated acute stress alters heart morphometry in male and female rats differently

Stress exerts deleterious effects on the cardiovascular system. Left ventricular hypertrophy has been identified as a risk factor for heart disease. The effects of stress on other heart parameters, including heart size and heart shape, are not well-characterized. In addition, the extent to which males and females differ in stress effects on these measures has not been examined, but may help to further explain gender differences in heart disease morbidity and mortality. The present experiment examined effects of mild daily stress on heart morphology and blood volume (obtained by ex-sanguination at decapitation) in 39 male and 40 female rats of two strains. Following 14 days of stress exposure, rats were killed and blood volume was measured. Heart length, heart weight, left ventricle cavity width, right ventricle width, lateral wall thickness, anterior wall thickness, posterior wall thickness, and septal wall thickness were measured. In males, after controlling for body weight, stress decreased heart length and left ventricle cavity width and increased septal wall thickness. In females, after controlling for body weight, stress reduced total blood volume, but did not significantly affect other heart parameters. These findings suggest that stress exposure can alter heart morphology and blood volume and that there are sex differences in these effects.     

Pupillary response of male and female subjects to pupillary difference in male and female picture stimuli

On exposure to a series of identical pictures of a young man and a young woman differing only in size of the pupils of the eyes, the eyes of married Ss dilated more to the opposite sex pictures than to the like sex pictures, dilated most to the opposite sex picture with the larger pupils, and dilated least to the like sex picture with the larger pupils. Difficulties with neutral stimuli were noted and an improved method of assessing picture stimuli brightness was described.     

Selective blockade of 5-HT2A receptors attenuates the increased temperature response in brown adipose tissue to restraint stress in rats

Previous studies have demonstrated that 5-HT2A receptors may be involved in the central control of thermoregulation and of the cardiovascular system. Our aim was to test whether these receptors mediate thermogenic and tachycardiac responses induced by acute psychological stress. Three groups of adult male Hooded Wistar rats were instrumented with: (i) a thermistor in the interscapular area (for recording brown adipose tissue temperature) and an ultrasound Doppler probe (to record tail blood flow); (ii) temperature dataloggers to record core body temperature; (iii) ECG electrodes. On the day of the experiment, rats were subjected to a 30-min restraint stress preceded by s.c. injection of either vehicle or SR-46349B (a serotonin 2A receptor antagonist) at doses of 0.01, 0.1 and 1.0 mg/kg. The restraint stress caused a rise in brown adipose tissue temperature (from, mean +/- s.e.m., 36.6 +/- 0.2 to 38.0 +/- 0.2 degrees C), transient cutaneous vasoconstriction (tail blood flow decreased from 12 +/- 2 to 5 +/- 1 cm/s), increase in heart rate (from 303 +/- 15 to 453 +/- 15 bpm at the peak, then reduced to 393 +/- 12 bpm at the steady state), and defaecation (6 +/- 1 pellets per restraint session). The core body temperature was not affected by the restraint. Blockade of 5-HT2A receptors attenuated the increase in brown adipose tissue temperature and transient cutaneous vasoconstriction, but not tachycardia and defaecation elicited by restraint stress. These results indicate that psychological stress causes activation of 5-HT2A receptors in neural pathways that control thermogenesis in the brown adipose tissue and facilitate cutaneous vasoconstriction.     

Self-control in male and female rats

Eight male and 8 female Wistar rats were exposed to a discrete-trial procedure in which they chose between the presentation of a small (one pellet) or a large (three pellets) reinforcer. The delay to the small and large reinforcer was 6.0 s in the first condition of Experiment 1. Subjects consistently chose the large reinforcer. When the delay to the small reinforcer was decreased to 0.1 s in the next experimental condition, all subjects continued to choose the large 6.0-s delayed reinforcer. When the contingencies correlated with the two levers were reversed in the next experimental condition, the majority of subjects (5 males and 6 females) still chose the large delayed reinforcer over the small immediately presented reinforcer. The delay to the small reinforcer was maintained at 6.0 s, but the delay to the large reinforcer was varied among 9.0, 15.0, 24.0, and 36.0 s in Experiment 2, in which 4 males and 4 females participated. Most subjects consistently chose the large increasingly delayed reinforcer, although choice for the small 6.0-s delayed reinforcer developed in some females when the large reinforcer was delayed for 24.0 or 36.0 s. These choice patterns were not predicted from a literal application of a model that says choice should favor the alternative correlated with the higher (amount/delay) ratio.     

Modulation of in vivo oxidative status by exogenous corticosterone and restraint stress in rats

Physical and psychological stressors not only enhance activity of the hypothalamo-pituitary-adrenocortical axis, but also cause oxidative damage by inducing an imbalance between the in vivo pro-oxidant and antioxidant status. The involvement of adrenal steroid stress hormones in oxidative damage associated with these stressors has not been extensively investigated. Therefore, this study was designed to probe any direct role of glucocorticoids on induction of oxidative processes by comparing the effects of low, intermediate and high doses of exogenously administered corticosterone, without other applied stressors, on a wide range of key components of the antioxidant defence system. The data presented here indicate a substantial decline in antioxidant defences by actions of corticosterone, evidenced by coordinate decreases in the activities in the brain, liver and heart of free-radical scavenging enzymes superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST) and glutathione reductase (GR), as well as the non-enzymatic antioxidants glutathione (GSH) and serum urate. Also, lipid peroxidation and protein carbonyl contents, oxidative stress markers, were found to be significantly increased in brain, liver and heart. The compromised in vivo antioxidant status was strikingly analogous to the deleterious effects of restraint stress, indicating a direct effect of stress hormones on induction of oxidative damage during physical or psychological stress. A dose-dependent decrease of SOD and CAT, and increase in protein oxidation was observed between the high (40 mg/kg) and low (10 mg/kg) doses of corticosterone. The findings have fundamental implications for oxidative stress as a major pathological mechanism in the maladaptation to chronic stress. Thus, the study suggests that stress hormones have a causal role in impacting oxidative processes induced during the adaptive response. This may hold important implications for pharmacological interventions targeting cellular antioxidants as a promising strategy for protecting against oxidative insults in various psychiatric and non-psychiatric conditions induced by physical or psychological stress.     

Acute predator stress impairs the consolidation and retrieval of hippocampus-dependent memory in male and female rats

We have studied the effects of an acute predator stress experience on spatial learning and memory in adult male and female Sprague-Dawley rats. All rats were trained to learn the location of a hidden escape platform in the radial-arm water maze (RAWM), a hippocampus-dependent spatial memory task. In the control (non-stress) condition, female rats were superior to the males in the accuracy and consistency of their spatial memory performance tested over multiple days of training. In the stress condition, rats were exposed to the cat for 30 min immediately before or after learning, or before the 24-h memory test. Predator stress dramatically increased corticosterone levels in males and females, with females exhibiting greater baseline and stress-evoked responses than males. Despite these sex differences in the overall magnitudes of corticosterone levels, there were significant sex-independent correlations involving basal and stress-evoked corticosterone levels, and memory performance. Most importantly, predator stress impaired short-term memory, as well as processes involved in memory consolidation and retrieval, in male and female rats. Overall, we have found that an intense, ethologically relevant stressor produced a largely equivalent impairment of memory in male and female rats, and sex-independent corticosterone-memory correlations. These findings may provide insight into commonalities in how traumatic stress affects the brain and memory in men and women.     

Responses of dominant and subordinate male rats to the odors of male and female conspecifics

The resident-intruder paradigm was used to examine the effects of social dominance and individual recognition on odor preferences and urine-marking in male rats. Resident males were significantly more aggressive than intruders and spent more time investigating the odors of familiar intruders. Resident males urine-marked most over the odors of females and familiar intruders while intruders marked least over the odor of the familiar resident. Intruders did not avoid investigating nor marking over the odors of familiar resident males or other conspecifics. These results suggest that individual odors of male rats may be more salient than a general odor of dominance, and that the dominant males increase their investigation and marking over the odors of familiar subordinates but not unfamiliar subordinates. The importance of olfactory learning during aggressive interactions is discussed.     

Maternal aggression in mice and rats towards male and female conspecifics

Although postpartum aggression is primarily studied in laboratory mice and rats, it is unclear how the two species compare in terms of the factors associated with peak levels of aggressive behavior. Using the same experimental protocol, we assessed the relative effect of intruder sex and time since parturition on the frequency of maternal aggression in Long-Evans rats and CFW mice. Females were studied for 2 consecutive cycles of pregnancy and lactation. During the first lactation, aggression was tested 2 times per week for 3 weeks in order to select animals that attacked at least once. During the second lactation, both pup care and aggressive behavior were assessed in detail. Testing occurred twice in each lactation week, with postpartum days 1–7, 8–14, and 15–21 considered weeks 1, 2, and 3, respectively. Maternal behavior towards 3 pups was observed for 5 minutes, followed by a confrontation with an intruder. Lactating females encountered female intruders once per week, and male intruders in the alternate weekly test. The same behaviors were measured in the 2 species, except for the tail rattle exhibited by mice and the aggressive posture shown by rats. Lactating rats and mice show similar decreases in pup care behavior as lactation progresses in time; yet the factors associated with peak levels of aggression differ between species. In Long-Evans rats, female intruders receive more attacks, threats, and aggressive postures than males. Frequency of attack bite and sideways threat declines in each passing week of lactation. Lactating mice are more aggressive toward male intruders throughout the lactation period. Mice still attack and threaten during the third week of lactation, but less often in comparison to the first week. Therefore, peak levels of aggression vary in mice and rats both as a function of intruder sex and lactation week.     

Prenatal maternal stress: Differential effects upon male and female offspring responses to restraint stress as adults

Pregnant primiparous rats were subjected to four days of light restraint stress on postconception days 7 through 10, inclusive, coincident with the development of the fetal gastrointestinal system. Twenty male and twenty female offspring from prenatally stressed and nonstressed rats were then subjected to two hours of supine cold-restraint as adults. Eighty percent of nonprenatally stressed offspring developed gastric lesions, while 47.5% of offspring of prenatally stressed mothers displayed lesions. A significant sex-stress interaction was detected, indicating that male offspring from prenatally stressed mothers display less severe gastric lesions in response to restraint stress as adults than do male offspring from nonprenatally stressed mothers. Female offspring from both prenatal stress conditions showed similar levels of stress-induced lesions.     

Adrenal gland responses to lipopolysaccharide after stress and ethanol administration in male rats

All forms of stress, including restraint stress (RS) and lipopolysaccharide (LPS) administration, activate the hypothalamic-pituitary-adrenal (HPA) axis. LPS binds to a recognition protein (CD14) and toll-like receptor 2/4 in different cells and tissues, including the adrenal gland, to induce the production of cytokines and cause upregulation of cyclooxygenase and nitric oxide synthase (NOS) enzymes. Acute ethanol exposure activates the HPA axis, but in some conditions prolonged administration can dampen this activation as well as decrease the inflammatory responses to LPS. Therefore, this study was designed to evaluate the adrenal response to a challenge dose of LPS (50 μg/kg) injected i.p., after submitting male rats to RS, twice a day (2 h each time) for 5 days and/or ethanol administration (3 g/kg) by gavage also for 5 days, twice daily. At the end of the experiment, plasma corticosterone concentrations and adrenal gland content of prostaglandin E (PGE) and NOS activity were measured as stress mediators. The results showed that repetitive ethanol administration attenuated the adrenal stress response to LPS challenge alone and after RS, by preventing the increase in plasma corticosterone concentrations and by decreasing the PGE content and NOS activity in the adrenal gland. Therefore, we conclude that moderate alcohol consumption could attenuate the effects of psychophysical stress and impair an inflammatory response.     

Male and female psychoneuroendocrine response to examination stress: A case report

Urinary catecholamine levels were investigated in one female and one male Ph.D. candidate during public defense of their Ph.D. theses as well as during 2 weeks preceding and 1 week following these examinations. Although females, in comparison to males, usually tend to show a weak adrenaline response to mental stress, a threefold increase was observed in both subjects. The results support the assumption that sex differences in adrenal-medullary responsiveness to stress is not determined by sex-specific biological factors alone and that a “male” responsiveness may be observed in achievement-oriented females exposed to a challenging real-life situation. Effects on urinary measures of cortisol obtained from the male subject resembled effects on adrenaline, showing that this kind of real-life stressor affects the sympathetic-adrenal medullary and the pituitary-adrenocortical systems similarly.     

Adaptation of anterior pituitary hormones to chronic noise stress in male rats

We have studied the effects of acute and chronic noise on serum levels of pituitary hormones in male Wistar rats. Acute noise increased serum levels of corticosterone, prolactin, and luteinizing hormone and decreased serum GH. FSH was unaffected by this stressor. Chronic noise did not modify basal levels of any hormone studied, however responsiveness of some hormones to the same stimuli was altered. Reduced corticosterone, prolactin, and GH responses to noise was observed after previous chronic exposure to this stimuli. LH response followed the same pattern although it did not reach statistical significance. It might be concluded that adaptation to a repeated stress stimulus is not confined to the pituitary-adrenal axis, however, the degree of adaptation could vary between different hormones.     

Genotype modulates prenatal stress effects on aggression in male and female mice

Prenatal stress (heat and restraint) significantly increased postpartum aggression (proportion of animals fighting and/or the intensity of the behavior) in C57BL/6J female mice and reduced the behavior in DBA/2J females. For intermale aggression, prenatal stress increased the behavior (intensity of aggression) in C57BL/6J males but did not affect aggressive behavior in DBA/2J animals. Infanticidal behavior (the killing of young) exhibited by male mice was not influenced by prenatal stress in either strain. Relative anogenital distance measurements in neonates at birth did not serve as a reliable predictor of strain variation in prenatal stress effects. Prenatal stress did not influence this measure of prenatal androgen exposure in DBA/2J or C57BL/6J females. For males, prenatal stress elevated relative anogenital distance in C57BL/6J mice and decreased this measure in DBA/2J animals. Prenatal stress effects on aggressive behavior in male and female mice therefore depend upon genotype. Strain-dependent differences may be modulated by differences in endocrine reactivity to prenatal stress/and or differential central neural tissue sensitivity to hormones.     

Mother rats interact differently with male and female offspring.

Lactating Long-Evans rats were observed to interact differently with male and female pups during the first 18 days postpartum. Differences in the mother's behavior were related to the gender composition of her litter (GHL), to the sex of a single introduced pup, and to the sex of individual pups within her litter. Major differences were the greater time spent in licking the anogenital region of own male pups and the greater stimulation of anogenital licking by male foster pups, an effect that did not interact with GHL or age of pup. The GHL interacted with day of testing to affect nest building and time spent near pups.