Hypothalamic-pituitary-adrenal Hyperactivity Research Articles

Research Progress on the Basic Pharmacodynamic Substance and Mechanism of <i>Citri Sarcodactylis Fructus</i> in Relieving Anxiety

Anxiety disorder resulting from the interaction of psychological factors-caused anxiety and mood disorder symptoms is one of the clinical mental diseases. Excessive worry, nervousness and fear often bring about several negative outcomes, and seriously impact the physical, mental, and social functioning of patients. What’s worse, with poor treatment, anxiety disorder may develop into mental illnesses such as depression and schizophrenia. The treatment of anxiety has mainly recourse to drug therapy and psychotherapy; however, Western drug therapy represented by 5-hydroxytryptamine reuptake inhibitor often causes evident adverse effects, including nausea and constipation, as well as poor long-term medication compliance of patients. Citri Sarcodactylis Fructus can sooth the liver and regulate qi, which can be applied to alleviate anxiety disorder as an ancillary drug. Modern pharmacological research revealed that bergamot volatile oil, also known as bergamot essential oil (BEO), is the main active chemical component of Citri Sarcodactylis Fructus for anti-anxiety. BEO has been confirmed to exert an anti-anxiety effect through modulating neuronendocrine-immune network, including immunoregulation, suppression of hyperactive hypothalamic-pituitary-adrenal (HPA) axis, enhancement of function of hypothalamic-pituitary-thyroid (HPT) axis, modulation of neurotransmitter, and promotion of neurotrophic effect. The study discusses the current research status regarding the application of Citri Sarcodactylis Fructus for anti-anxiety in recent years, and deeply probes into the mechanism of Citri Sarcodactylis Fructus playing an anti-anxiety role via neuronendocrine-immune network, in an effort to provide references to clinical treatment of anxiety disorder and new ideas for developing drugs targeting anxiety disorders.

Effect of Papaver rhoeas hydroalcoholic extract on blood corticosterone and psychosocial behaviors in the mice model of predator exposure-induced post-traumatic stress disorder

The function of hypothalamic-pituitary-adrenal (HPA) axis and psychosocial behaviors are affected in post-traumatic stress disorder (PTSD). Based on presence of several beneficial alkaloids in Papaver rhoeas (PR) plant, we assessed the effects of PR hydroalcoholic extract on blood corticosterone and psychosocial behaviors in the mice model of predator exposure-induced PTSD. Male NMARI mice were assigned into two main groups (control or PTSD) according to stress exposure (presence or absent of the predator). Each main group was divided into four subgroups according to treatment with the different doses of PR extract. Mice were treated intraperitoneally by PR extract at three different doses (1,5&10 mg/kg) 30 min before the beginning of test on days 1, 2&3. Corticosterone concentration determined in the blood samples on days 1, 3&21, and mice examined for the psychosocial behaviors on the third day. PTSD induction in mice by exposing to hungry predator increased blood corticosterone and changed the psychosocial and physiological behaviors. PR extract decreased blood corticosterone in PTSD mice on the third day as well as 21st day. Also, PR extract improved the psychosocial and physiological behaviors in PTSD mice. Moreover, PR extract increased blood corticosterone in control mice at a dose-response manner. PR extract is able to decrease blood corticosterone in PTSD condition and probably prevent the HPA hyperactivity in PTSD mice when exposed to the stress stimuli. Accordingly, decreased blood corticosterone by PR extract might be involved in improvement of the physiological and psychosocial behaviors in PTSD mice.

Selective GPER Agonist G-1 Confers Neuronal Protection and Impacts Anxiety-Like Behaviours in Ovariectomized Wistar Rats Exposed to Global Cerebral Ischemia

Global cerebral ischemia (GCI) induces neuronal death in key hippocampal structures, leading to hypothalamic-pituitary-adrenal (HPA) axis dysregulation and increased anxiety-/depressive-like behaviours. Women experience higher risk of cardiovascular disease after menopause, with selective activation of non-classical G protein-coupled estrogen receptors (GPER) showing promising neuroprotection. This study aimed at investigating effects of acute and repeated selective GPER agonist G-1 exposure before GCI on post-ischemic CA1 pyramidal cell death and HPA hyperactivity. Forty-four ovariectomized Wistar rats were intraperitoneally injected daily for seven consecutive days with either vehicle saline, acute G-1 (vehicle for six days, G-1 for one; 50 µg/kg) or repeated G-1 (only G-1) up to 1 h before 10-min GCI or sham surgery. Anxiety- and depressive-like behaviours were assessed with the Elevated-Plus Maze (EPM) and the Sucrose Preference Test (SPT), respectively. Blood corticosterone levels after acute swim stress were measured via ELISA, and, upon perfusion, adrenal glands were weighed and CA1 samples stained with thionine. Results show protective effects of both acute and repeated G-1 exposure on CA1 neuronal density and on normalization of post-ischemic anxiety-like behaviours. Trends for ischemia-induced decreases in sucrose preference were found with no effect of G-1. Adrenal gland weight remained unchanged by treatment while corticosterone levels were increased by exposure to stress in all rats. These results show distinct effects of selective GPER activation on neuroprotection and post-ischemic stress response.

Hypothalamic‐pituitary‐adrenal axis activity and vascular function in healthy adults

The objective of this study is to assess the relationship between hypothalamic-pituitary-adrenal (HPA) axis activity, vascular function and insulin sensitivity in healthy adults. Open observational study. Thirty healthy adults were studied at the Endocrine Research Unit, Repatriation General Hospital, Adelaide, SA, Australia. HPA activity was assessed from the serum cortisol 30 min after 1 µg ACTH1-24 (Novartis Pharmaceuticals). Subjects with a cortisol below (n = 15) and above (n = 15) the median were categorized as low and high responders, respectively. Reactive hyperaemia index (RHI) was measured fasting to estimate endothelial function. Matsuda index was calculated from glucose and insulin concentrations collected fasting and 30 minutely for 2 h after a mixed meal (10 kcal/kg, 45% carbohydrate, 15% protein, 40% fat). The primary endpoint was the difference in RHI between low and high responders. There were no significant differences in age (61 ± 9 vs. 64 ± 7 years, p = .19), body mass index (BMI; 26 ± 3 vs. 24 ± 4 kg/m2 , p = .25) and sex (p = .71) between low and high responders. High responders had a lower RHI (2.1 ± 0.2 vs. 2.6 ± 0.2, p = .04) than low responders and there was a negative association between RHI and peak cortisol post ACTH1-24 (β = -.56, p < .01). There were no significant differences in Matsuda index (15.0 ± 2.4 vs. 22.7 ± 5.2, p = .19) between high and low responders. In healthy adults, endothelial dysfunction is likely to contribute to the association between HPA hyperactivity and increased cardiovascular risk. As insulin sensitivity was not different in high and low responders, endothelial dysfunction is not primarily secondary to insulin resistance.

Glucocorticoid Receptor Signaling in Diabetes.

Stress and depression increase the risk of Type 2 Diabetes (T2D) development. Evidence demonstrates that the Glucocorticoid (GC) negative feedback is impaired (GC resistance) in T2D patients resulting in Hypothalamic-Pituitary-Adrenal (HPA) axis hyperactivity and hypercortisolism. High GCs, in turn, activate multiple aspects of glucose homeostasis in peripheral tissues leading to hyperglycemia. Elucidation of the underlying molecular mechanisms revealed that Glucocorticoid Receptor (GR) mediates the GC-induced dysregulation of glucose production, uptake and insulin signaling in GC-sensitive peripheral tissues, such as liver, skeletal muscle, adipose tissue, and pancreas. In contrast to increased GR peripheral sensitivity, an impaired GR signaling in Peripheral Blood Mononuclear Cells (PBMCs) of T2D patients, associated with hyperglycemia, hyperlipidemia, and increased inflammation, has been shown. Given that GR changes in immune cells parallel those in brain, the above data implicate that a reduced brain GR function may be the biological link among stress, HPA hyperactivity, hypercortisolism and hyperglycemia. GR polymorphisms have also been associated with metabolic disturbances in T2D while dysregulation of micro-RNAs—known to target GR mRNA—has been described. Collectively, GR has a crucial role in T2D, acting in a cell-type and context-specific manner, leading to either GC sensitivity or GC resistance. Selective modulation of GR signaling in T2D therapy warrants further investigation.

Sex-dependent metabolic effects of pregestational exercise on prenatally stressed mice.

Stressful events during the prenatal period have been related to hyperactive hypothalamic-pituitary-adrenal (HPA) axis responses as well as metabolic changes in adult life. Moreover, regular exercise may contribute to the improvement of the symptoms associated with stress and stress-related chronic diseases. Therefore, this study aims to investigate the effects of exercise, before the gestation period, on the metabolic changes induced by prenatal stress in adult mice. Female Balb/c mice were divided into three groups: control (CON), prenatal restraint stress (PNS) and exercise before the gestational period plus PNS (EX+PNS). When adults, the plasmatic biochemical analysis, oxidative stress, gene expression of metabolic-related receptors and sex differences were assessed in the offspring. Prenatal stress decreased neonatal and adult body weight when compared to the pregestational exercise group. Moreover, prenatal stress was associated with reduced body weight in adult males. PNS and EX+PNS females showed decreased hepatic catalase. Pregestational exercise prevented the stress-induced cholesterol increase in females but did not prevent the liver mRNA expression reduction on the peroxisome proliferator-activated receptors (PPARs) α and γ in PNS females. Conversely, PNS and EX+PNS males showed an increased PPARα mRNA expression. In conclusion, pregestational exercise prevented some effects of prenatal stress on metabolic markers in a sex-specific manner.

The Role of Early Life Stress in HPA Axis and Anxiety.

Substantial evidence from various studies suggests a preeminent role for early adverse experiences in the development of psychopathology. The most recent studies reviewed here suggest that early life stressors are associated with an increased risk for anxiety disorders in adulthood. Early life stress predisposes individuals to develop a number of psychiatric syndromes, particularly affective disorders, including anxiety disorders, and is therefore a significant health problem.This review examines the emerging literature on the relationship between stress, hypothalamic-pituitary-adrenal (HPA) axis function, and generalized anxiety disorder (GAD), panic disorder, and phobias and the role of early life stress as an important risk factor for HPA axis dysfunction.The most consistent findings in the literature show increased activity of the HPA axis in depression associated with hypercortisolemia and reduced inhibitory feedback. In addition to melancholic depression, a spectrum of other conditions may be associated with increased and prolonged activation of the HPA axis, including panic, GAD, phobias and anxiety. Moreover, HPA axis changes appear to be state-dependent, tending to improve upon resolution of the anxiety syndrome. Interestingly, persistent HPA hyperactivity has been associated with higher rates of relapse. These studies suggest that an evaluation of the HPA axis during treatment may help identify patients who are at a higher risk for relapse. These findings suggest that this dysfunction of the HPA axis is partially attributable to an imbalance between glucocorticoid and mineralocorticoid receptors. Evidence has consistently demonstrated that glucocorticoid receptor function is impaired in anxiety disorders. Moreover, normal basal cortisol levels and hyper-responsiveness of the adrenal cortex during a psychosocial stressor are observed in social phobics. Finally, abnormal HPA axis activity has also been observed in generalized anxiety disordered patients. Early stressful life events may provoke alterations of the stress response and thus of the HPA axis that can endure during adulthood, predisposing individuals to develop psychopathology.

Pituitary Volume and Socio-Cognitive Functions in Individuals at Risk of Psychosis and Patients With Schizophrenia.

Objectives: Increased pituitary volume, which probably reflects hypothalamic-pituitary-adrenal (HPA) hyperactivity, has been reported in patients with schizophrenia and individuals at risk of psychosis. On the basis of potential role of abnormal HPA axis function on cognitive impairments in psychosis, we aimed to examine possible relations between the pituitary volume and socio-cognitive impairments in these subjects.Methods: This magnetic resonance imaging study examined the pituitary gland volume in 38 subjects with at-risk mental state (ARMS) [of whom 4 (10.5%) exhibited the transition to schizophrenia], 63 patients with schizophrenia, and 61 healthy controls. Social and cognitive functions of the ARMS and schizophrenia groups were assessed using the Brief Assessment of Cognition in Schizophrenia (BACS), the Schizophrenia Cognition Rating Scale (SCoRS), and the Social and Occupational Functioning Assessment Scale (SOFAS).Results: Both the ARMS and schizophrenia groups had a significantly larger pituitary volume compared to controls. In the schizophrenia group, the pituitary volume was negatively associated with the BACS working memory score. No association was found between the pituitary volume and clinical variables (medication, symptom severity) in either clinical group.Conclusion: Our findings support the notion of common HPA hyperactivity in the ARMS and schizophrenia groups, but abnormal HPA axis function may contribute differently to cognitive deficits according to the illness stages of schizophrenia.

Biological Mechanisms of Cancer-Induced Depression.

Patients with cancer are more likely to develop depression than the general population, which negatively impacts their quality of life and prognosis. In order to identify effective antidepressants catered toward cancer patients, the biology of depression in the context of cancer must be well-understood. Many theories have emerged postulating the mechanisms underlying the development of depressive disorder. Here, we review the role inflammation, a hyperactive hypothalamic-pituitary-adrenal (HPA) axis, and glutamate excitotoxicity may play in cancer-induced depression. Hopefully, novel therapeutics targeting these dysregulated pathways may be potent in ameliorating depressive symptoms in the cancer population.

Depression-related behavioural and neuroendocrine changes in the Spontaneously Diabetic Torii (SDT) fatty rat, an animal model of type 2 diabetes mellitus.

Depression is one of the most common psychiatric diseases and is commonly comorbid with type 1 or 2 diabetes mellitus (DM). However, the pathophysiology underlying the depressive state in DM remains poorly understood. Animal models are useful tools to investigate the association between depression and DM. In the present study we investigated whether the Spontaneously Diabetic Torii (SDT) fatty rat, a novel animal model of type 2 DM, shows depression-related features. We assessed depression-like behaviour, hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis, and neurotransmitter levels in the brain. Behaviour was evaluated using a forced swimming test, and the HPA axis was evaluated with changes in plasma corticosterone levels after a swimming stress exposure or dexamethasone challenge. In addition, serotonin (5-hydroxytryptamine; 5-HT), noradrenaline, glutamate and γ-aminobutyric acid (GABA) concentrations in the frontal cortex, hippocampus and brain stem were measured. In the forced swimming test, SDT fatty rats exhibited increased duration of immobility compared with control Sprague-Dawley (SD) rats. Moreover, basal corticosterone levels were significantly elevated in SDT fatty compared with control SD rats. However, there were no stress-induced increases or changes in dexamethasone-induced suppression of corticosterone in SDT fatty compared with control SD rats. Furthermore, there were significant changes in 5-HT concentrations in the prefrontal cortex, and in GABA and glutamate concentrations in the hippocampus in SDT fatty compared with controls. The results of the present study suggest that the SDT fatty rat may be an appropriate model for diabetes with comorbid depression associated with neurotransmitter impairments and aberrant basal HPA hyperactivity.

Antidepressant-like Effect of Bacopaside I in Mice Exposed to Chronic Unpredictable Mild Stress by Modulating the Hypothalamic-Pituitary-Adrenal Axis Function and Activating BDNF Signaling Pathway.

Preliminary studies conducted in our laboratory have confirmed that Bacopaside I (BS-I), a saponin compound isolated from Bacopa monnieri, displayed antidepressant-like activity in the mouse behavioral despair model. The present investigation aimed to verify the antidepressant-like action of BS-I using a mouse model of behavioral deficits induced by chronic unpredictable mild stress (CUMS) and further probe its underlying mechanism of action. Mice were exposed to CUMS for a period of 5 consecutive weeks to induce depression-like behavior. Then, oral gavage administrations with vehicle (model group), fluoxetine (12mg/kg, positive group) or BS-I (5, 15, 45mg/kg, treated group) once daily were started during the last two weeks of CUMS procedure. The results showed that BS-I significantly ameliorated CUMS-induced depression-like behaviors in mice, as characterized by an elevated sucrose consumption in the sucrose preference test and reduced immobility time without affecting spontaneous locomotor activity in the forced swimming test, tail suspension test and open field test. It was also found that BS-I treatment reversed the increased level of plasma corticosterone and decreased mRNA and protein expressions of glucocorticoid receptor induced by CUMS exposure, indicating that hypothalamic-pituitary-adrenal (HPA) axis hyperactivity of CUMS-exposed mice was restored by BS-I treatment. Furthermore, chronic administration of BS-I elevated expression levels of brain-derived neurotrophic factor (BDNF) (mRNA and protein) and activated the phosphorylation of extracellular signal-regulated kinase and cAMP response element-binding protein in the hippocampus and prefrontal cortex in mice subjected to CUMS procedure. Taken together, these results indicated that BS-I exhibited an obvious antidepressant-like effect in mouse model of CUMS-induced depression that was mediated, at least in part, by modulating HPA hyperactivity and activating BDNF signaling pathway.

Depressive-like phenotype induced by AAV-mediated overexpression of human α-synuclein in midbrain dopaminergic neurons

Parkinson's disease (PD) is a neurodegenerative disorder characterized by a progressive loss of nigral dopaminergic neurons and by the presence of aggregates containing α-synuclein called Lewy bodies. Viral vector-induced overexpression of α-synuclein in dopaminergic neurons represents a model of PD which recapitulates disease progression better than commonly used neurotoxin models. Previous studies using this model have reported motor and cognitive impairments, whereas depression, mood and anxiety phenotypes are less described. To investigate these psychiatric phenotypes, Sprague–Dawley rats received bilateral injections of a recombinant adeno-associated virus (AAV) vector expressing human α-synuclein or GFP into the substantia nigra pars compacta. Behavior was assessed at two timepoints: 3 and 8weeks post-injection. We report that nigral α-synuclein overexpression led to a pronounced nigral dopaminergic cell loss accompanied by a smaller cell loss in the ventral tegmental area, and to a decreased striatal density of dopaminergic fibers. The AAV-α-synuclein group exhibited modest, but significant motor impairments 8weeks after vector administration. The AAV-α-synuclein group displayed depressive-like behavior in the forced swim test after 3weeks, and reduced sucrose preference at week 8. At both timepoints, overexpression of α-synuclein was linked to a hyperactive hypothalamic–pituitary–adrenal (HPA) axis regulation of corticosterone. The depressive-like phenotype was also correlated with decreased nigral brain-derived neurotrophic factor and spinophilin levels, and with decreased striatal levels of the activity-regulated cytoskeleton-associated protein. This study demonstrates that AAV-mediated α-synuclein overexpression in dopamine neurons is not only useful to model motor impairments of PD, but also depression. This study also provides evidence that depression in experimental Parkinsonism is correlated to dysregulation of the HPA axis and to alterations in proteins involved in synaptic plasticity.

RELATIONSHIP BETWEEN THE CORTICAL THICKNESS AND SERUM CORTISOL LEVELS IN DRUG-NAÏVE, FIRST-EPISODE PATIENTS WITH MAJOR DEPRESSIVE DISORDER: A SURFACE-BASED MORPHOMETRIC STUDY.

In major depressive disorder (MDD) patients, higher morning cortisol levels due to a hyperactive hypothalamic-pituitary-adrenal (HPA) axis have been reported. The aim of the present study was to evaluate the relationship between cortical thinning and the serum cortisol levels during the first depressive episode in drug-naïve MDD patients using an automated surface-based morphometry (SBM) method. The institutional review board approved this prospective study. MR imaging data were obtained using a 3T scanner by a three-dimensional fast-spoiled gradient recalled acquisition with steady state (3D-FSPGR). Thirty drug-naïve patients with MDD and 41 age- and gender-matched healthy subjects (controls) were enrolled. We then used the SBM method (Freesurfer) to generate cortical thickness maps, and measured the cortical thickness in each subject. Morning blood samples were drawn from all participants for cortisol measurements. We found the serum cortisol levels were significantly higher in the MDD patients than in the controls. The MDD patients manifested significant thinning of the left lateral orbitofrontal cortex compared with the controls. There was a significant negative linear correlation between the thickness of the left lateral orbitofrontal cortex and the serum cortisol levels in the MDD patients. In the early stage of MDD, the thickness of the lateral orbitofrontal cortex was significantly reduced, and also showed a significant inverse correlation with the serum cortisol levels. Since the lateral orbitofrontal cortex contains a high concentration of glucocorticoid receptor, glucocorticoid receptor-mediated signaling transductions could contribute to neurotoxicity, which might occur when there are high cortisol levels in patients with MDD.

Recent advances in the role of cortisol and metabolic syndrome in age-related degenerative diseases.

The metabolic syndrome (MetS) presents an increasing prevalence in elderly people. A significant role in MetS is played by the stress response and cortisol. The hypothalamic-pituitary-adrenal (HPA) axis activity is increased by central (loss of hippocampal glucocorticoid receptors) and peripheral (11β-hydroxysteroid dehydrogenase type 1, 11β-HSD1, hyperactivity) mechanisms. The HPA hyperactivity has been found in chronic diseases affecting the endocrine (abdominal obesity with MetS, type 2 diabetes), cardiovascular (atherosclerosis, essential hypertension), and nervous systems (dementia, depression), in aging. A novel therapeutic approach (11β-HSD1 inhibition) is promising in treating the HPA axis hyperactivity in chronic diseases with MetS. A large-scale national clinical trial (AGICO, AGIng, and COrtisol study) has been proposed by our group to evaluate the role of cortisol and MetS in the main pathologies of aging (vascular and degenerative dementia, cardiovascular diseases, type 2 diabetes, abdominal obesity).

The influence of Hatha yoga as an add-on treatment in major depression on hypothalamic–pituitary–adrenal-axis activity: A randomized trial

ObjectivesThe impact of Hatha yoga as add-on treatment to quetiapine fumarate extended release (QXR) or escitalopram (ESC) in depressed patients on hypothalamic–pituitary–adrenal (HPA) axis activity was assessed. Methods60 inpatients suffering from major depressive disorder (MDD) according to DSM-IV were randomized for a 5 week treatment with Yoga or not (control group) and with either QXR (300 mg/day) or ESC (10 mg/day). Serial dexamethasone/corticotropin releasing hormone (DEX/CRH) tests were performed to assess HPA axis function. The Hamilton Depression Rating Scale (21-HAMD) was used weekly. ResultsA more pronounced down regulation of the HPA axis activity due to yoga could not be detected. The stepwise long term cortisol reduction was seen in both medication groups, irrespectively of yoga add-on treatment. In addition, cortisol improvers in week 1 of therapy (reduction in cortisol peak value within the DEX/CRH test) reached significant greater amelioration of depressive symptoms after 5 weeks. ConclusionsOur results suggest that antidepressant agents down regulate HPA axis function to a greater extent than additional Hatha yoga treatment. Moreover, an early reduction of HPA system hyperactivity after one week of pharmacological treatment seems to raise the possibility of a favorable treatment response.

Neuronal Mechanisms of Placebo Effects

Placebo responses are complex and work through several neurobiological mechanisms. The neurotransmitters implicated thus far are dopamine (DA), gamma-aminobutyric acid (GABA), cholecystokinin (CCK), opioids, serotonin, and endocannabinoids. Both conscious expectations and unconscious conditioning can bring about molecular changes using the above neurotransmitters along the distributed biological systems, subserving cognition, emotions, pain control, reward, and learning. Expectations can enhance DA secretion in the reward circuitry of the brain, which has a nucleus accumbens at its epicenter. The prefrontal cortex (PFC), which controls attention and emotional memories, negotiates the path to the reward. The nucleus accumbens (NAc), after capturing the sole attention of the PFC, is able to modulate arousal, emotional tone, and autonomic tone to make the brain seek reward of therapeutic benefit, even when no active treatment is offered. Both DA and endogenous opioids play a key role in modulation of placebo responsiveness. The negative expectations of the person regarding treatment or negative suggestions given by the treater can amplify anxiety and pain by activating several brain regions, such as the anterior cingulate cortex (ACC), PFC, and the insula. Thus, anticipatory anxiety generated acts on two independent pathways: the hypothalamic pituitary adrenal (HPA) axis and the CCKergic pro-nociceptive system. By acting on anxiety, benzodiazepines can block both pathways and reduce pain. But CCK antagonists such as proglumide can only prevent nocebo hyperalgesia, and have no effect on HPA hyperactivity. The ebb and the flow of opioid/CCKergic systems produce the opposing effects of placebo/nocebo. The activation/deactivation between endogenous opioids/DA in NAc helps us understand both placebo and nocebo responses. There are parallels between the placebo response and classical conditioning. Endocrine, immune, and autonomic responses can be conditioned by placebos. Both the expectancy and conditioning mechanisms mediate placebo responses contingent upon previous experiences and social observational learning.

Novel insights into the potential involvement of 5-HT7 receptors in endocrine dysregulation in stress-related disorders

A hyperactive hypothalamic-pituitary-adrenal (HPA) axis is a common feature of stress-related disorders, and the brain serotonin (5-HT) system plays a major role in HPA axis modulation. Glucocorticoids and stress profoundly affect the 5-HT system so it is possible that alterations of endocrine 5-HT mechanisms may underlie HPA axis overdrive in stress-related diseases. Available evidence suggests a role of 5-HT1A, 5-HT2A/2C and 5-HT7 receptors in HPA system activation, and pharmacological blockade of 5-HT7 receptors produces a fast-acting antidepressant-like action and shortens the onset of antidepressant-like effects of various classes of antidepressants. The mechanisms involved in this effect have not been elucidated, but recent findings suggest a role of 5-HT7 receptors in the development of HPA axis overdrive as a result of chronic stress. Remarkably, clinical findings have shown an association between corticosteroid-producing adenomas and expression of ectopic 5-HT7 receptors in corticosteroid-producing adrenocortical cells. These observations might therefore reveal an endocrine mechanism for the antidepressant-like action of 5-HT7 receptor blockers, possibly through normalization of HPA axis function. If such a preliminary hypothesis is confirmed, the potential therapeutic usefulness of 5-HT7 receptor antagonists could extend beyond depression to include other diseases, the pathophysiology of which has been associated with chronic stress and HPA axis dysregulation.

The hypothalamic–neurohypophysial system: genomes, genes and genetics

The hypothalamic–neurohypophysial system: genomes, genes and genetics

Suppression of Hypothalamic–Pituitary–Adrenal Axis by Acute Heroin Challenge in Rats During Acute and Chronic Withdrawal from Chronic Heroin Administration

It is known that heroin dependence and withdrawal are associated with changes in the hypothalamic-pituitary-adrenal (HPA) axis. The objective of these studies in rats was to systematically investigate the level of HPA activity and response to a heroin challenge at two time points during heroin withdrawal, and to characterize the expression of associated stress-related genes 30min after each heroin challenge. Rats received chronic (10-day) intermittent escalating-dose heroin administration (3×2.5mg/kg/day on day 1; 3×20mg/kg/day by day 10). Hormonal and neurochemical assessments were performed in acute (12h after last heroin injection) and chronic (10days after the last injection) withdrawal. Both plasma ACTH and corticosterone levels were elevated during acute withdrawal, and heroin challenge at 20mg/kg (the last dose of chronic escalation) at this time point attenuated this HPA hyperactivity. During chronic withdrawal, HPA hormonal levels returned to baseline, but heroin challenge at 5mg/kg decreased ACTH levels. In contrast, this dose of heroin challenge stimulated the HPA axis in heroin naïve rats. In the anterior pituitary, pro-opiomelanocortin (POMC) mRNA levels were increased during acute withdrawal and retuned to control levels after chronic withdrawal. In the medial hypothalamus, however, the POMC mRNA levels were decreased during acute withdrawal, and increased after chronic withdrawal. Our results suggest a long-lasting change in HPA abnormal responsivity during chronic heroin withdrawal.

Pituitary volume in schizophrenia spectrum disorders

IntroductionThere is converging evidence supporting hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis in schizophrenia spectrum disorders (SSD), such as schizotypal personality disorder (SPD), first-episode schizophrenia (FESZ) and chronic schizophrenia (CHSZ). Such an aberrant HPA activity might have volumetric consequences on the pituitary gland. However, previous magnetic resonance imaging (MRI) studies assessing pituitary volume (PV) in SSD are conflicting. The main objective of this study was to examine further PV in SSD. MethodsPV were manually traced on structural MRIs in 137 subjects, including subjects with SPD (n=40), FESZ (n=15), CHSZ (n=15), and HC (n=67). We used an ANCOVA to test PV between groups and gender while controlling for inter-subject variability in age, years of education, socioeconomic status, and whole brain volume. ResultsOverall, women had larger PV than men, and within the male sample all SSD subjects had smaller PV than HC, statistically significant only for the SPD group. In addition, dose of medication, illness duration and age of onset were not associated with PV. ConclusionChronic untreated HPA hyperactivity might account for smaller PV in SPD subjects, whereas the absence of PV changes in FESZ and CHSZ patients might be related to the normalizing effects of antipsychotics on PV. SPD studies offer a way to examine HPA related alterations in SSD without the potential confounds of medication effects.