Orexins in the regulation of the hypothalamic-pituitary-adrenal axis

Orexin-A and orexin-B are hypothalamic peptides that act via two G protein-coupled receptors, named orexin type 1 and type 2 receptors (OX1-Rs and OX2-Rs). The most studied biological functions of orexins are the central control of feeding and sleep, but in the past few years findings that orexin system modulates the hypothalamic-pituitary-adrenal (HPA) axis, acting on both its central and peripheral branches, have accumulated. Orexins and their receptors are expressed in the hypothalamic paraventricular nucleus and median eminence and orexin receptors in pituitary corticotropes, adrenal cortex, and medulla. Whereas the effects of orexins on adrenal aldosterone secretion are doubtful, compelling evidence indicates that these peptides enhance glucocorticoid production in rats and humans. This effect involves a 2-fold mechanism: 1) stimulation of the adrenocorticotropin-releasing hormone-mediated pituitary release of adrenocorticotropin, which in turn raises adrenal glucocorticoid secretion; and 2) direct stimulation of adrenocortical cells via OX1-Rs coupled to the adenylate cyclase-dependent cascade. The effects of orexins on catecholamine release from adrenal medulla are unclear and probably of minor relevance, but there are indications that orexins can stimulate in vitro secretion of human pheochromocytoma cells via OX2-Rs coupled to the phospholipase C-dependent cascade. Evidence is also available that orexins enhance the growth in vitro of adrenocortical cells, mainly acting via OX2-Rs. Moreover, findings suggest that the orexin system may favor HPA axis responses to stresses and play a role in the pathophysiology of cortisol-secreting adrenal adenomas.     

Disregulation of hypothalamic-pituitary-adrenal axis in the mentally retarded

Previous reports of cognitive and social improvement in the mentally retarded after administration of MSH/ACTH fragments suggested disregulation of the hypothalamic-pituitary-adrenal (HPA) axis. The current study examined the integrity of this system with the Dexamethasone Suppression Test (DST). The DST is a biological index of HPA integrity and recently has been used as a diagnostic aid for endogenous depression. Thirty-five mentally retarded patients were administered 1 mg of dexamethasone just after a sample of blood was taken. Blood samples were analyzed for cortisol by RIA at 11:00 p.m. (basal), 8:00 a.m., 4:00 p.m., and 10:00 p.m. Between 40% and 48% (depending on sampling) of the patients failed to suppress cortisol (greater than 4 micrograms/dl), after the DST challenge. The results suggested that a significant proportion of mentally retarded patients have a DST index reflecting a disordered HPA axis and complements earlier studies of cognitive enhancement observed after treatment with MSH/ACTH fragments. The possibility that the stress of hospitalization was related to a disordered HPA was suggested. The possible co-existence of depression in the mentally retarded invites further study.     

Effects of different treatments for hyperthyroidism on the hypothalamic-pituitary-adrenal axis

To investigate the effects of iopanoic acid (IA) and carbimazole on increased activity of the hypothalamic-pituitary-adrenal (HPA) axis in hyperthyroidism, we studied 14 women with hyperthyroidism caused by Graves' disease (n + 11) or toxic multinodular goitre (n + 3) before and after carbimazole or IA treatment. Seven normal women comprised the control group. Changes in thyroid-stimulating hormone, total and free thyroid hormones, arginine vasopressin (AVP), urinary free cortisol, adrenocorticotrophin (ACTH) and cortisol in response to human corticotrophin-releasing hormone (hCRH; 100 microg, i.v.) were estimated under basal conditions and after treatment with IA (3 g/day; n + 7) for 7 days or carbimazole (30 mg/day; n + 7) for 1 month. A higher ACTH response, with normal cortisol secretion, was observed in hyperthyroid patients in response to hCRH compared with the control group. After 7 days treatment, IA induced a significant reduction in total tri-iodothyronine (T(3)) and free T(3) to normal levels and a stronger ACTH response to hCRH, whereas plasma and urinary cortisol levels remained unchanged. Patients treated with carbimazole showed normalization of thyroid hormone levels, a reduction in basal and stimulated ACTH secretion and higher urinary free cortisol levels compared with pretreatment levels. Neither IA nor carbimazole treatment had any effect on AVP levels in hyperthyroid patients. In conclusion, hyperthyroid patients showed HPA axis hyperactivity of central origin with reduced cortisol responses, which were reversed by carbimazole treatment. The differential effects of IA and carbimazole on HPA function indicate that thyroid hormones have a role in modulation of the HPA axis.     

Alcohol-seeking behavior: the roles of the hypothalamic-pituitary-adrenal axis and the endogenous opioid system

Both the hormones of the hypothalamic-pituitary-adrenal (HPA) axis and the endogenous opioid system are activated in response to stress as well as after alcohol consumption, supporting the hypothesis that stress can influence both alcohol consumption and craving for alcohoL Activation of the HPA axis by stress or alcohol results in the production of glucocorticoid hormones, such as cortisol. Those hormones, in turn, are important for the release of the brain chemical dopamine in certain brain areas that are associated with the rewarding and reinforcing effects of alcohol and other drugs. Alcohol-induced release of certain endogenous opioids similarly results in dopamine release in those brain regions. Through this mechanism, both the HPA axis and the endogenous opioid system may influence alcohol consumption. Consequently, genetically determined differences in the activities of the HPA axis and endogenous opioid system may help determine a person's alcohol consumption level and vulnerability to alcoholism.     

The effects of antidepressants on the hypothalamic-pituitary-adrenal axis

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis has been found in some psychiatric disorders, especially in older patients with severe depression. Altered feedback inhibition, as demonstrated by increased circulating cortisol and nonsuppresssion of cortisol following administration of dexamethasone, may be to blame. Two glucocorticoid receptors control the HPA axis, the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). MR regulates normal HPA fluctuations and the GR regulates in times of stress. Long-term antidepressant treatment in humans has been shown to upregulate both GR and MR in the brain, whereas short-term treatment has been shown to downregulate GR and MR. After 6-9 weeks of treatment GR function returns to normal, and the MR stays upregulated. Chronic antidepressant treatment in rodents has been shown to reduce HPA activity, even in the absence of GR or MR upregulation. These effects of antidepressants on HPA regulation may be attributed in part to regulation of the multidrug resistance protein transporter, P-glycoprotein. Finding relationships between antidepressant action and HPA regulation leads to the conclusion that the disruption of the HPA may be more a contributing factor to depression than other biological abnormalities.     

Hyperactivity in the hypothalamic-pituitary-adrenal axis in demented patients with delirium

Occurrence of delirium is known to be related to, among other things, organic brain disorder, somatic disease and old age. It has been hypothesized that delirium is also associated with stress. Disturbances of the hypothalamic-pituitary-adrenal (HPA) system have been found in delirious patients in various studies. The aim of the present study was to determine the activity in the HPA axis in demented patients to ascertain whether the stress regulating system was more disturbed in patients with delirium than in those without delirium. Demented inpatients with no acute medical illness were included in the study. Basal cortisol levels in serum were measured and dexamethasone suppression test (DST) was performed. The most important finding of the study was a strong relationship between delirium and DST pathology irrespective of age and severity of dementia. It is suggested that certain demented individuals have an impaired HPA system and a low delirium threshold and respond to stress with delirium.     

Stress-related over-enhancement of the hypothalamic-pituitary-adrenal axis causes experimental neurolathyrism in rats

Neurolathyrism is a motor neuron disease that is caused by the overconsumption of grass peas (Lathyrus sativus L.) under stressful conditions. The neuro-excitatory β-N-oxalyl-L-α,β-diaminopropionic acid present in grass peas was proposed the causative agent of spastic paraparesis of the legs. Historical reports of neurolathyrism epidemics, studies of neurolathyrism animal models, and in vitro studies on the mechanism of β-N-oxalyl-L-α,β-diaminopropionic acid toxicity support the hypothesis that stress increases susceptibility to neurolathyrism. To elucidate the role of stress in neurolathyrism-induced motor dysfunction, we focused on the hypothalamic-pituitary-adrenal axis in a rodent model of neurolathyrism. Our results implicated increased glucocorticoid and neuroinflammation in the motor dysfunction (paraparesis) exhibited by the stress loaded rat models of neurolathyrism.     

The effect of inhaled corticosteroids on hypothalamic-pituitary-adrenal axis

Objectives:

The aim of this study was to compare systemic effects of high-dose fluticasone propionate (FP) and beclomethasone dipropionate (BDP) via pressurized metered dose inhaler on adrenal and pulmonary function tests.

Materials and Methods:

A total of 66 patients with newly diagnosed moderate persistent asthma without previous use of asthma medications participated in this single blind, randomized, parallel design study. FP or BDP increased to 1 500 μg/d in 62 patients who had not received oral or IV corticosteroids in the previous six months. Possible effects of BDP and FP on adrenal function were evaluated by free cortisol level at baseline and after Synacthen test (250 μg). Fasting plasma glucose and pulmonary function tests were also assessed. Similar tests were repeated 3 weeks after increasing dose of inhaled corticosteroids to 1 500 μg/d.

Results:

No statistically significant suppression was found in geometric means of cortisol level post treatment in both groups. After treatment in FP group, mean forced expiratory volume in one second (FEV1) and mean forced vital capacity (FVC) values improved by 0.17 l (5.66% ± 13.91, P=0.031) and 0.18 l (5.09% ± 10.29, P=0.010), respectively. Although FEV1 and FVC improved in BDP group but was not statistically significant. Oral candidiasis and hoarseness were observed in 6.5% patients receiving BDP, but hoarseness was found in 3.2% patients in FP group (P=0.288).

Conclusions:

The results indicate that safety profiles of high doses of BDP and FP with respect to adrenal function are similar, but FP is more efficacious than that of BDP in improving pulmonary function test.KEY WORDS: Adrenal cortex function tests, adrenal insufficiency, asthma, beclomethasone dipropionate, fluticasone     

Influence of psychological variables on the activity of the hypothalamic-pituitary-adrenal axis

Psychobiology is the discipline that attempts to integrate the impact of environmental and psychological variables on biological systems. This paper focuses on the psychobiology of the hypothalamic-pituitary-adrenal (HPA) axis and illustrates several processes that influence the response of the HPA axis. The interaction of the developing rodent or primate with their primary care giver has permanent long-term effects on the HPA axis. Manipulations that alter maternal behavior during critical periods of development permanently modify the HPA axis. The HPA axis can be programmed to be hypo-responsive or hyper-responsive as a function of time and length of maternal separation. In the adult organism, the HPA response to stress is highly dependent on specific psychological factors such as control, predictability, and feedback. In primates, social variables have been shown to diminish or exacerbate the HPA stress response. During the post-natal period of development, the mother appears to actively inhibit the pups' HPA axis. Different aspects of maternal behavior regulate different components of the HPA system.     

Effect of Ginkgo biloba extract EGb 761 on the nonspecific and humoral immune responses in a hypothalamic-pituitary-adrenal axis activation model

We evaluated the immune response of healthy control and stressed Wistar rats submitted to hypothalamic-pituitary-adrenal (HPA) axis activation. Rats were treated with Ginkgo biloba extract (EGb 761) orally (100 mg/kg per day for 7 days). EGb 761 stimulated the digestion index of peritoneal and alveolar macrophages (PM and AM) of stressed rats. Likewise, the cellular immune response measured using the delayed-type hypersensitivity response to sheep red blood cells (SRBC) and the humoral immune response (measured through an anti-SRBC response), were also restored in stressed rats. Thus, this G. biloba extract possesses immunostimulatory activity in addition to its broad spectrum of pharmacological effects.     

The hypothalamic-pituitary-adrenal axis and low-dose glucocorticoids in the treatment of septic shock

Severe sepsis is the leading cause of death among patients in intensive care units. Recombinant activated protein C is the only substance known to directly improve morbidity and mortality. Adrenal insufficiency occurs frequently in patients with sepsis and is associated with poor outcome. Although high-dose glucocorticoids have not positively affected clinical outcome, small trials in which low-dose glucocorticoids were administered to patients with septic shock and relative adrenal insufficiency have shown decreased mortality. The main effect of glucocorticoids in low-doses apparently is exerted through correction of suppression of the hypothalamic-pituitary-adrenal axis. However, the therapeutic benefits of glucocorticoids may be related to their antiinflammatory properties and endogenous catecholamine-enhancing effects.     

Role of the hypothalamic-pituitary-adrenal axis in reinstatement of cocaine-seeking behavior in squirrel monkeys

RATIONALE: Stress has been suggested to play a role in relapse to cocaine-seeking behavior. An important physiological system activated by stress is the hypothalamic-pituitary-adrenal (HPA) axis; however, evidence for a role of HPA axis activation in cocaine relapse has been contradictory. OBJECTIVES: This study examined the effects of pharmacological stimulation of the HPA axis on reinstatement of drug-seeking behavior and salivary cortisol levels in a non-human primate model of cocaine relapse. In addition, the effect of corticotropin releasing hormone type 1 receptor (CRH-R1) blockade on cocaine priming-induced reinstatement was investigated. METHODS: Squirrel monkeys were trained to self-administer cocaine under a second-order schedule in which behavior was maintained by IV drug injections and a drug-paired visual stimulus. A period of extinction was then imposed during which saline was substituted for cocaine and the stimulus was omitted. Subsequently, monkeys were tested for reinstatement of cocaine seeking following priming injections of drugs. During reinstatement tests, the drug-paired stimulus was restored. Salivary cortisol levels were determined to measure the effects of drug treatments on the HPA axis activity. RESULTS: Priming with corticotropin releasing hormone (10 and 50 microg/kg), adrenocorticotropic hormone (1 microg/kg), or cortisol (1-10 mg/kg) did not induce significant reinstatement of cocaine seeking. All of these treatments, however, resulted in a significant increase in salivary cortisol. In contrast, priming injections of cocaine (0.1-1.0 mg/kg) dose-dependently induced reinstatement of drug seeking, but did not increase salivary cortisol. The CRH-R1 antagonist CP-154,526 (10 mg/kg, IV) did not modulate cocaine priming-induced reinstatement of drug seeking, but attenuated CRH-induced increases in salivary cortisol. CONCLUSIONS: The results suggest that activation of the HPA axis is neither necessary nor sufficient for reinstatement of cocaine-seeking behavior in this non-human primate model of cocaine relapse.     

Plasma pregnenolone levels in cynomolgus monkeys following pharmacological challenges of the hypothalamic-pituitary-adrenal axis

Pregnenolone (PREG) is an endogenous neuroactive steroid that is increased in rodent brain and plasma after hypothalamic-pituitary-adrenal (HPA) activation by acute stress or ethanol administration. Plasma levels of PREG metabolites are altered by pharmacological challenges of the HPA axis, however little is known about HPA regulation of PREG levels in monkeys. PREG concentrations were determined by radioimmunoassay in plasma samples from cynomolgus monkeys, following challenge with naloxone (125 and 375 microg/kg), corticotropin-releasing factor (CRF; 1 microg/kg), dexamethasone (130 microg/kg), adrenocorticotropic hormone (ACTH; 10 ng/kg; 4-6 h after 0.5 mg/kg dexamethasone) and ethanol (1.0 and 1.5 g/kg). Naloxone increased PREG levels, while CRF appeared to increase metabolism of PREG to deoxycorticosterone (DOC). ACTH, administered after dexamethasone, reduced PREG levels, despite an increase in plasma cortisol. Ethanol did not alter PREG levels. Changes in PREG levels were correlated with changes in DOC levels after naloxone 125 microg/kg, CRF, ethanol 1.5 g/kg, and dexamethasone challenges. Furthermore, dexamethasone-induced changes in PREG levels were correlated with subsequent alcohol intake. These data suggest that PREG responses to dexamethasone challenge may represent a trait marker of alcohol drinking. The lack of effect of ethanol on PREG levels suggests differential regulation in non-human primates vs. rodents.     

Inhibition of the hypothalamic-pituitary-adrenal axis in food-deprived rats by a CCK-A receptor antagonist

The circadian activity of the hypothalamic-pituitary-adrenal (HPA) axis is regulated by caloric flow in rats. During the dark cycle, it has been shown that, in fasted rats, the time-course profile of plasma concentrations of adrenocorticotropin (ACTH) and corticosterone parallels the profile of food intake in ad libitum fed animals. Cholecystokinin (CCK) is involved in regulating food intake in rodents. CCK-8 reduces food intake by acting on CCK-A receptors subtype. This work aims at establishing an eventual relationship between the modulatory role of CCK on food intake and its effect on HPA axis activity during fasting. We studied the effect of CCK-A and CCK-B receptor antagonists on food intake during the first period of the dark cycle. Under these conditions we observed that the CCK-A receptor antagonist, SR-27897 (0.3 mg kg(-1)), but not the CCK-B receptor antagonist, L-365260 (1 mg kg(-1)), increases food-intake. In a second series of experiments we observed that the increase of both ACTH and corticosterone plasma level elicited by fasting, was prevented by SR-27897, but not by L-365260. These results indicate that CCK-A receptor blockade during fasting prevents the activation of the HPA axis.     

柴胡加龙骨牡蛎汤对抑郁动物下丘脑-垂体-肾上腺轴的影响

目的:探讨柴胡加龙骨牡蛎汤对慢性应激大鼠下丘脑垂体肾上腺(HPA)轴的影响。方法:采用不同应激因子交替持续应激21d复制大鼠慢性应激抑郁模型,经口分别给予柴胡加龙骨牡蛎汤浸膏干粉200、500mg·kg-1,观察柴胡加龙骨牡蛎汤对大鼠糖水消耗、开野实验行为学指标变化及血浆促肾上腺皮质激素(ACTH)、皮质酮(CORT)水平的影响。结果:经过21d慢性应激,大鼠出现糖水消耗量减少、开野实验水平得分及垂直得分均明显减少、中央格停留时间显著延长等抑郁状态,同时血浆ACTH、CORT浓度较空白对照组显著升高;经口给予柴胡加龙骨牡蛎汤后可显著改善慢性应激抑郁模型大鼠的行为学和神经内分泌变化。结论:柴胡加龙骨牡蛎汤可抑制慢性应激引起的HPA轴功能亢进,可改善大鼠的抑郁状态,具有较好的抗抑郁作用。     

Involvement of the endocannabinoid system in the ability of long-term tricyclic antidepressant treatment to suppress stress-induced activation of the hypothalamic-pituitary-adrenal axis.

The efficacy of antidepressants has been linked in part to their ability to reduce activity of the hypothalamic-pituitary-adrenal (HPA) axis; however, the mechanism by which antidepressants regulate the HPA axis is largely unknown. Given that recent research has demonstrated that endocannabinoids can regulate the HPA axis and exhibit antidepressant potential, we examined the hypothesis that the endocannabinoid system is regulated by long-term antidepressant treatment. Three-week administration of the tricyclic antidepressant desipramine (10 mg/kg/day) resulted in a significant increase in the density of the cannabinoid CB(1) receptor in the hippocampus and hypothalamus, without significantly altering endocannabinoid content in any brain structure examined. Furthermore, chronic desipramine treatment resulted in a reduction in both secretion of corticosterone and the induction of the immediate early gene c-fos in the medial dorsal parvocellular region of the paraventricular nucleus of the hypothalamus (PVN) following a 5 min exposure to swim stress. Acute treatment with the CB(1) receptor antagonist, AM251 (1 mg/kg), before exposure to swim stress, completely occluded the ability of desipramine to reduce both corticosterone secretion and induction of c-fos expression in the PVN. Collectively, these data demonstrate that CB(1) receptor density in the hippocampus and hypothalamus is increased by chronic tricyclic antidepressant treatment, and suggest that this upregulation could contribute to the ability of tricyclic antidepressants to suppress stress-induced activation of the HPA axis.     

Ingesting alcohol prior to food can alter the activity of the hypothalamic-pituitary-adrenal axis

There is an increasing evidence that long-term alcohol intake can promote damage to most of the body's major organs. However, regular consumption of a small-moderate amount of alcohol is often recommended as being beneficial to health and of concern is that the effect of ingesting commercially available alcohol products on steroid hormone synthesis under variable nutritional conditions has not been thoroughly investigated. Many individuals consume alcohol alone prior to a meal and the aim of the present study was to assess the effect of consuming a small-moderate amount of commercially available alcohol on the level of salivary cortisol and salivary dehydroepiandrosterone sulfate (DHEAS) before and after a meal. A total of 24 males aged 19-22 years participated in the current investigation. The experimental procedure required participants to fast for 6 h before being asked to ingest either 40 g alcohol in the form of red wine (n = 8), low alcohol and high beer (n = 8), white wine (n = 8) or the equivalent amount of placebo over a 135-min period before consuming food for 45-min. The level of blood alcohol, salivary cortisol and salivary DHEAS was assessed upon arrival and then at regular 45-min intervals during the 180-min experimental period. The results showed that the consumption of alcohol and placebo can significantly lower the level of salivary cortisol. However, the effect of consuming a small-moderate amount of commercially available alcohol on the level of salivary DHEAS was dependent on the nutritional content of the beverage with red wine promoting no change, white wine promoting a significant decrease, and beer having a variable effect on salivary DHEAS concentration when compared to placebo. It was concluded that the effect of commercially available alcohol on the HPA axis is not the same for all alcohol products and both the nutritional status of participants and the nutritional content of the alcoholic beverage being administered should be taken into consideration when investigating the effect of alcohol on the HPA axis.     

芍药苷对胶原诱导型关节炎大鼠下丘脑-垂体-肾上腺轴的影响

目的探讨芍药苷治疗胶原诱导型关节炎(CIA)是否与调节下丘脑-垂体-肾上腺(HPA)轴有关。方法 Wistar大鼠右足趾皮内注射牛Ⅱ型胶原(CⅡ)和弗氏完全佐剂制备CIA大鼠模型,7 d后大鼠背部和尾根部皮下注射CⅡ加强免疫1次。初次免疫后第14天ig给予地塞米松2 mg.kg-1或芍药苷25,50和100 mg.kg-1,每天1次,连续28 d。初次免疫后第14,21,28,35和42天观察CIA大鼠的足爪肿胀度和关节炎指数的变化。给药结束后第2天大鼠摘眼球取血,放射免疫法检测血浆促肾上腺皮质激素释放激素(CRH)、促肾上腺皮质激素(ACTH)和皮质酮(CS)含量;制备血清,用ELISA法检测白细胞介素4(IL-4)、干扰素γ(IFN-γ)、IL-1β、肿瘤坏死因子α(TNF-α)和抗CⅡ抗体含量。结果与正常对照组相比,模型对照组大鼠关节红肿,关节炎指数升高(P<0.01),血中CRH、CS、抗CⅡ抗体、IFN-γ、IL-1β和TNF-α水平明显升高(P<0.01),IL-4水平下降(P<0.01),ACTH无明显改变。ig给予芍药苷50和100 mg.kg-1可抑制CIA大鼠关节肿胀,降低关节炎指数(P<0.05),在第42天关节炎指数由模型对照组的6.4±0.7降至5.6±0.5和5.4±0.7(P<0.05);使模型对照组血清IFN-γ由(21.3±2.5)ng.L-1降至16.6±1.3和(16.1±1.9)ng.L-1(P<0.01),IL-1β由(37.3±4.2)ng.L-1降至32.1±2.9和(31.2±4.1)ng.L-1(P<0.01),TNF-α由(53.9±7.9)ng.L-1降至39.4±6.8和(31.3±6.1)ng.L-1(P<0.01),抗CⅡ抗体由(2.13±0.32)ng.L-1降至1.35±0.58和(1.10±0.42)ng.L-1(P<0.01),IL-4由(26.6±3.0)ng.L-1升至41.9±3.1和(49.1±4.2)ng.L-1(P<0.01);能使血浆CRH的水平由模型对照组的(2.3±0.5)μg.L-1升高至4.9±1.0和(5.3±1.1)μg.L-1(P<0.01),CS由(33±10)μg.L-1升高至47±9和(51±13)μg.L-1(P<0.01),ACTH水平亦有明显升高(P<0.01)。结论芍药苷治疗CIA可能与调节PHA轴有关。