Reduced response of the hypothalamo-pituitary-adrenal axis to alpha1-agonist stimulation during lactation

To determine whether altered noradrenergic activation of the hypothalamo-pituitary-adrenal (HPA) axis contributes to the attenuated neuroendocrine response to stress observed during lactation, the effect of intracerebroventricular injection of the alpha1-agonist methoxamine (100 microg) was compared between virgin and lactating rats. Virgin rats showed significant increases in plasma corticosterone after methoxamine, reaching 317 +/- 44 ng/ml at 10 min and remaining significantly elevated for more than 120 min, but lactating rats showed no significant increase in corticosterone levels. Furthermore, methoxamine induced an increase in paraventricular nucleus (PVN) CRF messenger RNA expression in virgin, but not lactating, animals. Both groups of rats exhibited comparable elevations in plasma PRL after methoxamine treatment. Arginine vasopressin messenger RNA expression within the parvocellular PVN was greater in the lactating animals than in the virgin controls, but methoxamine injection was without further effect. Studies performed on ovariectomized virgin rats and ovariectomized rats receiving estradiol or progesterone replacement failed to reproduce the attenuated HPA responses seen after methoxamine treatment, although methoxamine-induced PRL levels were greatly increased by estradiol, probably arising from an effect on hormone synthesis. In vitro electrophysiological recordings of PVN neurons in hypothalamic slices from proestrous virgin and lactating rats showed that 45-52% of neurons in both groups exhibited excitatory responses to 10(-4) M methoxamine, but there was a differential response to 10(-5) M methoxamine, with PVN neurons from lactating animals failing to show a response. These data show a selective down-regulation of alpha1-mediated activation of the HPA axis in lactating animals. This may contribute to the attenuated stress-induced activation of the HPA axis during lactation.     

Effects of endothelin-1 on the rat pituitary-adrenocortical axis under basal and stressful conditions

Endothelins (ETs) and their receptor subtypes A and B (ETA and ETB) are expressed in the various components of the mammalian hypothalamo-pituitary-adrenal (HPA) axis, but their involvement in the functional regulation of HPA is controversial. To gain insight into this topic, we have investigated the effects of ET-1 and/or the specific antagonists of ETA and ETB receptors (BQ-123 and BQ-788, respectively) on the plasma concentrations of ACTH, corticosterone and aldosterone of non-stressed (control) and ether- or cold-stressed rats. The study of the effects of the administration of the two ET-receptor antagonists alone could provide informations about the possible action of endogenous ETs on the HPA axis. Exogenous ET-1 increased ACTH, corticosterone and aldosterone blood levels in control rats, as well as evoked a sizable enhancement of the HPA axis response to ether stress and a marked depression of the response to cold stress. BQ-123 and BQ-788 did not prevent the stimulatory effect of exogenous ET-1 in control rats, but when administered alone, raised the plasma concentrations of ACTH, corticosterone and aldosterone. Both ET-receptor antagonists magnified the HPA axis response to ether and cold stresses, but their effect was not counteracted by exogenous ET-1. Although very difficult to interpret, our present findings allow us to conclude that endogenous ETs play a role in the maintenance of the basal activity of rat HPA axis acting through ETA and ETB receptor subtypes, which are partially insensitive to BQ-123 and BQ-788. Conversely, the involvement of ETs in the modulation of the HPA axis responses to various stresses is very doubtful.     

Increased fat intake during lactation modifies hypothalamic-pituitary-adrenal responsiveness in developing rat pups: a possible role for leptin

High fat feeding reportedly enhances hypothalamus-pituitary-adrenal (HPA) responses to stress in adult rats. The present study tested whether elevated fat intake during suckling could have short and/or long lasting consequences on HPA regulation in the offspring. Mothers were fed either a control (C; 5% fat) or high fat (HF; 20% fat) diet during the last week of gestation and throughout lactation. After weaning (day 21), pups from C and HF mothers were fed a chow diet. Offspring from both C- and HF-fed mothers were tested for ACTH and corticosterone responses to stress on postnatal days 10 and 35. We found that HF feeding produced higher lipid levels in the milk of HF compared with C lactating rat dams and that offspring of these mothers had significantly increased retroperitoneal fat pad weight and relative adipose mass on day 21 as well as elevated plasma leptin levels on days 10 and 21 of age. After weaning, pups from the HF mothers had lower plasma leptin levels than those from C mothers. Maternal dietary fat affected HPA responsiveness in the offspring in an age-related manner. Neonatal pups (day 10) from the HF mothers exhibited a reduction in the ACTH and corticosterone responses to ether stress. However, in 35-day-old offspring from HF-fed dams, stress-induced ACTH secretion was increased compared with that in pups from the C-fed mothers. These results demonstrate that maternal diet and increased fat intake through the milk are important regulators of HPA responsiveness in neonates and prepubertal rats. During neonatal life, the blunted stress responsiveness seen with elevated fat intake and the resulting high leptin levels might protect the pups from excessive HPA activation. After removal of the maternal dietary influence and reduced leptin levels, enhanced ACTH stress responses are observed as in adult rats fed a HF diet. Because of the inverse relationship between plasma levels of leptin and HPA responses in pups, the possibility exists that the effects of the HF diet on stress responsiveness are mediated by changes in leptin exposure during development.     

The pulsatile characteristics of hypothalamo-pituitary-adrenal activity in female Lewis and Fischer 344 rats and its relationship to differential stress responses

The dynamic patterns of basal and stimulated hypothalamo-pituitary-adrenal (HPA) activity of freely moving female Lewis and Fischer 344 rats were compared using an automated blood-sampling system. Both strains showed pulsatile corticosterone release throughout the 24 h cycle. Lewis rats showed clear circadian variation in both pulse frequency (8.4 +/- 0.4 pulses between 1700-2300 h vs. 5.3 +/- 0.8 pulses between 0500-1100 h; P < 0.05) and height (198 +/- 27 ng/ml between 1700-2300 h vs. 107 +/- 14 ng/ml between 0500-1100 h; P < 0.05). Fischer rats exhibited pulses of similar frequency and height to those in Lewis rats during the evening, but showed no circadian variation, resulting in higher mean daily corticosterone concentrations. Although both strains showed behavioral and HPA responses to white noise stress (10 min; 114 dB), Fischer rats showed much greater increases in total activity, grooming, and rearings, and two important differences in the corticosterone responses were observed. First, in Lewis rats a clear relationship existed between basal and stimulated HPA activities, in that a significant response was seen only when the stress coincided with the rising (secretory active) phase of a basal pulse. Noise stress coinciding with a falling (nonsecretory) phase elicited no significant response. In contrast, Fischer rats showed similar responses regardless of the underlying pulse phase. Second, after the peak response at 20 min (Lewis, 237 +/- 67 ng/ml; Fischer, 390 +/- 57 ng/ml), corticosterone levels fell rapidly in Lewis rats, but remained maximally elevated for 20 min in Fischer rats, resulting in a significantly greater integrated response. The corticosterone response to i.v. CRF was unaffected by pulse phase in both strains, suggesting that a suprapituitary mechanism mediates the phase-dependent response to stress in the Lewis strain. CRF-induced corticosterone levels rose more rapidly in Fischer rats, peaking at 10 min (473 +/- 95 ng/ml) compared with 30 min (390 +/- 75 ng/ml) in Lewis rats, suggesting greater pituitary sensitivity in this strain. Thus, differences in both central and pituitary control of the HPA axis contribute to the strain difference in stress responsiveness between female Lewis and Fischer rats.     

Evidence for mineralocorticoid receptor facilitation of glucocorticoid receptor-dependent regulation of hypothalamic-pituitary-adrenal axis activity

These studies further evaluated the relative role of mineralocorticoid (type I) and glucocorticoid (type II) receptors in mediating corticosteroid feedback regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Acute treatment of rats with the selective mineralocorticoid receptor antagonist, RU28318 (50 mg/kg sc), produced elevated basal corticosterone levels in the morning, but had no effect on basal corticosterone levels in the evening or on restraint stress corticosterone levels at either time of day. Acute treatment with the selective glucocorticoid receptor antagonist, RU40555 (30 mg/kg sc) had no effect on basal or restraint stress corticosterone levels at either time of day. However, combined treatment with RU28318 and RU40555 produced an elevation of evening basal corticosterone levels (and morning basal on one occasion) and produced an increase in corticosterone levels during and after stress at both times of day. In a separate experiment conducted in the morning, the combined RU28318 and RU40555 treatment also produced elevated ACTH responses during restraint stress. Based on available corticosteroid receptor measures, the RU28318 treatment was estimated to selectively occupy approximately 85% of mineralocorticoid receptors in rat brain, whereas the RU40555 treatment was estimated to selectively occupy approximately 50% of glucocorticoid receptors in rat brain. We conclude that mineralocorticoid receptor activation is necessary and sufficient to maintain low basal corticosterone levels during the circadian trough, whereas glucocorticoid receptor activation is necessary to constrain corticosterone secretion during the circadian peak or during acute stress. However, even during the circadian peak or acute stress, mineralocorticoid receptor activation plays an important role in facilitating the glucocorticoid receptor dependent regulation of HPA axis activity by corticosterone.     

Augmented ACTH responses to stress in adrenalectomized rats replaced with constant, physiological levels of corticosterone are partially normalized by acute increases in corticosterone

Adrenalectomized rats replaced with constant, physiological levels of corticosterone via a subcutaneous pellet (Pellet) have normal basal morning ACTH but exhibit enhanced and prolonged ACTH responses to stress vs. sham-operated (Sham) rats. It has not been determined if the lack of either stress-induced or circadian increases in corticosterone, both of which are missing in Pellet rats, may account for this enhanced response. To test the extent to which stress-associated increases in corticosterone alone can normalize stress-induced hypersecretion of ACTH, we approximated endogenous secretion by injecting additional corticosterone in Pellet rats via an indwelling subcutaneous cannula, 5 min before hypoxia stress (10% O2). A corticosterone dose of 666 micrograms/kg (Pellet+B), but not 333 micrograms/kg (Pellet+Low B), produced plasma corticosterone levels comparable to those in Shams and normalized stress-induced but not post-stress plasma ACTH. Administration of the type II corticosteroid receptor antagonist RU 38486 30 min before corticosterone reversed this inhibition. We conclude that enhanced ACTH responses to stress in Pellet rats result in large part from lack of type II receptor-mediated feedback inhibition by corticosterone increases during stress, although prior circadian increases in corticosterone may also be required.     

A regulatory loop between the hypothalamo-pituitary-adrenal (HPA) axis and circulating leptin: a physiological role of ACTH

The product of the ob/ob gene, leptin, is known to be able to exert a modulator, role on HPA axis function. The aim of the present study was to determine whether endogenous ACTH and glucocorticoids exert any regulatory effect on leptin secretion. For this purpose bilaterally adrenalectomized (ADX) or sham operated (Sham) adult male rats were implanted with an indwelling i.v. catheter. A subgroup of ADX animals received, at the same time of surgery, a s.c. corticosterone (B) pellet (75 mg) (ADX+B). All animals were subjected to experimental designs 7 days after surgery. Our results indicate, as expected, that 7-day ADX animals have several fold increased basal ACTH plasma levels and non detectable circulating B, whereas ADX+B rats showed basal plasma ACTH levels in the range of Sham values and plasma B concentrations of about 5 microg/dl. Interestingly, basal plasma leptin levels were significantly (P < 0.05) decreased by 7 days post ADX, and B replacement therapy (ADX+B) restored circulating leptin to Sham levels. Acute dexamethasone (Dxmn, 30 microg/kg body weight, i.v.) treatment induced a very rapid decrease in plasma ACTH concentrations in both Sham and ADX rats, as well as a decrease in plasma B levels in Sham rats. Interestingly, Dxm test had no effect on plasma leptin levels in Sham animals; however, in ADX rats, the synthetic glucocorticoid increased plasma leptin concentrations, restoring the levels observed in Sham rats. This effect occurred at the same time when plasma ACTH levels were decreasing toward basal Sham values. These results clearly indicate that, beside the known effects of leptin on HPA axis function, circulating ACTH and glucocorticoid are able to modulate leptin secretion in plasma. The lack of circulating glucocorticoid and/or increased plasma ACTH concentrations, are responsible for decreasing leptin output, whereas decreased plasma ACTH concentrations allow an increase of leptin secretion in blood. Our data strongly support the existence of a closed, bi-directional, circuit between HPA axis function and adipose tissue metabolism. They further indicate the physiological relevance of different types of stress associated with many phenotypes of obesity.     

An initial, three-day-long treatment with alcohol induces a long-lasting phenomenon of selective tolerance in the activity of the rat hypothalamic-pituitary-adrenal axis

We determined whether an initial alcohol challenge induced long-lasting changes in the activity of the hypothalamic-pituitary-adrenal (HPA) axis. Adult male rats received intragastric injections of the vehicle or a moderately intoxicating dose of alcohol (3.0 gm/kg) daily for 3 d. When animals were acutely challenged with alcohol 3-12 d later, their ACTH and corticosterone responses were significantly blunted, compared with that of vehicle-pretreated rats. In contrast, exposure to mild electric foot shocks induced a pattern of ACTH secretion that was comparable in animals administered alcohol or the vehicle previously, indicating a lack of cross-tolerance. No significant differences were observed in pituitary responsiveness to corticotropin-releasing factor or vasopressin in rats pretreated with the vehicle or alcohol. The influence of the initial drug treatment was not mimicked by exposure to foot shocks, nor was it prevented by administering a potent corticotropin-releasing factor antagonist to block the elevations in plasma ACTH and corticosterone induced by this initial treatment. Finally, we found that rats injected initially with the vehicle and challenged subsequently with alcohol exhibited the expected increased neuronal activation (measured by the upregulation of steady-state mRNA and protein levels of immediate early genes) in the paraventricular nucleus of their hypothalamus. In contrast, this response was markedly decreased in animals exposed previously to the drug. To our knowledge, this is the first report that exposure to a stress (i.e., alcohol), although not immediately altering the response of the HPA axis to this particular signal, induces a selective tolerance that is both slow to develop and long-lasting. The primary mechanism mediating the ability of an initial drug treatment to decrease subsequent responses of the HPA axis to a second drug challenge seems to be the inability of hypothalamic neurons to respond adequately to this second challenge.     

Tumour necrosis factor-alpha and interleukin-2 differentially affect hippocampal serotonergic neurotransmission, behavioural activity, body temperature and hypothalamic-pituitary-adrenocortical axis activity in the rat

Intraperitoneal endotoxin injection and central administration of interleukin (IL)-1beta profoundly activate hippocampal serotonergic neurotransmission. This study was designed to investigate, using in vivo microdialysis, the effects of another endotoxin-induced proinflammatory cytokine, tumour necrosis factor-alpha, and the effects of the non-inflammatory cytokine, IL-2, on hippocampal extracellular levels of serotonin. To compare the effects of these cytokines on neurotransmission with the effects on physiological parameters and behaviour, hypothalamic-pituitary-adrenocortical (HPA) axis activity, body temperature and behavioural activity were monitored as well. Time-dependent changes in serotonergic neurotransmission and HPA axis activity were determined by measuring serotonin, its metabolite 5-hydroxyindoleacetic acid and free corticosterone in dialysates. Total behavioural activity was scored by assessing the time during which rats were active. Core body temperature was measured by biotelemetry. Intracerebroventricular injection of 50 or 100 ng recombinant murine tumour necrosis factor-alpha exerted no effect on hippocampal serotonergic neurotransmission, and induced no signs of sickness behaviour. However, these doses produced a dose-dependent increase in body temperature and free corticosterone levels. In contrast, intracerebroventricular administration of 500 ng, but not of 50 ng, recombinant human IL-2 produced a marked increase in hippocampal extracellular concentrations of serotonin and 5-hydroxyindoleacetic acid, accompanied by a pronounced behavioural inhibition and other signs of sickness. Moreover, both doses of IL-2 caused a dose-dependent increase in body temperature and free corticosterone levels. Interestingly, intracerebroventricular pretreatment with the IL-1 receptor antagonist showed that the effects of IL-2 on hippocampal serotonin were completely dependent on endogenous brain IL-1. However, IL-1 seemed to play only a minor role in the IL-2-induced increase in free corticosterone. Taken together, the results show that cytokines produce partially overlapping brain-mediated responses, but are selectively effective in stimulating hippocampal serotonergic neurotransmission and inducing sickness behaviour. Moreover, we postulate that activation of hippocampal serotonin release is instrumental in the full development of behavioural inhibition.     

Effect of corticotropin releasing hormone on the pituitary-adrenocortical activity under basal and social stress conditions

The effect of social crowding stress on the CRH-induced hypothalamic-pituitary-adrenocortical (HPA) responsiveness was assessed in rats crowded for 3 days, when the HPA response to neurotransmitter receptors stimulation was powerfully reduced. CRH given systemically dose-dependently increased the secretion of corticosterone. The increase was not affected by pretreatment with prazosin or propranolol, an alpha 1- or beta-adrenergic receptor antagonist, indicating the lack of involvement of adrenergic receptors in that stimulation. In the corticosterone response to CRH administered icv, a moderate involvement of hypothalamic alpha 1-adrenergic receptors and neuronal noradrenaline seems possible. The corticosterone responses to CRH given by either route to rats exposed to social crowding stress were identical with the responses of unstressed controls. Our results for the first have time shown that social crowding stress does not impair the HPA responsiveness to CRH stimulation.     

Divergent prolactin and pituitary-adrenal activity in rats selectively bred for different dopamine responsiveness

The present study explores the significance of brain dopamine phenotype for individual variation in the neuroendocrine stress response of the rat. For this purpose, we used two Wistar rat lines previously selected for high or low responsiveness of the dopamine system to apomorphine using the gnawing response as the selection criterion. Systemic administration of the drug evoked in apomorphine-susceptible (apo-sus) rats a vigorous gnawing response, whereas apomorphine-unsusceptible (apo-unsus) rats did not gnaw under these conditions. These two rat lines represent individuals displaying extreme differences in gnawing behavior that otherwise coexist in a normal Wistar population. In this study basal and stress-induced hypothalamic-pituitary-adrenal activity and PRL release were measured in chronically cannulated, freely moving rats that endured a conditioned emotional response. Tyrosine hydroxylase messenger RNA (mRNA), corticosteroid receptor mRNA, and in vivo retention of [3H]corticosterone were measured in rat brain sections using in situ hybridization and in vivo autoradiography. The result show that 1) apo-sus rats had a markedly reduced PRL response to stress compared to apo-unsus animals, whereas basal levels were not significantly different. A12 dopaminergic neurons in the arcuate nucleus expressed significantly higher levels of tyrosine hydroxylase mRNA in apo-sus rats, suggesting that the reduced stress-induced PRL release could be due to an increased inhibitory control by dopaminergic neurons; 2) in apo-sus rats, stress resulted in a sustained elevation of ACTH and free corticosterone levels, whereas the total corticosterone levels were not different between the two rat lines; 3) under basal morning conditions, apo-sus rats had significantly higher plasma ACTH, but, in contrast, lower free corticosterone than apo-unsus rats; total plasma corticosterone levels were not different; 4) the basal evening ACTH level was elevated in apo-sus rats; after removal of the adrenals in the morning, this increased ACTH level in apo-sus rats persisted into the afternoon 6 h postadrenalectomy; and 5) hippocampal mineralocorticoid (MR), but not glucocorticoid (GR), receptor capacity for the ligand comparable between the groups; the MR of apo-sus rats displayed an increased retention of [3H]corticosterone in all hippocampal cell fields measured 24 h adrenalectomy; MR and GR mRNA in hippocampus as well as GR mRNA in the paraventricular nucleus were not significantly different in the two rat lines. In conclusion, the data suggest a common genetic background for individual variation in stress responsiveness and dopamine phenotype. High dopamine reactivity is linked to a reduced PRL and an increased ACTH response after stress. These high dopamine responders display a hyporesponsive adrenal cortex and corticosteroid feedback resistance associated with altered brain corticosteroid receptor properties.     

Endocrine profile and neuroendocrine challenge tests in transgenic mice expressing antisense RNA against the glucocorticoid receptor

A transgene expressing antisense RNA complementary to a fragment of the glucocorticoid receptor cDNA was incorporated into the mouse genome and resulted in a transgenic animal that has decreased glucocorticoid receptor function. The transgenic mice showed basal plasma ACTH and corticosterone levels similar to those of the normal control animals. We have further investigated changes in HPA axis regulation by use of different neuroendocrine challenge tests including a dexamethasone suppression test (DST). In comparison to normal mice, a tenfold higher dose of dexamethasone (i.e. 20 micrograms/100 g body weight) was required to suppress the basal corticosterone levels of transgenic mice. Dexamethasone (2 micrograms/100 g body weight) produced a long-lasting suppression of plasma ACTH and corticosterone levels in control mice, whereas in transgenic animals only a short-lasting decrease in ACTH levels was apparent. Corticotropin-releasing hormone (CRH) administration resulted in an enhanced response in plasma ACTH levels in transgenic mice, whereas the corticosterone response was markedly reduced. The discrepancy between ACTH and corresponding corticosterone secretions in transgenic mice could be attributed, in part, to a reduced sensitivity of the adrenal gland to stimulation by ACTH. Pituitaries of transgenic mice contained about 50% less proopiomelanocortin (POMC) mRNA than those of control animals. No significant differences were noted in the ACTH or protein contents of normal and transgenic mice pituitary glands although a slight increase in protein content of the transgenic mouse adrenal gland was apparent. In conclusion, transgenic mice with impaired GR function show major disturbances in HPA axis regulation which seem to be caused by the primary defect in conjunction with secondary modifications in, amongst others, pituitary CRH receptor system(s), sympathetic output and adrenal development. This mouse is therefore a useful model to study the consequences of life-long defective GR function and HPA axis regulation in general.     

Corticotropin releasing factor receptor 1-deficient mice display decreased anxiety, impaired stress response, and aberrant neuroendocrine development

Corticotropin releasing factor (CRF) is a major integrator of adaptive responses to stress. Two biochemically and pharmacologically distinct CRF receptor subtypes (CRFR1 and CRFR2) have been described. We have generated mice null for the CRFR1 gene to elucidate the specific developmental and physiological roles of CRF receptor mediated pathways. Behavioral analyses revealed that mice lacking CRFR1 displayed markedly reduced anxiety. Mutant mice also failed to exhibit the characteristic hormonal response to stress due to a disruption of the hypothalamic-pituitary-adrenal (HPA) axis. Homozygous mutant mice derived from crossing heterozygotes displayed low plasma corticosterone concentrations resulting from a marked agenesis of the zona fasciculata region of the adrenal gland. The offspring from homozygote crosses died within 48 hr after birth due to a pronounced lung dysplasia. The adrenal agenesis in mutant animals was attributed to insufficient adrenocorticotropic hormone (ACTH) production during the neonatal period and was rescued by ACTH replacement. These results suggest that CRFR1 plays an important role both in the development of a functional HPA axis and in mediating behavioral changes associated with anxiety.     

Altered ACTH and corticosterone responses to interleukin-1 beta in male rats exposed to an alcohol diet: possible role of vasopressin and testosterone

We have previously shown that female rats exposed to an alcohol (ethanol, E) diet exhibited a blunted ACTH response to systemically administered interleukin-1 beta (IL-1 beta). Because of the presence of gender differences in the activity of the hypothalamic-pituitary-adrenal (HPA) axis, and of the possible role played by sex steroids in modulating the inhibitory influence of E in females, we studied the ability of a 10-day E diet to alter ACTH and corticosterone secretion of intact or castrated male rats injected with IL-1 beta or endotoxin, a releaser of endogenous cytokines. Pituitary responsiveness to secretagogues that mediate the endocrine effects of IL-1 beta, namely corticotropin-releasing factor (CRF) and vasopressin (VP), was also investigated. The ACTH responses of animals fed ad libitum (C group) or pair-fed (PF group) to the intravenous administration of IL-1 beta or endotoxin were not statistically different (p > 0.05); therefore, results from these two groups were combined in the initial experiments. Subsequent experiments only used E and C animals. When compared with this latter group, intact E males showed a significant (p < 0.01) decrease in ACTH levels measured 30 and 60 min after the intravenous injection of IL-1 beta or endotoxin. In contrast, E rats released as much corticosterone as C rats in response to IL-1 beta, but significantly (p < 0.05) more following administration of endotoxin (lipopolysaccharide). The stimulatory effect of VP on ACTH release was also measurably blunted by alcohol, whereas that of CRF was not. In none of these experiments were any significant differences observed between C and PF rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Glucocorticoids and aging

In this review we analyze the morphologic changes, hypothalamic-pituitary-adrenal (HPA) axis functions, glucocorticoid (GC) receptors, and steroidogenic enzyme activities in both animals and humans during aging. In rodent studies, older animals tend to show: 1) hypertrophy of adrenal zona fasciculata (ZF) cells; 2) neuronal loss in the hypothalamic area; 3) loss of GC receptors in the hippocampus; 4) raised circulating adrenocorticotropic hormone (ACTH) and GC levels, and increased release of corticotropin-releasing hormone from the hypothalamus; 5) reduced suppression of endogenous GC secretion after administration of dexamethasone; 6) decreased attenuation of response to chronic stress; and 7) increased activity of P450scc and 21-hydroxylase. According to the GC cascade hypothesis, stress and GCs facilitate the aging process in rats. Stress induces downregulation of GC receptors in the hippocampus, then impairs GC feedback on stress-induced HPA axis activation. Finally, an increase in the basal level of corticosterone and extended GC secretion following stress occurs. Because activation of the hippocampus decreases HPA axis function, the unrestrained elevation of GC concentration and the reduction in the level of GC receptors in the hippocampus may gradually weaken the feedback mechanisms and halt the response to stress. In humans, there are conflicting reports of HPA axis function during aging, so it is difficult to make a final conclusion regarding the relationship between aging and HPA axis function.     

Incidence of pup killing and parental behavior in virgin female and male rats (Rattus norvegicus): Differences between Wistar and Sprague-Dawley stocks.

Investigated the responses toward young shown by males and nulliparous females in 2 outbred stocks of laboratory rats (214 Sprague-Dawley and 166 Wistar rats) in 3 experiments. Sprague-Dawley females showed maternal behavior either spontaneously (35% of the naive Ss) or through concaveation (92% of the initially neutral virgins). Of the Wistar females, however, only 10% showed maternal behavior spontaneously, and only 29% of the neutral virgins came to behave maternally during 15 days of concaveation. Prepubertal cohabitation with lactating Ss did not facilitate maternal responsiveness in adulthood in the Wistar virgin females. Of the Sprague-Dawley males, 50% showed paternal behavior spontaneously, and only 4% killed the young. Among the Wistar males, however, only 4% showed paternal behavior spontaneously, and 76% killed pups. It is suggested that such profound differences between outbred stocks of Ss may be a source of discrepancies between the results of studies dealing with the induction of parental behavior in nonlactating rats. (25 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Prenatal alcohol exposure results in hyperactivity of the hypothalamic-pituitary-adrenal axis of the offspring: modulation by fostering at birth and postnatal handling

Exposure of fetal rats to alcohol results in permanent hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis. In contrast, postnatal handling or fostering have been reported to restrain HPA activity. Because of the deleterious consequences of a hyperresponsive HPA axis, we thought that the possibility that postnatal manipulations might be able to reverse the influence of prenatal alcohol treatment deserved investigation. To test this hypothesis, we exposed rat dams to alcohol by inhalation during the second week of gestation. At birth, pups were either fostered or remained with their dam. For the first 3 weeks, litters were handled daily for 15 min or left undisturbed. At 22 days of age, male and female pups were decapitated under basal conditions, after 10 min of mild electro-footshock, or 10 min after footshock had been terminated. As expected, prenatal exposure to alcohol induced increased adrenocorticotropin (ACTH) secretion in response to footshock, and postnatal handling of control pups resulted in a suppression of corticosterone and ACTH release, although changes in this latter hormone did not reach statistical significance. Surprisingly, however, pups exposed to alcohol that were also fostered and handled after birth, showed an ACTH response to footshock stress that was significantly larger than all other groups. This unexpected response may be due to alterations in maternal-pup behaviors and may indicate that these manipulations act on different neuronal substrates within the central HPA of young rats. Further studies are needed to determine whether adrenal regulation is also altered in animals exposed to alcohol prenatally and reared in a similar manner.     

The role of interleukin-6 in the activation of the hypothalamo-pituitary-adrenocortical axis and brain indoleamines by endotoxin and interleukin-1 beta

Interleukin-6 (IL-6) is one of several cytokines that can stimulate the hypothalamo-pituitary-adrenocortical (HPA) axis. Because IL-6 is produced in response to the administration of endotoxin (LPS) and interleukin-1 (IL-1), it is possible that IL-6 contributes to the neuroendocrine and neurochemical changes induced by them. In this study, intraperitoneal (i.p.) injection of LPS elevated plasma concentrations of IL-6 while activating the HPA axis in a dose-dependent manner. Both responses reached a peak at around 2-3 h. Mouse IL-1beta administration (100 ng, i.p.) induced large increases in plasma corticosterone and a substantial, but short-lived increase in plasma IL-6 with a peak at 2 h. Pretreatment of mice intraperitoneally with a monoclonal antibody to mouse IL-6 significantly attenuated the plasma ACTH and corticosterone responses to LPS at 3 h, but not at 1 h. Anti-IL-6 treatment also attenuated the LPS-induced increases of tryptophan and the serotonin catabolite, 5-hydroxyindoleacetic acid (5-HIAA), but not that of the norepinephrine catabolite, 3-methoxy,4-hydroxyphenylethyleneglycol (MHPG). Pretreatment of mice with anti-IL-6 significantly attenuated the IL-1-induced increases of plasma ACTH and corticosterone at 2 h, but not at 4 h. The IL-1-induced increases of MHPG, tryptophan and 5-HIAA in hypothalamus and brain stem were not significantly altered. These results suggest that IL-6 contributes to the later phases of the LPS- and IL-1-induced stimulations of the HPA axis and to the indoleaminergic responses to LPS, but not to IL-1.     

Facilitation of feedback inhibition through blockade of glucocorticoid receptors in the hippocampus

In the present study the effects of intracerebroventricular (i.c.v.) and intrahippocampal administration of corticosteroid antagonists on basal hypothalamic-pituitary-adrenal (HPA) activity around the diurnal peak were compared in male Wistar rats. In two separate experiments the glucocorticoid receptor (GR) antagonist RU 38486 and the mineralocorticoid receptor (MR) antagonist RU 28318 were tested. One hour after GR antagonist injection, significant increases in plasma ACTH and corticosterone levels were observed in the i.c.v. treated rats, when compared to vehicle. In contrast, a significant decrease in ACTH levels, and a slight, but non-significant decrease in corticosterone concentrations were attained one hour after intrahippocampal injection of the GR antagonist. Injection of the MR antagonist, on the other hand, resulted in enhanced ACTH and corticosterone levels irrespective of the site of injection. These findings suggest that negative feedback inhibition at the circadian peak involves hippocampal MRs and extrahippocampal (hypothalamic) GRs. The latter feedback inhibition overrides a positive feedback influence exerted by endogenous corticosteroids through hippocampal GRs.