Evidence that a factor besides progesterone, prolactin, or plasma-estradiol-binding protein inhibits estrogen-induced sexual receptivity in pregnant rats.

Daily administration of estradiol benzoate stimulated significantly less lordotic behavior in rats during the second half of pregnancy than in ovariectomized females that received subcutaneous progesterone implants, pituitary grafts that raised plasma prolactin, or both treatments combined. Following an initial facilitation of receptivity, females with progesterone implants showed only moderate reductions in lordosis quotients over 3 test days. The capacity of plasma from pregnant rats to bind estradiol was found to increase significantly during the second half of pregnancy. However, daily administration to pregnant rats of a synthetic estrogen, R 2858, which is not bound by plasma protein, was no more effective than estradiol benzoate in stimulating receptive behavior. Administration of estradiol benzoate also stimulated significantly lower levels of sexual behavior in pregnant females than in females in which pseudopregnancy had been prolonged by previous hysterectomy or induction of uterine decidualization. These findings suggest that some endocrine factor other than progesterone, prolactin, or estradiol-binding protein is primarily responsible for the potent suppression of behavioral responsiveness to estrogen which occurs in pregnant rats. It is suggested that 5 alpha-reduced androgens may cause these behavioral effects.     

Cardiovascular responses to open-field stress in rats: sex differences and effects of gonadal hormones

We studied sex differences in cardiovascular responses to stress using a new radio-telemetry model in which freely-moving Spontaneously Hypertensive rats (SHR) are exposed to open-field novelty stress. This model allowed simultaneous assessment of cardiovascular and behavioural responses to psychological stress. Female SHR in the diestrous stage of their estrous cycle had markedly greater pressor and tachycardic responses to open-field exposure when compared to either female rats not in diestrous or male SHR. Treatment of ovariectomized SHR with estrogen alone had no significant effect on cardiovascular reactivity, while a combined treatment of estrogen and progesterone slightly, but significantly attenuated their pressor response to open-field stress. In addition, treatment of castrated male rats with testosterone significantly enhanced their pressor responses to stress when compared to values obtained before treatment. None of the hormone treatments had any significant effect on heart rate responses to stress. Neither at different stages of the estrous cycle nor after hormone treatments were there any marked changes in behavioural responses in the open-field, making it unlikely that the differences in cardiovascular stress responses were caused by changes in behavioural activity. These data demonstrate differences in cardiovascular stress responses that seem to be dependent on the stage of the estrous cycle. They suggest that particularly androgens, such as testosterone, may enhance pressor responses to stress. On the other hand, a combination of estrogen and progesterone, rather than estrogen alone, may have a small attenuating effect on cardiovascular reactivity.     

Measuring stress responses in postpartum mothers: perspectives from studies in human and animal populations

Reduced hypothalamic-pituitary-adrenal (HPA) responses to stress during the last week of pregnancy and lactation have been consistently observed in rat studies. Several contributing factors have been proposed for this phenomenon in lactation, including the suckling stimulus from the pups, hormones (oxytocin and prolactin) and opioids, a decrease in the ability of noradrenaline to potentiate hypothalamic responses and changes in pituitary responsiveness to ACTH secretagogues (AVP and CRF). In contrast to this vast literature using the rat model, only few studies have addressed this issue in the human population. The consensus is that women engaging in breastfeeding activities exhibit reduced anxiety, although the reductions in neuroendocrine and autonomic responses to stressors are variable, in part because of the different nature of the stressors used. Further work is required to investigate how additional factors, such as maternal parity or emotional salience of the stressor can affect stress responsiveness in postpartum women. Here, we review first the findings regarding stress responsiveness during lactation in both rat and human studies, and then discuss potential research avenues and methodological issues that could be the lead to future research protocols in human subjects. Knowing the reciprocal relationship in the mother-infant dyad, it is clear that investigation of the mechanisms regulating stress responses and mental health in postpartum mothers can only be beneficial to the development of the infant.     

The brain prolactin system: involvement in stress response adaptations in lactation

This review focuses on prolactin as a potential candidate for the regulation of emotional and neuroendocrine stress responses in the brain. In particular, we summarise evidence for a brain prolactin receptor-mediated anxiolytic action both in female and male rats, and for inhibitory actions on the reactivity of the hypothalamic-pituitary-adrenal (HPA) axis and the neurohypophysial oxytocin system. These physiological functions of the brain prolactin system are especially relevant in the peripartum period, as an attenuation of behavioural and neuroendocrine stress responses has been described during pregnancy and lactation. At this time, there is an increase in brain prolactin receptor expression and binding, and an increase in hypothalamic prolactin gene expression. In the absence of a selective prolactin receptor antagonist, complementary approaches including chronic intracerebral infusion of prolactin, and antisense targeting of the long form of the brain prolactin receptor were used to investigate the actions of prolactin. The hypothesis of a brain prolactin system activated in the peripartum period which contributes to the adaptive changes in stress responsiveness in order to support reproductive functions is strongly emphasised.     

Lactation and stress: protective effects of breast-feeding in humans

Whilst most research on breast-feeding has been designed to assess its importance for infant health or to find a human nutrient replacement for infant formula, the effects of breast-feeding on maternal health have received little scientific attention. In several animal studies lactation has been shown to be associated with a marked blunting of physiological and behavioral responses to physical and psychological stress. However, the literature on the effects of lactation on stress in humans remains limited. This review focuses primarily on recent findings on the effects of breast-feeding on neuroendocrine and behavioral responses to acute stress exposure in lactating women. The available data suggest that breast-feeding suppresses the hypothalamic-pituitary-adrenal (HPA) axis response to physical and psychosocial stress. However, lactation in women, in contrast to lactating rats, does not seem to result in a general restraint of the endocrine stress response during the whole period of lactation. Recent data strongly suggest that the blunted HPA axis response to stress in women seems to be counterbalanced if the acute stressor, at least when of a psychosocial nature, occurs later than 1 h after suckling. Further elucidation of the underlying psychobiological mechanisms involved in suppressed stress responses during lactation will no doubt lead to new insights into improved health sequelae of breast-feeding in women and to a better understanding of the psychobiology of human stress protection in general.     

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.     

Perinatal bromopride treatment: effects on sexual behavior of male and female rats

Effects of different perinatal bromopride treatments on sexual behavior were examined in adult male and female rats of Wistar origin. Female rats of mothers treated with bromopride (BRO) during lactation (VB group) and during pregnancy and lactation (BB group) showed lower lordosis quotients than those of controls (VV group). Females of mothers treated with BRO only during pregnancy (BV group) showed no differences in lordosis quotient when compared to the VV group. There were no significant differences in male sexual behavior between experimental and control groups. The effect of bromopride on the control of sexual behavior is discussed.     

Social and hormonal factors influencing infanticide and its suppression in adult male Long-Evans rats (Rattus norvegicus)

In a series of six experiments, the experiential and hormonal factors influencing infanticide in Long-Evans hooded rats were examined. Males, but not females, purchased from a breeder as adults exhibited infanticide at high rates, whereas males reared in the laboratory until adulthood were less likely to be infanticidal. Sexual experience reduced the rate of infanticide in laboratory-reared males, and cohabitation with a female through pregnancy and lactation (including exposure to pups) inhibited infanticide in previously infanticidal males. Fourteen days of cohabitation with a pregnant female following copulation inhibited infanticide in males purchased from a breeder, but copulation without cohabitation and copulation followed by cohabitation with a nonpregnant (ovariectomized) female did not inhibit infanticide. Castration of laboratory-reared males in adulthood did not reduce their rate of infanticide, whereas testosterone implants increased the number of males exhibiting infanticide. The importance of hormonal and experiential factors for controlling infanticide in male rats is discussed.     

Stress-induced progesterone secretion and progesterone receptor immunoreactivity in the paraventricular nucleus are modulated by pubertal development in male rats

Male rats show a differential adrenocortical response to stress before and after pubertal development, such that prepubertal animals have a more prolonged stress-induced corticosterone response compared to adults. Whether pubertal maturation affects other adrenocortical responses to stress is currently unknown. To address this question, we assessed stress-induced progesterone secretion in both intact and gonadectomized prepubertal (28 days of age) and adult (77 days of age) male rats either before or after exposure to a 30 min session of restraint stress. We found that prepubertal males show a greater and more prolonged stress-induced progesterone response compared to adults. We also found a similar effect in castrated prepubertal and adult males, indicating the differential stress-induced progesterone response is not gonadal in origin. We also examined progesterone receptor (PR) levels by immunohistochemistry in the paraventricular nucleus (PVN) of the hypothalamus, a key regulatory nucleus of the hypothalamic-pituitary-adrenal (HPA) axis, and found lower PR protein expression in the PVN of prepubertal compared to adult males. These data indicate that in addition to corticosterone, stress-induced adrenocortical progesterone levels are differentially affected by pubertal maturation. Furthermore, these data raise the possibility of different progesterone sensitivity of the PVN before and after puberty. The significance of this differential response is presently unknown. However, given the pleiotropic effects of progesterone on male physiology and behaviour, it is likely that the disparate post-stress exposure to progesterone affects the prepubertal and adult male differently.     

Prolactin in rats is attenuated by conspecific touch in a novel environment

Prolactin is released in response to physical and psychological stress, the latter of which involves an animal’s interpretation of its environment as potentially dangerous. This interpretation might be altered by social buffering, as defined by the presence of a social partner. In support of this claim, I previously found that the presence of a conspecific during exposure to the open field caused lower levels of prolactin in juvenile rats than did exposure to the open field alone. Because testing with a conspecific allowed the animals to touch, physical contact may have been necessary for the reduction of prolactin. To test this hypothesis, juvenile male and female rats in the present study were exposed to the open field (1) alone, (2) with a conspecific separated by a Plexiglas partition, or (3) with a conspecific without a partition. Touch was necessary to reduce stress as measured by prolactin levels.     

Relationship between maternal aggression and maternal care in the rat

Aggression among female rats is almost entirely confined to the period of late pregnancy and lactation. Behaviorally it is similar to the aggression of males including piloerection and lateral attacks, but it differs in its function. Unlike male aggression which serves to establish a social hierarchy and a territory, i. e., is competitive, maternal aggression is protective, i. e., it serves to prevent predation of the mother's offspring. In this respect it is closely related temporally and causally to maternal care; if the offspring are removed maternal aggression wanes almost immediately–its function no longer exists! Studies on aggression by mothers, among rats, from the author's laboratory are reviewed and comparisons made with maternal care. As noted, maternal aggression and maternal care are closely related during the cycle of maternal behavior and they share a similar hormonal basis and possibly the effect of uterine stimulation, but maternal care requires prolactin and the decline of progesterone while maternal aggression appears independent of pituitary hormones and does not require a decline in progesterone. Maternal aggression like maternal care appears to be organized into a hormonal phase, during pregnancy, parturition, and for about a week postpartum and a nonhormonal phase thereafter. Bilateral radiofrequency lesions of the lateral midbrain peripeduncular nucleus (PPN) produce deficits in maternal aggression if made on lactation day 7 (L7), but not earlier, without producing significant deficits in maternal behavior. Experiments showed that the PPN does not mediate hormonally stimulated maternal aggression; it appears to mediate only nonhormonally stimulated maternal aggression. Studies on the role of pregnancy hormones on long-term retention of maternal aggression and the role of olfaction in maternal aggression are also reviewed. © 1994 Wiley-Liss, Inc.     

Influence of Regularity of Exposure to Chronic Stress on the Pattern of Habituation of Pituitary-Adrenal Hormones, Prolactin and Glucose

The effect of regularity of exposure to two different chronic stressors (noise or immobilization (IMO)) on the pattern of habituation of pituitary-adrenal (PA) hormones, prolactin and glucose was evaluated in adult male rats. Animals were chronically subjected to either regular or irregular time schedule of noise (30 min/day) or IMO (2 h/day) for two weeks. The day after the last stress session the rats were killed without stress or after having been subjected to 30 min of the homotypic stressor. Whereas regular noise did not affect food intake, body weight gain or adrenal weight, irregular noise decreased body weight gain and induced a moderate adrenal hypertrophy. In addition, previous daily exposure to regular but not to irregular noise reduced both prolactin and corticosterone responses to acute noise. In contrast, glucose response to acute noise was reduced after both regular and irregular exposure to chronic noise. Either regular or irregular exposure to chronic IMO decreased food intake and body weight and increased adrenal weight to the same extent. Likewise, no influence of regularity of exposure to chronic IMO on corticosterone and prolactin responses to acute IMO was observed. However, habituation of the ACTH response to acute IMO was observed in rats subjected to chronic regular IMO, but not in rats subjected to chronic irregular IMO. Finally, acute IMO-induced hyperglycemia diminished to the same extent after regular and irregular IMO. From these results we can conclude that: first, the process of habituation of the PA axis to chronic stress is greatly dependent upon factors such as regularity of exposure to the stressor and stressor intensity, and second, the influence of regularity on the pattern of habituation to a repeated stressor is dependent on the physiological variable we are dealing with.     

Gender differences in acute and chronic stress in Wistar Kyoto (WKY) rats

While females are considered more susceptible to depressive behavior, this assertion is not strongly supported by the experimental literature. Since stress contributes to depressive behavior, male and female Wistar Kyoto (WKY) rats were exposed to either one session (acute stress) or 5 sessions (chronic stress) of restraint plus cold in order to study depressive behavior in male and female rats. After their respective treatment exposure, rats were tested in the open field test (OFT) and for retention of a passive-avoidance (P-A) task. One stress session resulted in significant immobility in the OFT for males, whereas 5 sessions were required to produce similar immobility in female rats. Acute stress interfered with the retention of the P-A response for males, while both acute and chronic stress produced poor P-A responses in female rats. Food consumption decresed, progressively, as a function of stress sessions, in female rats, whereas feeding in males returned to control levels after five stress days. Both acute and chronic stress exacerbated the stress ulcer response in male rats, but not in female rats. Chronic, but not acute, stress resulted in an increase in serotonin transporter mRNA levels in the dorsal raphe nucleus of both male and, female rats. The general consensus from these data suggested that female rats were more vulnerable to chronic stress and consequently supported the notion that females may be more susceptible to stress induced behavioral depression.     

Long-term effects of footshock and social defeat on anxiety-like behaviours in rats: Relationships to pre-stressor plasma corticosterone concentration

We compared the consequences of two stressors, 'unnatural' inescapable footshocks (IFSs) and 'natural' social defeat (SD), on behaviours typically sensitive to stress [sucrose preference, open field (OF), elevated plus maze (EPM) and acoustic startle responses (ASRs)] and the association with pre-stressor plasma corticosterone concentration. After initial blood sampling, rats (n?=?20 per group) were exposed to either 10 IFSs (1?mA intensity, 5?s duration each) or to 1?h SD (defeat by an aggressive resident male rat and further exposure but separated in a small cage) or to control procedures (handling). Rats were tested once for ASR (day 19), while the other behavioural tests were applied once weekly for 3 weeks. Both stress groups showed short-lasting lowered sucrose preference, and in the EPM they showed shorter total distance moved, shorter distance moved on open arms and less time on open arms compared to controls. In the OF test, IFS rats showed shorter total distance moved up to 2 weeks after stress. The SD group showed shorter total distance moved in the OF, which was only significant 2 weeks after stress. Low pre-stressor plasma corticosterone concentration was only associated with defecation (IFS rats) and latency to enter open arms in the EPM (all low corticosterone subgroups, n?=?10 per subgroup). SD rats with high initial plasma corticosterone concentration showed enhanced ASR compared to the other subgroups with high initial plasma corticosterone concentration (n?=?9 per subgroup). The results indicate that footshock and SD, while generally leading to an increase in anxiety behaviours, represent qualitatively different stressors.     

Estradiol and progesterone in the control of sexual receptivity in female rats

Estradiol (E₂) and progesterone (P) are both required for induction of sexual behavior in female rats under physiological conditions. Administration of E₂ in brief pulses can induce the behavior in ovariectomized rats. P does not normally exert inhibitory or anti-estrogenic effects on the behavior. The decline of sexual receptivity in ovariectomized E₂+P-treated rats is dependent upon the amount of E₂ and P given but independent on the continued presence of either hormone. Ovariectomized animals treated with a constant amount of E₂ show a behavioral rhythm which is disrupted by hypothalamic lesions and it is suggested that peptidergic neurons in the suprachiasmatic nuclei of the hypothalamus rhythmically inhibit the behavior of ovariectomized E₂-treated rats.     

Gender differences in acute and chronic stress in Wistar Kyoto (WKY) rats.

While females are considered more susceptible to depressive behavior, this assertion is not strongly supported by the experimental literature. Since stress contributes to depressive behavior, male and female Wistar Kyoto (WKY) rats were exposed to either one session (acute stress) or 5 sessions (chronic stress) of restraint plus cold in order to study depressive behavior in male and female rats. After their respective treatment exposure, rats were tested in the open field test (OFT) and for retention of a passive-avoidance (P-A) task. One stress session resulted in significant immobility in the OFT for males, whereas 5 sessions were required to produce similar immobility in female rats. Acute stress interfered with the retention of the P-A response for males, while both acute and chronic stress produced poor P-A responses in female rats. Food consumption decreased progressively, as a function of stress sessions, in female rats, whereas feeding in males returned to control levels after five stress days. Both acute and chronic stress exacerbated the stress ulcer response in male rats, but not in female rats. Chronic, but not acute, stress resulted in an increase in serotonin transporter mRNA levels in the dorsal raphe nucleus of both male and female rats. The general consensus from these data suggested that female rats were more vulnerable to chronic stress and consequently supported the notion that females may be more susceptible to stress-induced behavioral depression. Key Words: WKY rats, acute and chronic stress, gender, passive avoidance, open field behavior, stress-ulcer, adrenal weight, serotonin, dorsal raphe nucleus     

Analysis of appetitive motivation in preweanling rats: application of bromocryptine mesylate

Two experiments investigated discrimination learning with preweanling rats (Rattus norvegicus) following different experimental deprivation treatments. In Experiment 1, 10- to 11-day-old Sprague-Dawley rats were deprived for 24 h of either nutrients and maternal contact through placement in an incubator or only nutrients by placement in the nest of a bromocryptine mesylate-treated dam. Bromocryptine mesylate inhibits prolactin release and thereby prevents lactation with only minimal effect on maternal behaviors. After the deprivation period, pups were trained to perform a spatial discrimination for milk infusion into the oral cavity or for the opportunity to suckle the dry nipples of an anesthetized dam. The results revealed, irrespective of deprivation treatment, that pups failed to acquire a simple T-maze spatial discrimination for milk reward although they rapidly learned to approach and locate an anesthetized dam to suckle. Experiment 2 followed up with a different procedure. Results indicated that during bouts of suckling rat pups preferred an active, lactating dam letting down milk to an identical dam not letting down milk due to her pretreatment with bromocryptine mesylate. These results illustrate a constraint on learning which affects immature rats. The capability to learn on appetitively motivated spatial discrimination appears intricately tied to the context in which training occurs. Results are discussed according to how the organism's expectancy can mediate performance.     

The Effect of Selective Serotonin Releasing Agents in the Chronic Mild Stress Model of Depression in Rats

Chronic exposure to mild unpredictable stress has been found to depress the consumption of, and preference for, highly palatable sucrose solution in rats. Stress-induced behavioral deficits may be maintained for a long time, however chronic administration of clinically effective antidepressants can restore normal behavior. This is the first report showing that Sprague-Dawley rats can be used in this model. A preference deficit in this strain of rats took at least 7 weeks to develop; about twice the time required when hooded Lister or Wistar rats are used in this model. Water consumption was not effected by chronic exposure to the mild stress regime and/or by chronic administration of the selective serotonin (5-HT) releasing agent MMAI (5-methoxy-6-methyl-2-aminoindan). The stress-induced deficit in sucrose intake was completely reversed by chronic treatment with MMAI (5 mg/kg, 2 x day) over 3 weeks in the two-bottle tests. In single-bottle tests, chronic treatment with the selective 5-HT releasers, MMAI (5 mg/kg, 2 x day) or MTA (p-methylthioamphetamine; 5 mg/kg, 2 x day), reversed the deficit in rewarded behavior (anhedonia) measured as a decrease in the consumption of 1% sucrose solution in the chronic mild stress model of depression in rats. With the experimental procedure employed, and at a dose of 10 mg/kg/day of 5-HT releasers, the magnitude and onset of this effect were greater than observed following similar administration of the selective 5-HT reuptake inhibitor (SSRI) sertraline (10 mg/kg/day), used as a standard anti-depressant drug.     

Differences in adrenocortical secretory and gene expression responses to stimulation in vitro by ACTH or prolactin between high- and low-avoidance Hatano rats

Rats of the Hatano high-avoidance (HAA) and low-avoidance (LAA) strains have been genetically selected on the basis of their two-way active avoidance behavior, and have different endocrine responses to stress. The present study focused on the adrenal steroid hormone responses of the Hatano strains and identifies differences in regulation of the adrenal cortex in vitro of HAA and LAA rats. Although incubation with prolactin (PRL) and/or adrenocorticotrophic hormone (ACTH) resulted in a dose-dependent increase of corticosterone and progesterone release by adrenal cells from both HAA and LAA male rats, the responses were markedly increased for adrenal cells from LAA rats as compared with HAA rats. This finding suggested that adrenal glands of HAA rats are less sensitive to PRL and/or ACTH than adrenals from LAA rats. Several possible intra-adrenal regulators were investigated. The basal level of expression of steroidogenic acute regulatory protein (StAR) and the long form of the PRL receptor (PRLR-L) mRNAs was higher in adrenals of LAA rats. ACTH treatment of adrenal cells from HAA rats resulted in statistically significant increases in melanocortin receptor 2 (MC2R) mRNA expression, while neither ACTH nor PRL altered MC2R mRNA expression in adrenal cells of LAA rats. Conversely, the increase in PRLR-L mRNA expression induced by PRL was observed only in adrenal cells from LAA rats. Treatment of adrenal cells with PRL and/or ACTH increased the expression of StAR and CYP11A1 mRNAs for both Hatano strains. However, the induction of StAR mRNA expression was higher in LAA rats, but the CYP11A1 response was lower. These findings indicate that adrenal cells of the LAA strain have higher sensitivity to secretagogues than those of the HAA strain. These results suggest that PRL may also be important in stimulating secretion of adrenal steroid hormones.     

Effects of chronic social stress during lactation on maternal behavior and growth in rats

Maternal mood disorders such as depression and chronic anxiety can negatively affect the lives of not only mothers, but also of partners, offspring, and future generations. Chronic exposure to psychosocial stress is common in postpartum mothers, and one of the strongest predictors of postpartum depression is social conflict. The objective of the current study was to evaluate the effects of chronic social stress (CSS) during lactation on the maternal behavior (which consists of maternal care and aggression toward a novel conspecific) of lactating rats, as well as on the growth of the dams and their offspring. It was hypothesized that chronic daily exposure to a novel male intruder would alter the display of maternal behavior and impair growth in both the dam and offspring during lactation due to the potentially disruptive effects on maternal behavior and/or lactation. The data indicate that CSS during lactation attenuates maternal care and the growth of both dams and pups, and increases self-grooming and maternal aggression toward a novel male intruder. These results support the use of CSS as a relevant model for disorders that impair maternal behavior and attenuate growth of the offspring, such as postpartum depression and anxiety.