Hypothalamo-pituitary-adrenal System Research Articles

Application of Single Prolonged Stress Induces Post-traumatic Stress Disorder-like Characteristics in Mice.

We tried to clarify the applicability of a single prolonged stress (SPS) protocol as post-traumatic stress disorder (PTSD) model in mice. To investigate PTSD pathophysiology, we conducted hypothalamo-pituitary-adrenal (HPA) negative feedback testing at 1, 4, 8 and 12 weeks after the SPS by administrating a dexamethasone (DEX) suppression test. The SPS induced over-suppression of the HPA system by DEX treatment at 8 and 12 weeks. To investigate PTSD-like behavioral characteristics, we subjected mice to testing in a light/dark box (to assess anxiety), a Y-maze (working memory), a cliff avoidance (visual cognition), and an open field (locomotor activity) at 1, 4, 8 and 12 weeks after the SPS. In the light/dark box test, the SPS-applied mice spent significantly less time in the light box at 8 or 12 weeks. In the cliff avoidance test, the SPS-applied mice spent significantly less time in the open area at 1 week. However, in both the Y-maze test and the open field test, SPS-applied mice tended toward slight decreases in a time-dependent manner until 12 weeks. Therefore, SPS-applied mice may thus be useful for assessing characteristics relevant to PTSD that coincide with changes in the HPA axis.

The effects of sex steroid hormones on the activities of basic carboxypeptidases in the hypothalamo–pituitary–adrenal system of male and female mice after stress

The effects of testosterone and progesterone on the activities of carboxypeptidase E and phenylmethylsulfonyl fluoride-inhibited carboxypeptidase (PMSF-CP) after stress induced by an intraperitoneal injection of olive oil were studied in male and female mice. Sex-related differences in the activities of the studied carboxypeptidases were observed in both intact and stress-exposed animals, as well as after the injection of the steroid hormones. In females, stress and hormones mostly decreased the activity of carboxypeptidases, which resulted in the attenuation of differences between females and males. The alterations in the PMSF-CP activity were stronger than in the activity of carboxypeptidase E. The involvement of these enzymes in the mechanism of stress and formation of sex-related differences in the functioning of the hypothalamo–pituitary–adrenal system, as well as the mechanism of the effects of sex-steroid hormones on the activities of these carboxypeptidases, are discussed.

Hypothalamo-pituitary adrenal axis and sympatho-adrenal medullary system responses to psychological stress were not attenuated in women with elevated physical fitness levels.

It is not clear if higher levels of cardiorespiratory fitness are associated with lower hypothalamo-pituitary adrenal (HPA) axis and sympatho-adrenal medullary (SAM) system reactivity to psychological stress in women. The association between cardio-metabolic risk markers and acute physiological responses to psychological stress in women who differ in their cardiorespiratory fitness status has also not been investigated. Women with high (n = 22) and low (n = 22) levels of fitness aged 30-50 years (in the mid-follicular phase of the menstrual cycle) were subjected to a Trier Social Stress Test (TSST) at 1500 h. Plasma concentrations of cortisol, adrenaline (Adr), noradrenaline (NA), and dopamine (DA) were measured in samples collected every 7-15 min from 1400 to 1700 h. Heart rate and blood pressure were measured at the same time points. Low-fit women had elevated serum triglyceride, cholesterol/HDL ratio, fasting glucose, and HOMA-IR levels compared with high-fit women. While cortisol, Adr, NA, HR, and blood pressure all demonstrated a significant response to the TSST, the responses of these variables did not differ significantly between high- and low-fit women in response to the TSST. Dopamine reactivity was significantly higher in the low-fit women compared with high-fit women. There was also a significant negative correlation between VO2 max and DA reactivity. These findings suggest that, for low-fit women aged 30-50 years, the response of HPA axis and SAM system to a potent acute psychological stressor is not compromised compared to that in high-fit women.

Acute inflammation in the joint: Its control by the sympathetic nervous system and by neuroendocrine systems

Inflammation of tissues is under neural control involving neuroendocrine, sympathetic and central nervous systems. Here we used the acute experimental inflammatory model of bradykinin-induced plasma extravasation (BK-induced PE) of the rat knee joint to investigate the neural and neuroendocrine components controlling this inflammation. 1. BK-induced PE is largely dependent on the sympathetic innervation of the synovium, but not on activity in these neurons and not on release of norepinephrine. 2. BK-induced PE is under the control of the hypothalamo-pituitary-adrenal (HPA) system and the sympatho-adrenal (SA) system, activation of both leading to depression of BK-induced PE. The inhibitory effect of the HPA system is mediated by corticosterone and dependent on the sympathetic innervation of the synovium. The inhibitory effect of the SA system is mediated by epinephrine and β2-adrenoceptors. 3. BK-induced PE is inhibited during noxious stimulation of somatic or visceral tissues and is mediated by the neuroendocrine systems. The nociceptive-neuroendocrine reflex circuits are (for the SA system) spinal and spino-bulbo-spinal. 4. The nociceptive-neuroendocrine reflex circuits controlling BK-induced PE are under powerful inhibitory control of vagal afferent neurons innervating the defense line (connected to the gut-associated lymphoid tissue) of the gastrointestinal tract. This inhibitory link between the visceral defense line and the central mechanisms controlling inflammatory mechanisms in body tissues serves to co-ordinate protective defensive mechanisms of the body. 5. The circuits of the nociceptive-neuroendocrine reflexes are under control of the forebrain. In this way, the defensive mechanisms of inflammation in the body are co-ordinated, optimized, terminated as appropriate, and adapted to the behavior of the organism.

Effects of selective serotonin reuptake inhibitor treatment on plasma oxytocin and cortisol in major depressive disorder

BackgroundOxytocin is known for its capacity to facilitate social bonding, reduce anxiety and for its actions on the stress hypothalamopituitary adrenal (HPA) axis. Since oxytocin can physiologically suppress activity of the HPA axis, clinical applications of this neuropeptide have been proposed in conditions where the function of the HPA axis is dysregulated. One such condition is major depressive disorder (MDD). Dysregulation of the HPA system is the most prominent endocrine change seen with MDD, and normalizing the HPA axis is one of the major targets of recent treatments. The potential clinical application of oxytocin in MDD requires improved understanding of its relationship to the symptoms and underlying pathophysiology of MDD. Previous research has investigated potential correlations between oxytocin and symptoms of MDD, including a link between oxytocin and treatment related symptom reduction. The outcomes of studies investigating whether antidepressive treatment (pharmacological and non-pharmacological) influences oxytocin concentrations in MDD, have produced conflicting outcomes. These outcomes suggest the need for an investigation of the influence of a single treatment class on oxytocin concentrations, to determine whether there is a relationship between oxytocin, the HPA axis (e.g., oxytocin and cortisol) and MDD. Our objective was to measure oxytocin and cortisol in patients with MDD before and following treatment with selective serotonin reuptake inhibitors, SSRI.MethodWe sampled blood from arterial plasma. Patients with MDD were studied at the same time twice; pre- and post- 12 weeks treatment, in an unblinded sequential design (clinicaltrials.govNCT00168493).ResultsResults did not reveal differences in oxytocin or cortisol concentrations before relative to following SSRI treatment, and there were no significant relationships between oxytocin and cortisol, or these two physiological variables and psychological symptom scores, before or after treatment.ConclusionsThese outcomes demonstrate that symptoms of MDD were reduced following effective treatment with an SSRI, and further, stress physiology was unlikely to be a key factor in this outcome. Further research is required to discriminate potential differences in underlying stress physiology for individuals with MDD who respond to antidepressant treatment, relative to those who experience treatment resistance.

Antidepressant effects of the extract YZ-50 from Polygala tenuifolia in chronic mild stress treated rats and its possible mechanisms

YZ-50 is an active fraction obtained from the root of Polygala tenuifolia Willd. (Polygalaceae) extract and it has been reported previously to exert beneficial effects on mental health in depressed sufferers, however, its mechanism of action remains unresolved. This study utilized the chronic mild stress (CMS) model of depression in Sprague-Dawley rats to evaluate the effects of YZ-50 on depressive behaviors. Furthermore, we tested the hypothesis that the capacity of YZ-50 to reverse the harmful effects of CMS is relative to the hypothalamo-pituitary-adrenal (HPA) system and brain-derived neurotrophic factor (BDNF) in the hippocampus. Repeated administration of YZ-50 for 28 days at the doses of 140 and 280 mg/kg in CMS, YZ-50 reversed the CMS-induced changes in sucrose consumption, plasma corticosterone levels and open field activity. In addition, CMS significantly decreased hippocampal BDNF mRNA levels. However, YZ-50 counteracted a decrease in hippocampal BDNF mRNA caused by CMS. In conclusion, YZ-50 reversed the harmful effects of CMS on mood and behaviors in rats and it possesses an antidepressant property that is at least in part mediated by the neuroendocrine and neuropropective systems, and it is likely that the HPA system plays an important role in this process.

Hypothalamus-pituitary-adrenal activity during human sleep: a coordinating role for the limbic hippocampal system.

This review focuses on experiments in humans examining the regulation of the hypothalamo-pituitary-adrenal (HPA) system during nocturnal sleep. The HPA system is a most important mediator of the organism's response to stress. The early phase of nocturnal sleep dominated by extended epochs of slow wave sleep (SWS), is the only time of day in which secretory activity of this axis is subject to a pronounced and persistent inhibition resulting in minimum concentrations of ACTH and cortisol. During late sleep predominated by rapid eye movement (REM) sleep. HPA secretory activity reaches a diurnal maximum. Comparison of the response to administration of exogenous secretagogues of ACTH in men during sleep and nocturnal wakefulness indicated that early sleep, and in particular SWS, is associated with an inhibition of pituitary-adrenocortical responsiveness, which is presumably due to hypothalamic secretion of an as yet unknown release inhibiting factor of ACTH. Pituitary-adrenocortical responsiveness during early sleep was disinhibited after canrenoate which is a selective blocker of mineralocorticoid receptors (MR) located primarily in limbic-hippocampal structures. Hippocampal neuronal networks are known to integrate corticosteroid feedback via both, the MR and the classical glucocorticoid receptor (GR). Prevailing MR related activity in this network seems to act as a trigger for the inhibition of the HPA system. During early sleep, the same hippocampal network appears to be concurrently involved in the formation of declarative memory. Activation of GR after administration of dexamethasone completely blocked the formation of declarative memory during early sleep, indicating that the inhibition of HPA secretory activity is a necessary prerequisite for this memory process. Dysfunction of the described neuro-endocrine mode of regulation during early sleep is present in patients with Cushing's disease, in patients with severe depression and in aged humans. All of these groups show insufficient inhibition of HPA secretory activity particular prominent during early sleep, and reduced SWS in concert with impairments of declarative memory function. First clinical trials suggest that this trias of symptoms may benefit from intranasal treatment with neuropeptides like vasopressin and growth hormone releasing hormone.

Stress and its influence on reproduction in pigs: a review

The manifestations of stress, defined as a biological response to an event that the individual perceives as a threat to its homeostasis, are commonly linked to enhanced activity of the hypothalamo-pituitary-adrenal (HPA) axis and the activation of the sympathetic adreno-medullary (SA) system. Activation of the HPA system results in the secretion of peptides from the hypothalamus, principally corticotropin releasing hormone (CRH), which stimulates the release of adrenocorticotropic hormone (ACTH) and beta-endorphin. ACTH induces the secretion of corticosteroids from the adrenal cortex, which can be seen in pigs exposed to acute physical and/or psychological stressors. The present paper is a review of studies on the influence of stressors on reproduction in pigs. The effects of stress on reproduction depend on the critical timing of stress, the genetic predisposition to stress, and the type of stress. The effect of stress on reproduction is also influenced by the duration of the responses induced by various stressors. Prolonged or chronic stress usually results in inhibition of reproduction, while the effects of transient or acute stress in certain cases is stimulatory (e.g. anoestrus), but in most cases is of impairment for reproduction. Most sensitive of the reproductive process are ovulation, expression of sexual behaviour and implantation of the embryo, since they are directly controlled by the neuroendocrine system.

Persistent depressive state after chronic stress in rats is accompanied by HPA axis dysregulation and reduced prefrontal dopaminergic neurotransmission

Exposure to stress is thought to play an important role in the etiology of depression. Dysregulation of the hypothalamo-pituitary-adrenal (HPA) axis characterized by glucocorticoid negative feedback resistance is frequently observed in human depressives. Additionally, dysfunctions of the dopaminergic and serotonergic systems in the prefrontal cortex (PFC) are thought to be involved in the development of a depressive state. In rats, chronic stress induces a behaviorally depressive state, concomitant with dysregulation of the HPA axis and reductions in dopaminergic and serotonergic transmissions in the PFC. Considering that dysregulation of the HPA axis is associated with relapse and persistency of depression, it is possible that the chronic stress-induced depressive state persists during long-term rest after its exposure. In the present study, we examined this possibility in rats and found that the behaviorally depressive state in the rotarod test, negative feedback resistance in the dexamethasone suppression test, and a decrease in the extracellular concentration of dopamine but not serotonin in the PFC persisted for 3 months following a 4-week stress session. These results suggest that dysregulation of the HPA system and reduced dopaminergic transmission in the PFC underlies persistent behavioral depression following chronic stress.

Responses of the Hypothalamopituitary Adrenal Axis and the Sympathoadrenal System to Isolation/Restraint Stress in Sheep of Different Adiposity

There is evidence that levels of adipose tissue can influence responses of the hypothalamopituitary-adrenal (HPA) axis to stress in humans and rats but this has not been explored in sheep. Also, little is known about the sympathoadrenal responses to stress in individuals with relatively different levels of adipose tissue. We tested the hypothesis that the stress-induced activation of the HPA axis and sympathoadrenal system is lower in ovariectomized ewes with low levels of body fat (lean) than ovariectomized ewes with high levels of body fat (fat). Ewes underwent dietary manipulation for 3 months to yield a group of lean ewes (n = 7) with a mean (±SEM) live weight of 39.1 ± 0.9 kg and body fat of 8.9 ± 0.6% and fat ewes (n = 7) with a mean (±SEM) live weight of 69.0 ± 1.8 kg and body fat of 31.7 ± 3.4%. Fat ewes also had higher circulating concentrations of leptin than lean ewes. Blood samples were collected every 15 min over 8 h when no stress was imposed (control day) and on a separate day when 4 h of isolation/restraint was imposed after 4 h of pretreatment sampling (stress day). Plasma concentrations of adrenocorticotropic hormone (ACTH), cortisol, epinephrine and norepinephrine did not change significantly over the control day and did not differ between lean and fat ewes. Stress did not affect plasma leptin levels. All stress hormones increased significantly during isolation/restraint stress. The ACTH, cortisol and epinephrine responses were greater in fat ewes than lean ewes but norepinephrine responses were similar. Our results suggest that relative levels of adipose tissue influence the stress-induced activity of the hypothalamopituitary-adrenal axis and some aspects of the sympathoadrenal system with fat animals having higher responses than lean animals.

The DEX/CRH neuroendocrine test and the prediction of depressive relapse in remitted depressed outpatients

Hypothalamo–pituitary–adrenal (HPA) system dysfunction is the most characteristic biological alteration found in a majority of depressed patients. Accumulating evidence suggests that the combined dexamethasone (DEX)/corticotropin-releasing hormone (CRH) test is highly sensitive to detect HPA system abnormalities. The aim of this study was to evaluate whether the DEX/CRH test has a predictive value for the risk of depressive relapse in outpatients who are in clinical remission from a major depressive episode. Thirty-eight depressed outpatients (23 women, 15 men) in remission (MADRS score ⩽8) underwent the DEX/CRH test and were followed up for 12 months regarding the occurrence of a new depressive episode. In parallel we recruited 24 controls (13 men and 11 women). The main result is a statistically significant difference concerning the delta and AUC numbers for cortisol plasmatic values between the group of patients who relapsed during the 1-year follow-up and control subjects, but not between the group of patients with prolonged remission and controls. These results suggest that in outpatients who are in clinical remission from a major depressive episode, high delta and AUC values in the DEX/CRH test compared to controls subjects can be associated with a higher risk of relapse.

Beneficial effects of exercise and its molecular mechanisms on depression in rats

Exercise showed the beneficial effects on mental health in depressed sufferers, whereas, its underlying mechanisms remained unresolved. This study utilized the chronic unpredictable stress (CNS) animal model of depression to evaluate the effects of exercise on depressive behaviors and spatial performance in rats. Furthermore, we tested the hypothesis that the capacity of exercise to reverse the harmful effects of CNS was relative to the hypothalamo–pituitary–adrenal (HPA) system and brain-derived neurotrophic factor (BDNF) in the hippocampus. Animal groups were exposed to CNS for 4 weeks with and without access to voluntary wheel running. Stressed rats consumed significantly less of a 1% sucrose solution during CNS and exhibited a significant decrease in open field behavior. On the other hand, they showed impaired spatial performance in Morris water maze test 2 weeks after the end of CNS. Further, CNS significantly decreased hippocampal BDNF mRNA levels. However, voluntary exercise improved or even reversed these harmful behavioral effects in stressed rats. Furthermore, exercise counteracted a decrease in hippocampal BDNF mRNA caused by CNS. In addition, we also found that CMS alone increased circulating corticosterone (CORT) significantly and decreased hippocampal glucocorticoid receptor (GR) mRNA. At the same time, exercise alone increased CORT moderately and did not affect hippocampal GR mRNA levels. While, when both CNS and exercise were combined, exercise reduced the increase of CORT and the decrease of GR caused by CMS. The results demonstrated that: (1) exercise reversed the harmful effects of CNS on mood and spatial performance in rats and (2) the behavioral changes induced by exercise and/or CNS might be associated with hippocampal BDNF levels, and in addition, the HPA system might play different roles in the two different processes.

Stress and anxious-related behaviors in Lurcher mutant mice

Blood corticosterone levels (CORT) were measured before and after the completion of the elevated +-maze test in cerebellar Lurcher mutant and control mice. Consistent with the existence of a much more pronounced activation of the hypothalamo–pituitary–adrenal (HPA) system in the mutants, our results showed that while basal CORT were similar in mutants and controls, the surge of this stress indicator was enhanced in the Lurcher mice after completion of a behavioral test of anxiety. In contrast, at the behavioral level, we also observed that Lurcher exhibited significantly reduced anxiety related indices; they spent a significant greater amount of time in the aversive places of the apparatus and entered them more frequently than non mutant mice. It is proposed that rather than less anxious, the Lurcher mice are less inhibited than controls when placed in anxiogenic situation and that such poor inhibition could be causally related to changes in HPA system regulation. The overall patterns of our behavioral and endocrinological results thereby provided the evidence that cerebellar circuitry is involved in producing changes in physiological and behavioral stress-related emotional responses.

Hippocampal and hypothalamic function after chronic stress.

Hyperactivity of the hypothalamo-pituitary-adrenal (HPA) axis is often observed in association with and even prior to the onset of major depression. It is presently unclear (1) which molecular and cellular processes contribute to hyperactivity of parvocellular hypothalamic neurons (key regulators of the HPA system) and (2) how HPA axis hyperactivity can lead to attenuation of central serotonergic transmission, a crucial factor in the onset of clinical symptoms. In an attempt to address these issues in an experimental model we used rats exposed to chronic unpredictable stressors, a paradigm causing prolonged HPA-axis hyperactivity. In the first study spontaneous and evoked GABA-mediated input to parvocellular neurons in the paraventricular hypothalamic nucleus was recorded with the whole cell patch-clamp technique. The frequency, but not other properties, of spontaneous GABA-mediated inhibitory postsynaptic currents was reduced after chronic stress, resulting in a reduced amplitude of the evoked GABA current. This potentially would disinhibit parvocellular neurons, provided that other inputs are unchanged. In the second study, responses of CA1 hippocampal neurons to serotonin were recorded with microelectrodes. It appeared that the membrane hyperpolarization caused by activation of serotonin-1A receptors is attenuated in tissue from chronically stressed rats. However, no apparent changes in expression of the serotonin-1A or corticosteroid receptors were observed. This supports the notion that chronic stress eventually results in attenuation of serotonergic responsiveness by a mechanism not involving transcriptional regulation of the receptor. Follow-up studies will need to examine whether treatment with corticosteroid receptor antagonists can normalize the attenuated transmission after chronic stress.

The involvement of dopamine and nitric oxide in the endocrine and behavioural action of endomorphin-1

Previous publications have demonstrated a prominent central and corticotropin releasing hormone-mediated action of the endomorphins (EMs) on both open-field behaviour and the hypothalamo–pituitary–adrenal (HPA) axis. In the present experiments, the direct action of endomorphin-1 (EM1) on pituitary adrenocorticotropic hormone (ACTH) release, adrenal corticosterone secretion and the roles of nitric oxide (NO) and dopamine (DA) in the HPA and behavioural responses elicited by EM1 were investigated in mice. In vitro perifusion studies indicated that the action of EM1 on the HPA system appears to be confined to the hypothalamus, as EM1 did not influence the corticosterone secretion from adrenal slices and moderately attenuated the ACTH release from anterior pituitary slices. In in vivo experiments, N G-nitro- l-arginine (L-NNArg) pretreatment brought about a profound inhibition of both the endocrine and the behavioural responses. On the other hand, haloperidol completely abolished the increases in square crossing and rearing, without affecting corticosterone release. The direct action of EM1 on striatal DA release was therefore also investigated in an in vitro superfusion system. Although EM1 did not influence the basal release of tritiated DA, it significantly enhanced the transmitter release evoked by electric impulses and pretreatment with L-NNArg resulted in a considerable inhibition of the release elicited by EM1. In conclusion, our endocrine studies suggest an important role of NO in the mediation of the EM1-evoked corticosterone secretion. They also indicate that EM1 activates the HPA axis at a hypothalamic level and dopamine is not involved in this process. In contrast, the behavioural experiments reflect that the locomotor activation induced by EM1 is mediated by NO and dopamine, and the superfusion studies demonstrate that NO transmits the dopamine release enhancing effect of EM1.

The hypothalamo-pituitary-adrenal axis in multiple sclerosis.

During multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS), activation of the hypothalamo-pituitary-adrenal (HPA) axis is considered to modulate the immune system in such a way that the probability of recovery from a relapse is increased. In a series of postmortem studies we observed a significant activation of corticotropin releasing hormone (CRH) neurons and increased cortisol in the cerebrospinal fluid (CSF) of MS patients, indicating activation of the HPA axis in this disease. On the other hand, sepsis, while elevating cortisol in control subjects, did not associate with a further increase of cortisol in MS patients. Thus, the activated HPA-system in MS does not respond to an acute inflammatory stimulus. In order to investigate the role of chronic inflammation in the CNS in the activation of the HPA axis in MS, MS lesions in the hypothalamus were quantified and interleukin (IL)-6 levels in the CSF were determined. There was no difference in IL-6 levels between MS and control patients. A positive correlation was found between cortisol and IL-6 in control subjects with sepsis, but not in MS patients with sepsis or MS and control groups without sepsis. Thus, IL-6 in the CSF of MS patients is not the cause of the activation of the HPA system in MS. We found a remarkably high incidence (95% of the patients) of MS lesions in the hypothalamus, of which the majority (60%) were active. The more active lesions were present in the hypothalamus, the shorter the disease duration to the moment of death, indicative of a worse disease course. Preliminary data show suppression of the activation of CRH neurons by active hypothalamic MS lesions. We propose that this suppression of CRH neurons by active hypothalamic MS lesions causes the concomitant unfavorable disease course via an inadequate cortisol response during relapses of MS.

Behavioral and neuroendocrine actions of the Met-enkephalin-related peptide MERF

The effects and the mediation of the action of the proenkephalin derivative Met 5-enkephalin-Arg 6-Phe 7 (MERF) on the hypothalamo-pituitary-adrenal (HPA) system and open-field behavior were investigated in mice. Intracerebroventricular injection of the heptapeptide increased square crossing, rearing, and plasma corticosterone level. To characterize the receptors involved in these neuroendocrine processes, animals were pretreated either with the nonselective opioid antagonist naloxone or the κ-antagonist nor-binaltorphimine (nor-BNI). Both antagonists dose-dependently attenuated the HPA activation elicited by MERF. Naloxone also blocked the behavioral responses, but nor-binaltorphimine did not elicit a significant inhibition. The dopamine antagonist haloperidol and a corticotropin-releasing hormone (CRH) antagonist were also preadministered to shed light on the transmission of the actions of MERF. Both the motor responses and the HPA activation were diminished by the preadministration of the CRH antagonist, while haloperidol attenuated only square crossing and rearing. To investigate the direct effect of MERF on the dopaminergic system, dopamine release of striatal slices was measured in a superfusion system. Neither the basal nor the electric impulse-evoked dopamine release was modified by MERF. The results suggest that opioid-mediation predominate in the neuroendocrine actions of MERF, and the effect of the heptapeptide on the HPA system seems to be mediated by κ-receptors. In the behavioral responses evoked by MERF, both CRH release and the action of the dopaminergic neurons of the subcortical motor system might be involved. MERF also appears to activate the paraventricular CRH neurons, but dopaminergic transmission does not seem to play a significant role in its hypothalamic action.

Behavioral and neuroendocrine actions of endomorphin-2

The effects of intracerebroventricularly administered endomorphin-2 (EM2) on open-field activity and the hypothalamo-pituitary-adrenal (HPA) system were investigated. EM2 (0.25–1 μg) significantly increased both the locomotor and the rearing activity, resulting in a bell-shaped dose-response curve. EM2 also enhanced corticosterone release, with an even more profound downturn phase at higher concentrations. The corticotropin-releasing hormone (CRH) antagonist α-helical CRH 9–41 completely abolished the EM2-evoked endocrine and behavioral responses. These findings reinforce the hypothesis that the endomorphins may play a significant role in the regulation of locomotion, rearing activity and the HPA system through the release of CRH.

Combined Treatment with Corticosteroids and Moclobemide Favors Normalization of Hypothalamo-Pituitary-Adrenal Axis Dysregulation in Relapsing-Remitting Multiple Sclerosis: A Randomized, Double Blind Trial

Hyperresponsiveness of the hypothalamo-pituitary-adrenal (HPA) axis in multiple sclerosis (MS), an autoimmune inflammatory disease of the central nervous system, is presumably due to diminished corticosteroid receptor function. It probably influences the immune response, but its clinical significance is not clear. Similar HPA dysregulation occurs in depression and is reversible with successful antidepressant treatment. We conducted a double blind, placebo-controlled trial to evaluate the neuroendocrine effect of cotreatment with the antidepressant moclobemide as an adjunct to oral corticosteroids in MS. Twenty-one patients with definite relapsing-remitting MS (11 females, aged 33.9 ± 2.0 yr; Expanded Disability Status Scale score of neurological impairment, 2.0–6.5) in acute relapse were treated with placebo (n = 13) or 300 mg moclobemide (reversible monoamine oxidase A inhibitor; n = 8) for 75 days. All received oral fluocortolone from day 7 on, and the dose was tapered until day 29. Effects were evaluated using the combined dexamethasone-CRH test and clinically on days 1, 30, and 75. At baseline, the HPA axis was mildly activated, comparably for treatment groups [area under the curve for cortisol (AUC-Cort), 213.8 ± 76.8 arbitrary units in the moclobemide group vs. 225.8 ± 65.1 in the steroid alone group; mean ± sem]. In a group of healthy controls with comparable demographic characteristics, the AUC-Cort was 107.4 ± 14.1. Moclobemide cotreatment resulted in normalization of the HPA axis response, whereas the HPA system hyperresponse was maintained with steroids alone (AUC-Cort on day 30, 85.9 ± 22.8 vs.177.1 ± 68.5; on day 75, 111.0 ± 46.0 vs. 199.2 ± 64.6). The change in Expanded Disability Status Scale was comparable for both groups. Although corticosteroids alone had no effect on the HPA response using the dexamethasone-CRH test, treatment with moclobemide combined with corticosteroids favors normalization of the HPA response in relapsing-remitting MS.

Effects of brain natriuretic peptide on pituitary-adrenal activation in rats

The aim of this study was to characterize the effects of brain natriuretic peptide (BNP) on the hypothalamo-pituitary-adrenal (HPA) responses to different stress paradigms (ether stress, electric shock and restraint). Rats were subjected to the stressful stimuli after intracerebroventricular administration of BNP (32.5 ng − 6.5 μg) and plasma corticosterone was used as an indicator of the HPA activation. BNP did not modify the basal secretion, but inhibited the stress-induced rise in plasma corticosterone in a dose-dependent manner. BNP proved most effective in decreasing the corticosterone response to ether stress and attenuated the electric shock and restraint-induced HPA activation to a lesser extent. These results confirm the view that BNP takes part in the regulation of the HPA system.