Adrenal Hypertrophy Research Articles

Depressive and cardiovascular disease comorbidity in a rat model of social stress: a putative role for corticotropin-releasing factor

Depression is associated with medical comorbidities, particularly cardiovascular disease. However, mechanisms linking depression and cardiovascular disease remain unclear. This study investigated whether the rat resident-intruder model of social stress would elicit behavioral dysfunctions and autonomic changes characteristic of psychiatric/cardiovascular comorbidity. Furthermore, the efficacy of the corticotropin-releasing factor-1 (CRF(1)) receptor antagonist, NBI-30775 (NBI), or the tricyclic antidepressant, desipramine (DMI), to prevent social stress-induced behavioral, neuroendocrine, and cardiovascular changes were evaluated. Adult male rats were exposed to resident-intruder stress (seven consecutive days) and systemically administered NBI (10 mg/kg/7 days), DMI (10 mg/kg/14 days), or vehicle. The efficacy of NBI and DMI to alter the behavioral and neuroendocrine responses to social stress was assessed. Furthermore, their effects on stress-induced forced swim behavior (FST), bladder and adrenal weight, and heart rate variability (HRV) were examined. NBI, but not DMI, increased time spent in an upright, defensive posture and the latency to submit to the resident. Additionally, only NBI reduced social stress-induced adrenocorticotropic hormone and corticosterone release. Social stress increased FST immobility, caused bladder and adrenal hypertrophy, and decreased HRV. Both NBI and DMI blocked stress-induced increases in immobility during the FST. However, only NBI inhibited social stress-induced adrenal and bladder hypertrophy and decreases in heart rate variability. Rat resident-intruder stress paradigm models aspects of psychiatric/medical comorbidity. Furthermore, the CRF system may contribute to both the behavioral response during social stress and its behavioral and autonomic consequences, offering insight into potential therapy to treat these comorbid conditions.

Effects of long‐acting somatostatin analogues on adrenal growth and phosphoribosyl pyrophosphate formation in experimental diabetes

Adrenal growth and increased adrenal function occur in experimental diabetes. Previously, we have shown that phosphoribosyl pyrophosphate (PRPP) and PRPP synthetase increased rapidly between 3 and 7 days after induction of diabetes with streptozotocin (STZ), with less marked changes in enzymes of the pentose phosphate pathway. The present study examines the earlier phase of 1-3 days following induction of diabetes, seeking to elucidate whether control of PRPP production is a result of diabetic hyperglycaemia, or to a more general re-ordering of hormonal factors. To investigate this question, the role of insulin and two different long-acting somatostatin analogues, Angiopeptin and Sandostatin, were used in a well-established animal model. PRPP was chosen specifically as a target for these studies in view of its central role in nucleotide formation and nicotinamide mononucleotide synthesis via Nampt which is the rate-limiting step in the synthesis of NAD and which has been shown to have multiple roles in cell signalling in addition to its known function in glycolysis and energy production. Treatment with the somatostatin analogues ab initio effectively abolished the adrenal growth, the increase in PRPP formation and the rise of PRPP synthetase activity in the first 7 days of diabetes, without having any significant effect on blood glucose values. This suggests that elevated glucose per se is not responsible for the diabetic adrenal hypertrophy and implies that growth factors/hormones, regulated by somatostatin analogues, play a significant role in adrenal growth processes.

La tuberculose surrénalienne : à propos d’un cas

Isolated adrenal tuberculosis is rare, and represents between 1-2% of the etiologies of adrenal masses called incidentalomas. A 32-year-old woman, without notable medical history, was hospitalized for pain in the left hypochondrium, lasting for two months in a context of apyrexia and weight loss amounted to 5 kg. Clinical examination was normal, but abdominopelvic CT objectified bilateral adrenal hypertrophy predominantly left with bilateral linear calcifications. The chest radiograph was normal, adrenal hormones were normal. The research of BK in sputum and urine were negative on direct examination and culture. The tuberculin was 12 mm and HIV status was negative. A left adrenal biopsy was done and histopathological study of tuberculous lesions was found confirming caseofolliculaire adrenal tuberculosis. The patient has been treated with antibacillaire with favorable evolution. In light of this observation, the authors make the point on this rare disease.

Effects of short term forced oral breathing: Physiological changes and structural adaptation of diaphragm and orofacial muscles in rats

ObjectiveWe studied adaptation of diaphragm and orofacial muscles as well as hormonal responses to forced oral breathing (lasting for only 4 days) following reversible bilateral nasal obstruction performed on day 8 post-natal male rats. DesignMuscle myosin heavy chain (MHC) composition and hormone levels were analysed during two periods: 1 and 3 days after obstruction (days 9 and 11 post-natal), and following 3 months recovery with nasal breathing (90 days, adult). ResultsDiaphragm muscle showed significant increases in adult isoforms (MHC 1, 2a) in oral breathing group versus control. We observed increases in MHC neonatal and adult type 1 isoforms in muscles involved with oral breathing, masseter superficialis and anterior digastric. No changes were observed in the levator nasolabialis muscle involved with nasal breathing. Reversible nasal obstruction was associated with reduced growth of the olfactory bulbs lasting into adulthood, and an initial decrease in lung growth followed by recovery at 90 days. Adrenal hypertrophy was observed after 1 day of nasal obstruction and lasted into adulthood. The “stress” hormone response was variable, increased (over 1000%) during the obstruction but normal by adulthood. An increase in plasma testosterone was observed during the obstruction, and a decrease in thyroid hormone levels throughout. ConclusionsVery short term nasal obstruction, i.e. forced oral breathing, leads to long term hormonal changes and respiratory muscle fibre adaptation.

Effects of chronic immobilization stress on anxiety-like behavior and basolateral amygdala morphology in Fmr1 knockout mice

Several lines of clinical evidence support the idea that fragile X syndrome (FXS) may involve a dysregulation of hypothalamic-pituitary-adrenal axis function [Wisbeck et al. (2000) J Dev Behav Pediatr 21:278-282; Hessl et al. (2002) Psychoneuroendocrinology 27:855-872]. We had tested this idea in a mouse model of FXS (Fmr1 KO) and found that the hormonal response to acute stress was similar to that of wild-type (WT) mice [Qin and Smith (2008) Psychoneuroendocrinology 33:883-889]. We report here responses to chronic stress (CS) in Fmr1 KO mice. Following restraint for 120 min/d, 10 consecutive days, we assessed dendrite and spine morphology in basolateral amygdala (BLA). We also monitored behavior in an elevated plus maze (EPM) and the hormonal response to this novel spatial environment. After CS, mice of both genotypes underwent adrenal hypertrophy, but effects were greater in WT mice. Behavior in the EPM indicated that only WT mice had the expected increase in anxiety following CS. Serum corticosterone and adrenocorticotropic hormone (ACTH) levels were both increased following the spatial novelty of EPM, and there were no differences between genotypes in the hormonal responses. BLA dendritic branching increased proximal to the soma in WT, but in Fmr1 KO mice branching was unaffected close to the soma and slightly decreased at one point distal to the soma. Similarly, spine density on apical and basal dendrites increased in WT but decreased in Fmr1 KO mice. Spine length on apical and basal dendrites increased in WT but was unaffected in Fmr1 KO mice. These differences in behavioral response and effects on neuron morphology in BLA suggest a diminished adaptive response of Fmr1 KO mice.

5-HT 1B mRNA expression after chronic social stress

Chronic stress contributes to vulnerability for depression and drug addiction. The function of the serotonergic system has been found to be modified by chronic stress and these changes may play an important role in stress-related relapses to drug craving. The 5-HT 1B receptor is expressed in nucleus accumbens (NAc) projection neurons and modulates drug reward mechanisms and there is evidence suggesting that stress alters the regulation and function of these receptors. To examine the role of these receptors in integrating the effects of stress on reward mechanisms, we examined whether chronic or acute social defeat stress (SDS) regulates 5-HT 1B mRNA in dorsal and ventral striatum, regions that are critical for integrating the effects of environmental stressors on reward motivated behavior. In addition, 5-HT 1B mRNA regulation in response to another acute stressor, inescapable tailshock, was measured. Our results indicate that intermittent and daily SDS procedures attenuated body weight gain, induced adrenal hypertrophy, and reduced the preference for saccharin, a sweet solution preferred by normal rats. There was a trend for daily, but not intermittent SDS to increase 5-HT 1B receptor mRNA levels in nucleus accumbens. Therefore, in the next experiment, we examined daily SDS in greater detail and found that it increased 5-HT 1B receptor mRNA expression in rostral nucleus accumbens shell, an area especially associated with reward functions. Neither acute SDS, nor acute tailshock stress had a significant impact on 5-HT 1B mRNA expression in the striatum. Since increased 5-HT 1B receptor expression in nucleus accumbens shell neurons can facilitate cocaine and alcohol reward mechanisms, this adaptation in endogenous 5-HT 1B mRNA may be involved in the SDS-associated increase in vulnerability for developing addiction.

Primary bilateral adrenal lymphoma revealed by hemophagocytic syndrome

Primary adrenal lymphoma is rare. It is often bilateral and in most of the cases of B-cell type. The clinical features are various and not specific. We report a case of a 69-year-old woman who had a diffuse large B-cell lymphoma associated with hemophagocytic syndrome. The abdominal imaging reveals the existence of bilateral adrenal hypertrophy. A CT scan-guided biopsy concluded to a diffuse large B-cell lymphoma CD 20-positive associated EBV. The treatment consisted on “CHOP like” chemotherapy associated with rituximab. Primary adrenal lymphoma has a poor prognosis, even more poorly if associated with hemophagocytic syndrome.

Some effects of experimentally-produced cigarette smoke on the growth, vitamin C metabolism and organ weights of guinea-pigs.

Abstract Guinea-pigs receiving a controlled dietary intake of L-xyloascorbic acid (ascorbic acid, vitamin C) inhaled experimentally produced cigarette smoke for periods of up to 20 min each day. Growth rate was significantly depressed by the smoke treatment, an effect at least in part attributable to a reduction in food intake. Growth of individual organs was not depressed to the same extent as that of the body as a whole. The lungs of the animals receiving smoke were significantly heavier than those of control animals (P < 0·05). The concentration of ascorbic acid in the adrenal glands was significantly lower in the animals receiving smoke than in the controls (P < 0·01). The smoke-induced depression of the adrenal gland ascorbic acid was apparent after 4 days; after 18 days marked adrenal hypertrophy accompanied the lowered ascorbic acid levels.

Adaptogenic potential of curcumin in experimental chronic stress and chronic unpredictable stress-induced memory deficits and alterations in functional homeostasis

The present study was designed to investigate the role of curcumin in chronic stress and chronic unpredictable stress-induced memory deficits and alteration of functional homeostasis in mice. Chronic stress was induced by immobilizing the animal for 2h daily for 10days, whereas chronic unpredictable stress was induced by employing a battery of stressors of variable magnitude and time for 10days. Curcumin was administered to drug-treated mice prior to induction of stress. Body weight, adrenal gland weight, ulcer index and biochemical levels of glucose, creatine kinase, cholesterol, corticosterone, thiobarbituric acid reactive substances (TBARS) and reduced glutathione (GSH) were evaluated to assess stress-induced functional changes. Memory deficits were evaluated using the elevated plus maze (EPM) model. Chronic stress and chronic unpredictable stress significantly increased the levels of corticosterone, glucose and creatine kinase and decreased cholesterol levels. Moreover, chronic stress and chronic unpredictable stress resulted in severe memory deficits along with adrenal hypertrophy, weight loss and gastric ulceration. Chronic stress and chronic unpredictable stress also increased oxidative stress assessed in terms of increase in TBARS and decrease in GSH levels. Pretreatment with curcumin (25 and 50mg/kg p.o.) attenuated chronic stress and chronic unpredictable stress-associated memory deficits, biochemical alterations, pathological outcomes and oxidative stress. It may be concluded that curcumin-mediated antioxidant actions and decrease in corticosterone secretion are responsible for its adaptogenic and memory restorative actions in chronic and chronic unpredictable stress.

Phenotypic profiling of parents with cryptic nonclassic congenital adrenal hyperplasia: findings in 145 unrelated families

To comprehensively phenotype parents identified with nonclassic congenital adrenal hyperplasia (NCCAH) by family genetic studies, termed here as cryptic NCCAH and to define the incidence of cryptic NCCAH in the parents of a large cohort of patients with 21-hydroxylase deficiency. Genotyping was performed on 249 parents of 145 unrelated congenital adrenal hyperplasia (CAH) patients. Parents with two CYP21A2 mutations underwent extensive evaluation. Of the 249 parents, ten (4%; seven females and three males) were identified as having cryptic NCCAH. The majority was of ethnicities previously reported to have a higher incidence of NCCAH. Cosyntropin stimulation performed in eight parents provided biochemical confirmation (17-hydroxyprogesterone range 56-364 nmol/l) and cortisol response was ≤500 nmol/l in three parents (38%). Of the seven women (27-54 years) with cryptic NCCAH, four had prior infertility, two reported irregular menses, two had treatment for hirsutism, one had androgenic alopecia. Men were asymptomatic. All cryptic NCCAH parents reported normal puberty and had normal height. Adrenal hypertrophy and a small adrenal myelolipoma were observed in two parents; testicular adrenal rest tissue was not found. Parents diagnosed with NCCAH by genetic testing are mostly asymptomatic. Temporary female infertility and suboptimal cortisol response were commonly observed. Ongoing glucocorticoid therapy is not indicated in adults with CAH identified by family genotype studies unless symptomatic, but glucocorticoid stress coverage should be considered in select cases. Parents of a child with CAH have a 1:25 risk of having NCCAH; if the mother of a child with CAH has infertility, evaluation for NCCAH is indicated.

Chronic cardiac pressure overload induces adrenal medulla hypertrophy and increased catecholamine synthesis

Increased activity of the sympathetic system is an important feature contributing to the pathogenesis and progression of chronic heart failure. While the mechanisms and consequences of enhanced norepinephrine release from sympathetic nerves have been intensely studied, the role of the adrenal gland in the development of cardiac hypertrophy and progression of heart failure is less well known. Thus, the aim of the present study was to determine the effect of chronic cardiac pressure overload in mice on adrenal medulla structure and function. Cardiac hypertrophy was induced in wild-type mice by transverse aortic constriction (TAC) for 8weeks. After TAC, the degree of cardiac hypertrophy correlated significantly with adrenal weight and adrenal catecholamine storage. In the medulla, TAC caused an increase in chromaffin cell size but did not result in chromaffin cell proliferation. Ablation of chromaffin α(2C)-adrenoceptors did not affect adrenal weight or epinephrine synthesis. However, unilateral denervation of the adrenal gland completely prevented adrenal hypertrophy and increased catecholamine synthesis. Transcriptome analysis of microdissected adrenal medulla identified 483 up- and 231 downregulated, well-annotated genes after TAC. Among these genes, G protein-coupled receptor kinases 2 (Grk2) and 6 and phenylethanolamine N-methyltransferase (Pnmt) were significantly upregulated by TAC. In vitro, acetylcholine-induced Pnmt and Grk2 expression as well as enhanced epinephrine content was prevented by inhibition of nicotinic acetylcholine receptors and Ca(2+)/calmodulin-dependent signaling. Thus, activation of preganglionic sympathetic nerves innervating the adrenal medulla plays an essential role in inducing adrenal hypertrophy, enhanced catecholamine synthesis and induction of Grk2 expression after cardiac pressure overload.

Augmentation of immune response by chicoric acid through the modulation of CD28/CTLA-4 and Th1 pathway in chronically stressed mice

This study demonstrates the protective effect of chicoric acid (CA) on chronic restraint stress-induced altered T lymphocyte subset distribution and corresponding cytokine secretion patterns in experimental Swiss albino mice. CA has the potential to restore diminished immune response and Th1/Th2 homeostasis in chronically stressed mice as evident by significant increase in lymphocyte proliferation and CD3 +, CD4 + and CD8 + T cell population. Interestingly, chicoric acid imparted immunostimulation mainly by upregulating the expression of CD28 and CD80 and downregulating CTLA-4. It exerted stimulatory effect on IL-12, IFN-gamma and IL-2 and suppressed the increased IL-10 levels in chronically stressed mice. It also exhibited a significant lowering effect on raised corticosterone levels and reversed the chronic stress-induced hypertrophy of adrenal glands and atrophy of thymus and spleen, thereby showing its normalizing effect on HPA axis. Our results reveal that CA has the potential to reverse the impact of chronic restraint stress on immune status by normalizing corticosterone levels and augmenting Th1 cytokine profile along with the co-stimulatory molecules particularly CD28/CTLA-4 pathway that plays a very important role in generation of an effective immune response in immune compromised situations.

Effect of Pueraria tuberosa on Cold Immobilization Stress Induced Changes in Plasma Corticosterone and Brain Monoamines in Rats

The study was carried out to establish the anti-stress effect of Pueraria tuberosa in relation to the levels of plasma corticosterone and norepinephrine (NE), dopamine (DA) and 5-hydroxytryptamine (5-HT) in whole brain and hypothalamus and compared with Withania somnifera (adaptogen). Adult male Wistar rats pretreated with 70% hydroethanolic extract of P. tuberosa tuber root (PTE) at the doses of 50, 100, 200 and 400 mg/kg, for 5 consecutive days. W. somnifera rhizome extract (WSE) at 100 mg/kg was used as reference drug. The rats were subjected to cold immobilization stress (IS) for 2 h. Thereafter, the animals were sacrificed and ulcer formation in gastric mucosa was noted. Weights of adrenals and spleens were also taken. Further, plasma corticosterone levels were estimated by spectrophotoflurometrically. Simultaneously, brain monoamines like, NE, DA and 5-HT were determined in whole brain and hypothalamus region HPLC electrochemical detector. IS for 2 h damaged the gastric mucosal layers, enhanced plasma corticosterone levels and increase adrenal glands and spleen weight. Further, IS elevated NE, DA and 5-HT levels both in whole brain and hypothalamus. PTE significantly protected the gastric mucosa, lowered corticosterone level in blood and negated the hypertrophy of adrenals and spleen. PTE (200 and 400 mg/kg) and WSE (100 mg/kg) significantly decreased IS elevated NE, DA and 5-HT both in whole brain and hypothalamus. These data suggest that anti-stress effect of Pueraria tuberosa may be modulated by monoaminergic system.

The Brain Renin-Angiotensin System Controls Divergent Efferent Mechanisms to Regulate Fluid and Energy Balance

The renin-angiotensin system (RAS), in addition to its endocrine functions, plays a role within individual tissues such as the brain. The brain RAS is thought to control blood pressure through effects on fluid intake, vasopressin release, and sympathetic nerve activity (SNA), and may regulate metabolism through mechanisms which remain undefined. We used a double-transgenic mouse model that exhibits brain-specific RAS activity to examine mechanisms contributing to fluid and energy homeostasis. The mice exhibit high fluid turnover through increased adrenal steroids, which is corrected by adrenalectomy and attenuated by mineralocorticoid receptor blockade. They are also hyperphagic but lean because of a marked increase in body temperature and metabolic rate, mediated by increased SNA and suppression of the circulating RAS. β-adrenergic blockade or restoration of circulating angiotensin-II, but not adrenalectomy, normalized metabolic rate. Our data point to contrasting mechanisms by which the brain RAS regulates fluid intake and energy expenditure.

Successful application of technetium-99m-labeled octreotide acetate scintigraphy in the detection of ectopic adrenocorticotropin-producing bronchial carcinoid lung tumor: a case report

IntroductionThe diagnostic efficacy of somatostatin receptor scintigraphy labeling with 111 indium in the localization of tumors has been assessed in a limited number of patients with contradictory outcomes. Here, we describe the case of a patient with an ectopic adrenocorticotropic hormone-producing bronchial carcinoid tumor diagnosed preoperatively using technetium-99m-labeled octreotide acetate scintigraphy.Case presentationA 29-year-old Asian man presented to our hospital with the typical clinical features of Cushing's syndrome, which he had had for a duration of 18 months. The results of a biochemical evaluation revealed he had adrenocorticotropic hormone-dependent Cushing's syndrome. The results of a spiral abdominal computed tomography scan showed he had bilateral adrenal hypertrophy. A magnetic resonance image of the patient's brain showed he had a normal hypophysis. Whole body technetium-99m-labeled octreotide acetate scintigraphy was performed to check for the presence of an ectopic adrenocorticotropic hormone-producing tumor. The scan results showed a small focal increase in uptake in the lower lobe of our patient's right lung, just above his diaphragm. A spiral chest computed tomography scan also revealed a small non-specific lesion in the same region. A transthoracic biopsy was then performed. Pathological evaluation confirmed the diagnosis of a carcinoid tumor, of the adrenocorticotropic hormone-producing type. After surgical removal, the patient's symptoms resolved and significant clinical improvement was achieved.ConclusionsThis case report shows that technetium-99m-labeled octreotide acetate scintigraphy can effectively detect an ectopic adrenocorticotropic hormone-producing bronchial carcinoid.

Exercise Protects The Heart Against Arrhythmias Induced By Thiol Oxidation

The ability of exercise to confer resistance against cardiac ischemia/reperfusion injury is well known, although the mechanisms underlying exercise-induced cardioprotection have not been fully characterized. Previous work by our group has shown that oxidizing myocardial thiols can induce ventricular arrhythmias by overwhelming mitochondrial anti-oxidant defenses, collapsing mitochondrial membrane potential, and activating energy-sensitive potassium channels in the sarcolemma. PURPOSE: The following study was conducted to see if prior exercise could attenuate the extent of electrical dysfunction in hearts receiving the thiol-oxidant diamide. METHODS: Female Sprague-Dawley rats (3-4 months old) were placed in two groups: sedentary (Sed; n=10) or exercise (Ex; n=8). Animals in the Ex group were run for 10 consecutive days on a motorized treadmill, and Sed counterparts were placed on the non-moving treadmill each day as handling controls. Each exercise bout consisted of 15/30/15 minutes at a treadmill speed of 15/30/15 meters per minute (10% incline). Twenty-four hours after the last exercise bout hearts were excised and placed on a modified Langendorff apparatus for continuous monitoring of volume-conducted electrocardiogram, left ventricular function, and coronary flow. Following a 15 minute baseline period, hearts were switched to a buffer containing 200 μM diamide for 35 minutes, followed by a 25 minute washout period. RESULTS: The training protocol did not elicit markers of systemic stress such as adrenal hypertrophy (adrenal weights were 38 ± 3 and 39 ± 2 mg for Sed and Ex, respectively; P > 0.05) or splenic atrophy (spleen weights were 573 ± 27 and 624 ± 32 mg for Sed and Ex, respectively; P > 0.05). Exercise protected hearts against arrhythmias induced by diamide, as evidenced by: 1) lower incidence of non-reverting ventricular arrhythmia (70% of Sed hearts and 38% of Ex hearts experienced non-reverting arrhythmia), and 2) delayed time to non-reverting arrhythmia (12 ± 3 min and 20 ± 3 min in Sed and Ex, respectively; P < 0.05). Arrhythmia scores were significantly lower in the Ex group (5.8 ± 0.5) compared to Sed (7.2 ± 0.5; P < 0.05). Coronary flow rates during diamide washout were not different between the Sed (7.7 ± 1.1 mL/min*g heart wt) and Ex (8.4 ± 1.8 mL/min*g heart wt) groups (P > 0.05). CONCLUSIONS: Our results show that exercise training protects the heart from arrhythmias when challenged with an oxidizing agent, supporting the hypothesis that exercise-induced protection against arrhythmias involves maintenance of bioenergetics secondary to heightened oxidant buffering capacity.

Effect of high-fat diet on stress responsiveness in borderline hypertensive rats

Stress in combination with genetic susceptibility is a factor in the development of hypertension. We used borderline hypertensive rats to investigate whether exposure to high-fat and/or junk-food diet at different stages of ontogeny has programing consequences on stress responses. Wistar dams were fed a high- or low-fat diet for 6 weeks prior to mating with spontaneously hypertensive males, and during gestation. At birth, litters were fostered either to a dam in the same or an alternative diet condition as during gestation. After weaning, male offspring were fed either a control-chow diet or an intermittent junk food fatty diet. Between postnatal days 57–61, half of the rats in each dietary group received daily social defeat sessions using a resident-intruder protocol, and the other half were unstressed controls. Blood pressure was measured indirectly both before and after each defeat session. On the final day, rats were killed for physiological measures. Socially defeated rats showed large increases in serum corticosterone concentration and adrenal hypertrophy, indicating the effectiveness of this non-adapting stressor. Serum corticosterone level was also higher in rats fed with the junk-food diet post-weaning compared with those fed with chow only, but there were no significant effects of gestational or lactational dietary history.

Functional role of Calcium-stimulated adenylyl cyclase 8 in adaptations to psychological stressors in the mouse: implications for mood disorders

The Ca2+/calmodulin stimulated adenylyl cylcase 8 (AC8) is a pure Ca2+ sensor, catalyzing the conversion of ATP to cAMP, with a critical role in neuronal plasticity. A role for AC8 in modulating complex behavioral outcomes has been demonstrated in AC8 knock out (KO) mouse models in which anxiety-like responses were differentially modulated following repeated stress experiences, suggesting an involvement of AC8 in stress adaptation and mood disorders. To further investigate the role of this enzyme in phenotypes relevant for psychiatric conditions, AC8 KO mice were assessed for baseline behavioral and hormonal parameters, responses to repeated restraint stress experience, and long-term effects of chronic social defeat stress. The lack of AC8 conferred a hyperactive-phenotype both in home-cage behaviors and the forced swim test response as well as lower leptin plasma levels and adrenal hypertrophy. AC8 KO mice showed baseline “anxiety” levels similar to wild type littermates in a variety of procedures, but displayed decreased anxiety-like responses following repeated restraint stress. This increased stress resilience was not seen during the chronic social defeat procedure. AC8 KO did not differ from wild type mice in response to social stress; similar alterations in body weight, food intake and increased social avoidance were found in all defeated subjects. Altogether these results support a complex role of cAMP signaling pathways confirming the involvement of AC8 in the modulation of stress responses. Furthermore, the hyperactivity and the increased risk taking behavior observed in AC8 KO mice could be related to a manic-like behavioral phenotype that warrants further investigation.

Differential response of A 68930 and sulpiride in stress-induced gastric ulcers in rats

Dopamine is linked to gastrointestinal functions. However, its exact nature in stress-induced gastric pathology is still not clear. In the present study, an attempt has been made to identify the effects of dopamine in stress-induced gastric ulcers, and concurrent alterations in various ulcer-influencing factors such as plasma corticosterone levels, gastric mucosal PGE 2 content and proton pump activity. The dopamine D 1 receptor agonist (A 68930) and antagonist (SCH 23390), and D 2 receptor agonist (quinpirole) and antagonist (sulpiride) were used to evaluate their effects on acute stress (single immobilization for 150 min) and chronic unpredictable stress (two different types of stressors for 7 days) induced gastric ulcers in rats. Acute and chronic unpredictable stress significantly increased the gastric ulcer severity, adrenal hypertrophy and corticosterone levels, while gastric mucosal dopamine levels were decreased. Pretreatment of sulpiride (60 mg/kg) significantly reverted the acute stress-induced alterations, while A 68930 (0.25 mg/kg) significantly restored the acute and chronic unpredictable stress-induced alterations. In contrast, administration of SCH 23390 (0.1–0.5 mg/kg) and quinpirole (0.1–0.5 mg/kg) failed to alter acute stress-induced alterations. Further, A 68930 and sulpiride showed different response on proton pump inhibition under in-vitro condition. A 68930 (10–50 μg/ml) inhibited the gastric H + K +-ATPase activity comparable to positive control omeprazole, while sulpiride (10–50 μg/ml) had no effect. A 68930 also normalized the decreased gastric PGE2 content observed during chronic unpredictable stress. The histopathological evaluation of gastric mucosal tissue supported the observations regarding the gastroprotective effect of sulpiride during acute stress and of A 68930 during both acute and chronic unpredictable stress conditions. Our results provide important insights into the mechanism of dopamine-regulated pathways, which cause an overall pathophysiology of gastric stress ulcers and implicating the importance of D 1 agonist in ulcer protection. Thus, current study highlights the need to evaluate anti-stress and anti-ulcer agents in terms of their ability to modulate dopaminergic transmissions.

How should the psychological well‐being of zoo elephants be objectively investigated?

Animal welfare (sometimes termed "well-being") is about feelings - states such as "suffering" or "contentment" that we can infer but cannot measure directly. Welfare indices have been developed from two main sources: studies of suffering humans, and of research animals deliberately subjected to challenges known to affect emotional state. We briefly review the resulting indices here, and discuss how well they are understood for elephants, since objective welfare assessment should play a central role in evidence-based elephant management. We cover behavioral and cognitive responses (approach/avoidance; intention, redirected and displacement activities; vigilance/startle; warning signals; cognitive biases, apathy and depression-like changes; stereotypic behavior); physiological responses (sympathetic responses; corticosteroid output - often assayed non-invasively via urine, feces or even hair; other aspects of HPA function, e.g. adrenal hypertrophy); and the potential negative effects of prolonged stress on reproduction (e.g. reduced gametogenesis; low libido; elevated still-birth rates; poor maternal care) and health (e.g. poor wound-healing; enhanced disease rates; shortened lifespans). The best validated, most used welfare indices for elephants are corticosteroid outputs and stereotypic behavior. Indices suggested as valid, partially validated, and/or validated but not yet applied within zoos include: measures of preference/avoidance; displacement movements; vocal/postural signals of affective (emotional) state; startle/vigilance; apathy; salivary and urinary epinephrine; female acyclity; infant mortality rates; skin/foot infections; cardio-vascular disease; and premature adult death. Potentially useful indices that have not yet attracted any validation work in elephants include: operant responding and place preference tests; intention and vacuum movements; fear/stress pheromone release; cognitive biases; heart rate, pupil dilation and blood pressure; corticosteroid assay from hair, especially tail-hairs (to access endocrine events up to a year ago); adrenal hypertrophy; male infertility; prolactinemia; and immunological changes.