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Hypothalamo-pituitary-adrenal axis responses to various stressors are typically attenuated during lactation, including in rats selectively bred for high or low anxiety. As high-anxiety dams are more aggressive towards intruders than low-anxiety dams during maternal defence, we investigated their hypothalamo-pituitary-adrenal axis responses to this social stress. Maternal defence induced elevated stress responses in high-anxiety dams only; nerve-growth-factor-induced gene B mRNA expression in the parvocellular paraventricular nucleus and adrenocorticotropin hormone secretory responses were substantially enhanced after maternal defence. In contrast, secretory responses to a non-social stress (elevated platform) were not different between high- and low-anxiety dams. Thus, responsiveness of the stress axis in lactation is dependent upon the innate level of anxiety of the dam and, as a consequence, her reactiveness to social threat.

During parturition, the basal activity of the hypothalamo-pituitary-adrenal (HPA) axis of Wistar rats is strongly attenuated, whereas the oxytocin system is activated. We investigated the secretory responses of the HPA axis and oxytocin to exposure to a mild emotional stressor (airpuff) comparing virgin female, d 22 pregnant, and parturient rats. Furthermore, as the brain oxytocin system is activated in parturition and oxytocin has been shown to inhibit HPA axis responses in virgin rats, the role of brain oxytocin in the regulation of stress responses during parturition was investigated by intracerebroventricular administration of an oxytocin receptor antagonist before stressor exposure (0.75 micro g/5 micro l). In virgin female rats, exposure to airpuff increased ACTH (2.5 +/- 0.34-fold) and corticosterone (5.1 +/- 2.3-fold) secretion, but in late pregnancy and parturition, the stress-induced increase in ACTH (pregnancy: 1.9 +/- 0.41-fold; parturition: 1.3 +/- 0.13-fold) and corticosterone secretion (parturition: 1.8 +/- 0.40-fold) were strongly attenuated. Oxytocin secretion remained unchanged in response to airpuff in both virgin and parturient rats despite higher overall plasma concentrations in the latter. Oxytocin receptor blockade in the brain elevated basal and stress-induced ACTH secretion in virgin but not pregnant or parturient rats and had no effect on oxytocin secretion either in virgin or parturient rats. We conclude that the reactivity of the HPA axis to external stressors is strongly attenuated during parturition, and this cannot be disinhibited by blocking the receptor-mediated action of brain oxytocin.

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.

In several studies lactation has been shown to be associated with a hypothalamic-pituitary-adrenal axis hyporesponsiveness to physical and psychological stressors. As it is not known whether the marked blunting of endocrine stress reactivity in women can be ascribed to suckling as a short-term effect or to lactation in general, the acute effects of suckling on the hypothalamic-pituitary-adrenal axis and the sympathetic-adrenal-medullary system responses to mental stress were investigated in lactating women. Forty-three lactating women were randomly assigned either to breast-feed or to hold their infants for a 15-min period with the onset 30 min before they were exposed to a brief psychosocial stressor (Trier Social Stress Test). Both breast-feeding and holding the infant yielded significant decreases in ACTH, total plasma cortisol, and salivary free cortisol (all P < 0.01). There were no significant differences in baseline hormone levels between the groups 1 min before the stress test. In response to stress exposure, ACTH, total plasma cortisol, salivary free cortisol, norepinephrine, and epinephrine were significantly increased in all lactating women (all P < 0.001). However, total cortisol and free cortisol responses to stress were attenuated in breast-feeding women (P = 0.001 and P = 0.067, respectively), who also showed significantly decreasing PRL levels during the stress test (P = 0.005). In addition, there was no change in plasma oxytocin or vasopressin in response to the stressor. Breast-feeding as well as holding led to decreased anxiety (P < 0.05), whereas, in contrast, stress exposure worsened mood, calmness, and anxiety in the total group (all P < 0.001). From these data we conclude that lactation in women, in contrast to that in rats, does not result in a general restraint of the hypothalamic-pituitary-adrenal axis response to a psychosocial stressor. Rather, suckling is suggested to exert a short-term suppression of the cortisol response to mental stress.

In response to various stressors, oxytocin is released not only into blood, but also within hypothalamic and extrahypothalamic limbic brain regions. Here, we describe the involvement of intracerebrally released oxytocin in the regulation of the activity of the hypothalamo-pituitary-adrenal (HPA) axis by infusion of the oxytocin receptor antagonist (des Gly-NH(2) d(CH(2))(5) [Tyr(Me)(2), Thr(4)] OVT; pH 7.4; Dr. M. Manning, Toledo, OH, USA) either into the lateral cerebral ventricle (icv[0.75 microg/5 microl,]) or via retrodialysis (10 microg/ml, 3.3 microl/min, 15 min) into the hypothalamic paraventricular nuclei (PVN), the medio-lateral septum or the amygdala. Male Wistar rats fitted with a chronic jugular vein catheter and an icv guide cannula or a microdialysis probe targeting the respective brain region 4 days prior to the experiment were blood sampled under basal as well as stressful conditions. Rats were exposed to the elevated platform (emotional stressor) and/or to forced swimming (combined physical and emotional stressor). Blockade of the receptor-mediated action of endogenous oxytocin within the PVN resulted in an enhanced basal secretion of ACTH whereas, in response to forced swimming, ACTH secretion was rather reduced, indicating a tonic inhibitory effect of OXT on basal HPA axis activity, but a potentiating action under conditions of stress. Within the medio-lateral septum, antagonist treatment did not alter basal ACTH secretion, but significantly disinhibited ACTH secretion in response to the elevated platform, but not to forced swimming. Within the amygdala, no significant effects either on basal or stress-induced HPA axis activity could be found. The results indicate a differential involvement of brain oxytocin in the regulation of the HPA axis activity which depends both on the site of intracerebral oxytocin release and the stressor the animals are exposed to.

The possibility of sequence-dependent, transient, and local inhibition of neuropeptide or neuropeptide receptor expression within the brain makes antisense targeting an attractive approach for those interested in the involvement of brain neuropeptide systems in behavioral and neuroendocrine regulation. Here, I describe our attempts to manipulate the synthetic activity of peptidergic systems of the hypothalamic-neurohypophysial system, i.e. , oxytocin and vasopressin, and the hypothalamic-pituitary-adrenal (HPA) axis by antisense oligodeoxynucleotides. Detailed experimental protocols including different approaches for intracerebral antisense application in anesthetized or conscious rats are provided. As a consequence of local oxytocin or vasopressin antisense treatment within the hypothalamic supraoptic nucleus, various aspects of the neuronal activity are already altered after a few hours. Thus, we monitored electrophysiological parameters of oxytocinergic and vasopressinergic neurons, stimulus-induced expression of the Fos protein in oxytocin neurons, and stimulated release of oxytocin or vasopressin into blood as well as within the hypothalamus by dendrites and cell bodies as measured by simultaneous microdialysis in blood and brain, shortly after a single acute antisense infusion. We also employed chronic antisense infusion via osmotic minipumps or by repeated local infusion into the targeted brain region; for example, septal vasopressin receptor downregulation impairs the ability of male rats to discriminate between juvenile rats. Further, reduction of the amount of available CRH, vasopressin, and oxytocin within the hypothalamic paraventricular nuclei alters the neuroendocrine stress response of the HPA axis., (Copyright 2000 Academic Press.)

The hypothalamic-pituitary-adrenal axis is hyporesponsive to stress in late pregnancy, exemplified as reduced adrenocorticotropic hormone (ACTH) and corticosterone responses to restraint, but the mechanisms are unknown. We investigated forward drive and negative feedback upon the hypothalamic-pituitary-adrenal axis in pregnant rats. Corticotropin-releasing hormone (CRH) and vasopressin mRNA expression in the parvocellular paraventricular nucleus and mineralocorticoid and glucocorticoid receptor expression in the paraventricular nucleus and hippocampus were quantified with in situ hybridization. Because it can enhance the corticosterone negative feedback signal, 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) bioactivity in these brain regions and anterior pituitary was measured in vitro, and ACTH and corticosterone stress responses were measured after intracerebroventricular glycyrrhetinic acid, an 11beta-HSD inhibitor. Changes in corticosterone feedback on ACTH secretion were examined after pharmacological adrenalectomy by metyrapone and aminoglutethimide. Parvocellular paraventricular nucleus CRH mRNA content was reduced on day 21 and the CRH mRNA : vasopressin mRNA ratio was unaltered, indicating decreased production of both CRH and vasopressin. An increase in glucocorticoid receptor mRNA expression in the dentate gyrus (mineralocorticoid receptor mRNA expression was unaltered) and increased 11beta-HSD1 activity in the paraventricular nucleus and anterior pituitary suggest an increase in slow negative feedback mechanisms in pregnancy, but glycyrrhetinic acid did not modify the stress response. After metyrapone/aminoglutethimide treatment, corticosterone decreased ACTH secretion more slowly in pregnancy, indicating a decrease in rapid feedback sensitivity. Thus, reduced forward drive rather than increased effectiveness of glucocorticoid negative feedback may underlie stress hyporesponsiveness of the hypothalamic-pituitary-adrenal axis in pregnancy.

The effects of repetitive transcranial magnetic stimulation (rTMS) on various brain functions were investigated in adult male Wistar rats. The stimulation parameters were adjusted according to the results of accurate computer-assisted, magnetic resonance imaging-based reconstructions of the current density distributions induced by rTMS in the rat and human brain, ensuring comparable stimulation patterns in both cases. The animals were subjected to daily rTMS-treatment (three trains of 20 Hz; 2.5 s) for 8 weeks from the age of 4 weeks on. In the forced swim test these rats showed a more active stress coping strategy than the control rats. This was accompanied by a significantly attenuated stress-induced elevation of plasma ACTH concentrations. Pituitary changes accounting for the attenuation were ruled out by the corticotropin-releasing hormone test. Baseline concentrations of ACTH and corticosterone were indistinguishable in the two groups. No changes were found in the anxiety-related behavior of the rats on the elevated plus-maze or in behavior during the social interaction test. Accordingly, the binding characteristics of the benzodiazepine agonist [(3)H]flunitrazepam at the benzodiazepine/gamma-aminobutyric acid type A receptor complex were similar in the rTMS and control groups. In summary, chronic rTMS treatment of frontal brain regions in rats resulted in a change in coping strategy that was accompanied by an attenuated neuroendocrine response to stress, thus revealing parallels to the effects of antidepressant drug treatment.

The ageing process has been shown to have a profound impact on the hypothalamo-neurohypophysial system (HNS) and the hypothalamo-pituitary-adrenocortical (HPA) axis in humans as well as in rodents. Therefore, in this study, the intracerebral and peripheral release patterns of both vasopressin and oxytocin have been studied in aged male Wistar rats under basal conditions and in response to ethologically relevant stressors, using intracerebral microdialysis and chronic blood sampling techniques, respectively. Approximately a twofold higher basal release of arginine vasopressin (AVP) within the hypothalamic paraventricular nucleus (PVN), but not within the supraoptic nucleus (SON), was found in aged rats, whereas basal oxytocin (OXT) release did not differ in comparison with young rats. With increasing age the rise in intra-PVN release of both AVP and OXT was blunted in response to forced swimming. In contrast, the intra-SON release of AVP was unrelated to age. Simultaneously recorded basal secretion of both AVP and OXT from the neurohypophysis into blood was increased in aged rats, with a blunted OXT response to swim stress. Opposed to that, plasma AVP levels remained unchanged in both groups. Basal plasma levels of corticotropin (ACTH) and corticosterone were elevated in aged rats, whereas stress-elicited ACTH and corticosterone responses were indistinguishable. These results indicate age-related changes in the HNS and HPA axis with an enhanced basal activity opposed to a blunted response to stressors with increasing age. The increased basal release of AVP within the PVN suggests a role of intracerebral AVP in age-associated alterations of HPA axis regulation.

The ageing process in animals and humans is thought to be accompanied by a gradual impairment of corticosteroid receptor function, which is reflected by increased pituitary-adrenocortical hormone secretion at baseline and a number of aberrant neuroendocrine function test results. The latter include the ACTH and corticosteroid responses to a combined dexamethasone (DEX)/corticotropin-releasing hormone (CRH) challenge. The excessive hormonal response to this test among aged individuals has been taken as indirect evidence of enhanced endogenous arginine vasopressin (AVP) release, which - together with peripherally administered CRH - is capable of overriding DEX-induced ACTH suppression. The current study was designed to explore the role of endogenous AVP in mediating excessive hypothalamic-pituitary-adrenocortical (HPA) activity in ageing. The combined DEX/CRH test was administered to aged (22-24 months old) Wistar rats and the effect of the AVP type 1 (V1) receptor antagonist, d(CH(2))(5)Tyr(Me)AVP, on ACTH release was studied. Infusion of the V1 receptor antagonist after DEX pretreatment and before CRH administration prevented the CRH-induced rise in ACTH secretion in comparison with vehicle-treated aged rats (area under the concentration-time curve: 699+/-479 versus 2896+/-759; P<0.01). This difference was absent in young (3 months old) control rats. In situ hybridization showed an increased number of AVP mRNA-expressing neurons in the parvocellular but not the magnocellular, portion of the hypothalamic paraventricular nucleus in DEX-pretreated aged rats. The number and synthetic activity of parvocellular neurons expressing CRH mRNA was also increased. We have concluded that the increased HPA activity in aged rats involves enhanced synthesis and release of AVP from parvocellular neurons, possibly secondary to impaired corticosteroid receptor function.

Psychiatric patients suffering from anxiety disorders or endogenous depression exhibit increased activity in their hypothalamo-pituitary-adrenocortical (HPA) axis. Recently, two Wistar rat lines, bred for high (HAB) and low (LAB) anxiety-related behaviour on the elevated plus-maze, were described as a unique psychopathological animal model (1). The present study focused on the HPA axis reactivity of HAB and LAB animals to an emotional stressor. Thus, adult male HAB and LAB animals, fitted with jugular vein catheters 5 days prior to the experiment, were exposed to an open arm of the elevated plus-maze for 5 min. Whereas basal levels of ACTH and corticosterone were similar in both lines, HAB rats showed higher plasma concentrations at 5 and 15 min following stressor exposure (both hormones and both time points: P<0.01 vs LAB). Furthermore, increased basal (P<0.05 vs LAB) and stimulated (P<0.01 vs LAB) prolactin concentrations in HAB rats were found. In contrast to ACTH, corticosterone and prolactin, plasma oxytocin and vasopressin levels did not differ between HAB and LAB animals; oxytocin, but not vasopressin, responding to open arm exposure with a significant increase in both lines (P<0.05). In conclusion, particularly due to the association between inborn anxiety and HPA axis hyper-reactivity, the HAB rat represents a promising animal model for further investigation of the relationship between emotional disturbance and neuroendocrine activity.

During the last 2 days of pregnancy in rats, basal corticosterone secretion is enhanced, although the response of the hypothalamo-pituitary-adrenocortical (HPA) axis to emotional and physical stressors is blunted, independent of the action of endogenous opioids. In this study, alterations in the reactivity of the HPA axis, which may accompany parturition-related stimuli, and the involvement of endogenous opioids were examined in chronically catheterized rats. In vehicle-treated controls (n = 9), ACTH and corticosterone secretion decreased in preparation for birth (P < 0.01) and further declined immediately after delivery of the second pup (P < 0.01), remaining low for 150 min. In contrast, in animals injected with the opiate antagonist naloxone (5 mg ml(-1) kg(-1), i.v., n = 6) after delivery of the second pup, ACTH and corticosterone release were enhanced within 20 min (ACTH, 5.0-fold; corticosterone, 2.3-fold; P < 0.01 vs. controls) and returned to control levels after 90 min. In confirmation of previous reports, oxytocin secretion into blood was elevated in control rats after the onset of parturition (P < 0.01) and was further enhanced in the naloxone group (1.4-fold, P < 0.01 vs. control). Plasma lactate concentration was increased, 30 min after the onset of delivery (1.9-fold, P < 0.01), independent of the treatment. The data indicate that parturition-related events do not trigger HPA axis hormone release because of an effective inhibition by endogenous opioids. This nonresponsiveness of the HPA axis is likely to protect the pups' well-being during birth.

Endogenous opioid regulation of neurohypophysial and hypothalamo-pituitary-adrenal (HPA) axis hormone secretion in response to forced swimming (90 s in deep water at 19 degrees C) was investigated in virgin and 21-day-pregnant rats. There was no difference in basal plasma oxytocin concentrations between pregnant and virgin rats, but the opioid antagonist, naloxone, increased basal oxytocin secretion in the pregnant rats. Forced swimming increased oxytocin secretion similarly in pregnant and virgin rats, and this response was enhanced by naloxone. In pregnant rats naloxone had a greater effect (by 3.1-fold) than in virgins, showing stronger endogenous opioid restraint of an enhanced oxytocin secretory response to stress in pregnancy. Vasopressin secretion was not increased with forced swimming in virgin or pregnant rats, and naloxone had no effect. ACTH and corticosterone secretion in response to forced swimming was attenuated in pregnant rats compared to virgin rats, measured at 5 min. Naloxone had no effect on basal plasma ACTH or corticosterone concentration, but it reduced ACTH secretion in virgin rats 5 min after forced swimming; in pregnant rats naloxone had no such effect. Naloxone removed the pregnancy-related attenuation in corticosterone secretion measured at 5 min after forced swimming. Fifteen minutes after forced swimming, plasma corticosterone concentrations were not different between groups. In the late-pregnant rats, the increases in plasma ACTH and corticosterone induced by forced swimming were significantly prolonged compared to virgins. The results show that endogenous opioid inhibition emerges in pregnancy to restrict the responses of oxytocin neurones to a stressor. In contrast, the endogenous opioid enhancement of mechanisms regulating HPA axis secretory responses in virgin rats is not evident during pregnancy.

In order to test the hypothesis that prenatal hormones influence the emotional maturation of the offspring, the hypothalamo-pituitary-adrenal (HPA) axis activity was studied at the end of pregnancy in two rat breeding lines differing consistently in their innate anxiety-related behaviour in the elevated plus-maze. Virgin and pregnant rats were fitted with a chronic jugular vein catheter and tested 5 days later. The high basal level of anxiety-related behaviour (HAB) described in males and females of the HAB breeding line persists in pregnancy as indicated by a significantly reduced number of entries into and time spent on the open arms of the elevated plus-maze between days 18 and 20 of pregnancy compared with pregnant rats of the breeding line with low anxiety-related behaviour (LAB). In general, an increase in anxiety was found in both breeding lines in pregnancy compared with the respective virgin controls. With respect to HPA axis activity, increased basal levels of adrenocorticotropin (ACTH) and corticosterone have been found in pregnant rats of the HAB line compared with pregnant LAB rats. ACTH and corticosterone secretion in response to emotional and complex physical stressors (exposure to the elevated plus-maze and forced swimming, respectively) did not differ between virgin and pregnant rats of either breeding line. However, independent of the inborn emotionality of the animals, a general attenuation in the HPA axis response to stressors and to exogenous CRH could be confirmed in pregnant rats. The basal and stress-induced activity of the hypothalamo-neurohypophysial system secreting oxytocin and vasopressin was also tested, and no differences were found relating to the emotionality or reproductive state of the animals except for a reduced vasopressin secretion in pregnant HAB rats after forced swimming. The elevated basal activity of the HPA axis, including enhanced circulating concentrations of corticosterone in pregnant HAB rats, may influence both the neuroendocrine and emotional development of their offspring. Thus, the passing-on of maternal behavioural characteristics via prenatal, hormonal 'imprinting' has to be considered as a possible contribution to emotional maturation during an individual's development.