Novel in vitro perfusion system for the determination of hypothalamic-pituitary-adrenal axis responses

Introduction: The hypothalamic-pituitary-adrenal (HPA) axis is a three-gland component of the endocrine system and a key modulator of the stress response. We have developed a novel in vitro perfusion system to enable the study of pharmacological and hormonal challenges to tissue components of the HPA axis. In vivo studies have shown functional sex differences (sexual diergism) in HPA responses to cholinergic drugs, and in the present in vitro study, we examine these differences at several levels of the HPA axis. Methods: Hypothalami, pituitaries, and adrenal glands were collected from male and female rats (n=3 per sex). One-half hypothalamus, one-half pituitary, and one adrenal gland were placed individually into three Erlenmeyer flasks connected by tubing. Flasks were perfused with medium (pH 7.4) at 37 degrees C. Sampling ports between the flasks were used to collect buffer for determination of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and corticosterone (CORT) release from the hypothalamus, pituitary, and adrenal flasks, respectively, over an extended baseline period, to determine stability of the system, and after nicotine administration. Results: The perfusion system produced steady CRH, ACTH, and CORT baselines, the ACTH and CORT values being comparable to in vivo basal ACTH and CORT values in jugular-vein-cannulated rats. In vitro CRH, ACTH, and CORT responses to nicotine were significantly increased at 10 min and returned to baseline by 30 min, the CRH and ACTH responses from female tissues being greater than responses from male tissues. These sex differences were similar to those following nicotine administration in vivo. Discussion: The ability of this novel, dynamic in vitro system to replicate in vivo HPA axis responses supports its potential as a new method for pharmacological and toxicological studies.     

六味地黄汤及其拆方对快速老化小鼠免疫功能的调节作用

目的比较六味地黄汤全方（LW）及其拆方三补（地黄、山茱萸、山药）和三泻（茯苓、泽泻、牡丹皮）对快速老化小鼠（SAM）免疫功能的调节作用。方法分别灌胃给予SAM亚系小鼠（SAMP8）LW（10g/kg）、三补（6.4g/kg）和三泻（3.6g/kg）,每日1次,连续60d;抗快速老化亚系小鼠（SAMR1）作为对照。采用3H-TdR掺入法检测脾脏淋巴细胞增殖能力,流式细胞术观察脾脏CD3＋、CD4＋、CD8＋、CD19＋淋巴细胞百分率。结果与SAMR1组相比,SAMP8组经刀豆蛋白A（ConA）和脂多糖（LPS）诱导的脾细胞增殖能力、脾脏CD3＋、CD4＋细胞百分率、CD3＋/CD19＋和CD4＋/CD8＋比值均显著下降,而CD19＋细胞百分率显著上升;灌胃给予LW全方及折方对上述指标具有不同程度的改善作用,其中,LW对LPS诱导的脾细胞增殖能力、CD3＋和CD19＋细胞百分率、CD3＋/CD19＋比值、CD4＋细胞百分率及CD4＋/CD8＋比值的改善作用优于三补和三泻;三补对升高ConA诱导的脾细胞增殖能力优于LW和三泻,对脾脏CD3＋和CD19＋细胞百分率、CD3＋/CD19＋细胞比值及CD4＋细胞百分率的改善作用优于三泻;三泻升高CD4＋/CD8＋比值的作用优于三补。结论 LW可显著改善SAMP8低下的T、B淋巴细胞功能,纠正脾脏CD4＋/CD8＋T细胞亚群比例失衡,其作用优于单独应用三补和三泻;三补和三泻对SAMP8的免疫改善作用各有侧重,三补的作用可能在于调节T、B淋巴细胞的数量和功能,三泻则可能着重于调节T细胞亚群的比例。本研究提示LW对免疫功能的调节是三补和三泻相互协调综合作用的结果 ,该结果为揭示LW配伍规律及其科学内涵提供了一定的实验依据。     

Adrenocorticotropin (ACTH) and corticosterone secretion by perifused pituitary and adrenal glands from rodents exposed to 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD)

Although in utero maternal stress has been shown to have lasting effects on rodent offspring, fetal effects of chemically-induced alterations of the maternal hypothalamic-pituitary-adrenal axis (HPA) have not been well studied. This study examined the effects of in vivo 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure on pituitary-adrenal function in the male rat, pregnant female rat and pregnant female mouse. The secretion of adrenocorticotropin (ACTH) and corticosterone (CORT) in pituitary and adrenal glands, respectively, was assessed in ex vivo perifusion cultures. Male and pregnant female (gestation day 8) Sprague-Dawley rats were gavaged once with 10 microgram/kg TCDD, pregnant female mice once with 24 microgram/kg TCDD, and euthanized 10 days later. Hemi-pituitary (rat) or whole anterior pituitaries (mice) and right adrenal glands from the same animal were quartered, perifused under baseline and stimulated conditions. In both males and pregnant females, TCDD did not affect corticotropin releasing hormone (CRH)-stimulated ACTH secretion. Neither total pituitary ACTH nor plasma ACTH was altered in either sex or species by TCDD treatment. ACTH-stimulated CORT secretion was not affected by TCDD in either sex or species, and adrenal tissue and plasma CORT levels were unchanged in males and pregnant females by TCDD. However, the plasma ACTH:CORT ratio was decreased about 46% in male rats treated with TCDD. Plasma CORT levels were 23-fold higher and plasma ACTH levels were 1.5-fold higher in pregnant females than in male rats. In male versus female rats, adrenal CORT and anterior pituitary ACTH tissue levels were about 7.5- and 1.75-fold higher and ACTH, respectively. Female mouse adrenal tissue CORT was about 4-fold greater than female rat. The reduced plasma ACTH:CORT ratio in the male rat suggests that TCDD disturbs HPA function. Exposure of male rat to a 5-fold higher dose in earlier studies clearly demonstrated effects of TCDD on male rat HPA. The present study identified substantial HPA performance differences between male and pregnant female rats. The failure to detect a response to TCDD in pregnant female rat and mouse could be a function of both TCDD dose and the high level of secretion of both ACTH and CORT in pregnant animals. For the rat or mouse, a single exposure to TCDD during pregnancy does not appear sufficient to induce maternally-mediated developmental, reproductive and behavioral toxicity via the HPA axis.     

Effects of perinatal oxycodone exposure on the response to CRH in late adolescent rats

We hypothesized that prenatal oxycodone exposure suppresses the Hypothalamic–Pituitary–Adrenal (HPA) response to stress in late adolescence. Dark Agouti rats were given either intravenous oxycodone or vehicle (controls, CON) daily from gestation day 8 until postnatal day (PD) 5. At PD 45, the male and female offspring received intravenously either ovine corticotropin releasing hormone (CRH) or saline. Plasma adrenocorticotropic hormone (ACTH) and corticosterone (CORT) levels were determined before, and 15, 30, and 60 min after injection. Prenatal oxycodone had no effect on baseline ACTH values; CRH elicited a greater ACTH response than saline. In males, prenatal oxycodone delayed and enhanced the peak ACTH response to CRH, but had no effect in females. The CORT response to CRH was not different between oxycodone and CON; however mean CORT levels in females were significantly higher than those in males at baseline and after stimulation. These results demonstrate that prenatal oxycodone increases pituitary response to CRH in late adolescent male rats, but not in females. The absence of an enhanced adrenal response in oxycodone-exposed males suggests either desensitization or maximal adrenal response to a high CRH dose. The mechanisms of postnatal sex-specific HPA dysregulation following prenatal oxycodone remain to be elucidated.     

P物质对哮喘大鼠神经内分泌功能的调节

目的探讨哮喘大鼠脑内P物质在哮喘发作中的作用。方法以大鼠腹腔注射含百日咳和氢氧化铝的卵蛋白溶液制备哮喘动物模型,免疫组织化学方法(SABC)检测哮喘大鼠脑内c-fos蛋白,放射免疫法检测下丘脑室旁核(para-ventricular nucleus,PVN)内P物质(substance P,SP)的含量及正中隆起(ME)中促肾上腺皮质激素释放激素(cortico-tropin-releasing hormone,CRH)和外周血中促肾上腺皮质激素(adrenocorticotropic hormone,ACTH)、皮质酮(corticoster-one,CORT)含量,PVN内分别微量注射外源性SP、SP受体拮抗剂S0145,观察其对哮喘大鼠肺功能与下丘脑-垂体-肾上腺皮质功能轴(hypothalamus-pituitary-adrenal axis,HPA轴)活动的影响。结果哮喘大鼠发作时PVN内SP含量升高;正中隆起CRH与外周血中ACTH、CORT含量均降低(P<0.05),呼/吸时程比和气道阻力增加,膈肌放电积分、肺顺应性减小(P<0.01)。PVN内微量注射SP后哮喘大鼠的肺通气功能进一步下降,CORT、ACTH、CRH含量进一步降低(P<0.01)。SP受体阻断剂S0145则可逆转哮喘发生时大鼠肺功能与HPA轴的改变。结论哮喘大鼠下丘脑室旁核内SP可影响HPA轴的功能,参与哮喘发作。     

高脂饲料加STZ联合诱导的大鼠糖尿病模型HPA轴功能变化与糖脂代谢的关系

目的研究高脂饲料加小剂量STZ联合诱导的糖尿病大鼠HPA轴功能变化与糖脂代谢的关系。方法采用长期高脂饲料加STZ(30mg·kg-1ip)联合诱导的糖尿病模型,将其分为4组,即正常对照组、模型组、地黄寡糖(ROS)组和二甲双胍组,ROS组灌胃地黄寡糖(200mg·kg-1.d-1),二甲双胍组灌胃盐酸二甲双胍(200mg·kg-1.d-1);每周测定1次大鼠血糖和体重,给药4wk后收集24h尿液并断头处死,测定血浆中血脂(TC、TG、HDL-C)、胰岛素、CRH、ACTH、皮质酮及下丘脑中CRH、垂体中ACTH、24h尿液中尿糖及皮质酮(CORT)含量。结果与正常对照组相比,模型组血糖、尿糖、TC、TG均明显升高,肝糖原、HDL-C含量下降,地黄寡糖能逆转这些改变。同时模型与正常对照组相比,胰岛素和下丘脑中CRH下降明显,血浆中ACTH、CORT及垂体中ACTH、24h尿液中CORT总量都有所升高,ROS对其有一定的改善作用。结论高脂饲料加STZ诱导的糖尿病模型糖脂代谢紊乱可能与HPA的活性升高有关,中药地黄寡糖的降血糖作用可能与改善HPA功能有一定关系。     

六味地黄汤对快速老化小鼠海马差异表达基因的影响

目的研究六味地黄汤(LW)对快速老化小鼠(senescenceacceleratedmouse,SAM)海马差异表达基因的影响,揭示LW增强认知功能的分子作用机制。方法应用快速老化小鼠亚系SAMP8和SAMR1海马差异表达cDNA芯片,比较SAMP8和SAMR1、SAMP8阴性对照和SAMR1阳性对照、石衫碱甲处理的SAMP8和SAMP8阴性对照以及LW处理的SAMP8和SAMP8阴性对照8个基因表达谱,并对LW的药物效应基因进行比较。结果给予SAMP8LW后,基因DUSP12、NSF、STUB1、CAMKⅡα、AMFR、UQCRFS1和11个新基因的表达出现显著差异,这些基因涉及蛋白酪氨酸磷酸酶家族、苏氨酸/丝氨酸蛋白激酶家族、泛素连接酶和线粒体功能等,LW对SAMP8海马的基因表达具有明显的调控作用。结论提示LW作用于认知功能也许是通过维持正常的细胞增殖和分化、保护正常的突触传递、调节Ca2+信号转导、改善线粒体的功能等途径实现的,基因DUSP12、NSF、STUB1、CAMKⅡα、AMFR、UQCRFS1和11个新基因可能是LW改善学习记忆功能的潜在作用靶标。     

Fluvoxamine reduces responsiveness of HPA axis in adult female BPD patients with a history of sustained childhood abuse.

The aim of the study is to test whether fluvoxamine affects the function of the hypothalamic pituitary adrenal (HPA) axis in female borderline (borderline personality disorder, BPD) patients with and without a history of sustained childhood abuse. Special attention is given to the presence of comorbid major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). The HPA axis of 30 female BPD patients with (n = 17) and without (n = 13) a history of sustained childhood abuse was challenged with a combined dexamethasone and corticotropin releasing hormone test (DEX/CRH test) before and after 6 (n = 14) and 12 (n = 16) weeks of fluvoxamine treatment (150 mg/day). Both 6- and 12-week fluvoxamine treatments were associated with a significant and robust reduction of the adrenocorticotrophic hormone (ACTH) and cortisol response to the DEX/CRH test. The magnitude of the reduction was dependent on the presence of sustained childhood abuse, but not on the presence of comorbid MDD or PTSD: patients with a history of sustained childhood abuse showed the strongest reduction in ACTH and cortisol. In conclusion, Fluvoxamine treatment reduces the hyperresponsiveness of the HPA axis in BPD patients with a history of sustained childhood abuse. This effect is likely to be obtained in the first 6 weeks of treatment.     

Orcinol glucoside produces antidepressant effects by blocking the behavioural and neuronal deficits caused by chronic stress

This study focused on the antidepressant potential of orcinol glucoside (OG) and its possible mechanisms of action. We established a depressed rat model using 3 consecutive weeks of chronic unpredictable mild stress (CUMS). The antidepressant-like effect of OG was revealed using the sucrose preference test, the open field test, the forced swimming test (FST), and the tail suspension test (TST). The activity of the hypothalamic–pituitary–adrenal (HPA) axis was evaluated by detecting the serum corticosterone (CORT) concentrations and mRNA expression of corticotrophin-releasing hormone (CRH) in the hypothalamus. The protein expression levels of brain-derived neurotrophic factor (BDNF) and total phosphorylated-ERK1/2 were detected by western blot. The results showed that OG treatment (1.5, 3, or 6 mg/kg) alleviated the depression-like behaviour of rats under CUMS, as indicated by the increased sucrose preference and the decreased immobility in both the FST and TST, although the rearing frequency in the open field test increased only in the group that received the lowest dose (1.5 mg/kg OG). Rats that received OG treatment exhibited reduced serum CORT levels and CRH mRNA expression in the hypothalamus, suggesting that the hyperactivity of the HPA axis in CUMS rats was reversed by OG treatment. Moreover, OG treatment upregulated the protein levels of BDNF and phosphorylated-ERK1/2 in the hippocampus, even above control levels. Our findings suggest that OG improved depressive behaviour in CUMS rats by downregulating HPA axis hyperactivity and increasing BDNF expression and ERK1/2 phosphorylation in the hippocampus.     

The age-related degeneration of oligodendrocytes in the hippocampus of the senescence-accelerated mouse (SAM) P8: a quantitative immunohistochemical study

The senescence-accelerated mouse (SAM) is known as a murine model for accelerated aging. The SAMP8 shows age-related deficits of learning and memory at an earlier age than control mice (SAMR1). We investigated the changes in oligodendrocytes in the brain of SAMP8, using immunohistochemistry for myelin basic protein (MBP) and 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP) as an oligodendrocyte marker. SAMP8 at 10 months old showed a decrease in MBP-immunoreactivity (IR) and CNP-IR in the hippocampal CA1 subfield, compared with SAMR1. There were no significant differences in MBP and CNP old in the cerebral cortex and the optic tract between SAMR1 and SAMP8 at 10 months. Furthermore, we measured the area of MBP-IR in the CA1 subfield of both strains and found that the area of MBP-IR in SAMP8 had decreased progressively with age, compared with SAMR1. These results suggest that age-related degeneration of oligodendrocytes had occurred in the hippocampus of SAMP8.     

Exercise-Associated Changes in the Corticosterone Response to Acute Restraint Stress: Evidence for Increased Adrenal Sensitivity and Reduced Corticosterone Response Duration

Exercise promotes stress resistance and is associated with reduced anxiety and reduced depression in both humans and in animal models. Despite the fact that dysfunction within the hypothalamic pituitary adrenal (HPA) axis is strongly linked to both anxiety and depressive disorders, the evidence is mixed as to how exercise alters the function of the HPA axis. Here we demonstrate that 4 weeks of voluntary wheel running was anxiolytic in C57BL/6J mice and resulted in a shorter time to peak corticosterone (CORT) and a more rapid decay of CORT following restraint stress. Wheel running was also associated with increased adrenal size and elevated CORT following systemic administration of adrenocorticotropic hormone. Finally, the HPA-axis response to peripheral or intracerebroventricular administration of dexamethasone did not suggest that wheel running increases HPA-axis negative feedback through GR-mediated mechanisms. Together these findings suggest that exercise may promote stress resilience in part by insuring a more rapid and shortened HPA response to a stressor thus affecting overall exposure to the potentially negative effects of more sustained HPA-axis activation.     

痛泻要方对肝郁脾虚型腹泻型肠易激综合征大鼠肠道高敏性的治疗作用

目的 研究痛泻要方对肝郁脾虚型腹泻型肠易激综合征(diarrhea predominant irritable bowel syndrome,D-IBS)大鼠肠道高敏性的治疗作用。方法 采用番泻叶灌服与慢性束缚建立肝郁脾虚型D-IBS大鼠模型,观察痛泻要方对肝郁脾虚型D-IBS大鼠HPA轴的相关指标促肾上腺皮质激素释放激素(corticotropin releasing hormone,CRH)、血浆促肾上腺皮质激素(adrenocorticotropic hormone,ACTH)、皮质醇(cortisol,CORT),结肠组织中p38 MAPK、MSK1磷酸化及cAMP反应原件结合蛋白(cyclic-AMP response binding protein,CREB)表达水平的影响。结果 痛泻要方可以降低肝郁脾虚型D-IBS大鼠CRH、ACTH、CORT含量,抑制结肠组织中p38MAPK,MSK1磷酸化及CREB蛋白的表达,尤以痛泻要方高剂量组最为显著(P<0.05或P<0.01)。结论 痛泻要方对番泻叶灌服与慢性束缚建立的肝郁脾虚型D-IBS大鼠肠道敏感性具有显著降低的作用,其机制可能与下调p38 MAPK、MSK1磷酸化和CREB蛋白的表达,抑制HPA轴亢进有关。     

Association of HPA axis genes with suicidal behaviour in schizophrenia

Family, adoption and twin studies show that genetics influences suicidal behaviour, but do not indicate specific susceptibility variants. Stress response is thought to be mediated by the corticotrophin-releasing hormone (CRH), which is known to be a regulator of the hypothalamic-pituitary-adrenal pathway (HPA). Alterations in HPA system have been related to impulsivity, aggression and suicidal behaviour, common feature in schizophrenia. CRH is the hypothalamic factor that stimulates the pituitary gland. To search for markers conferring genetic susceptibility to suicide, we typed six HPA axis genes (CRH, CRHR1, CRHR2, CRHBP, MC2R, NC3R1) in a cohort of 231 subjects with schizophrenia in which 81 attempted suicide. The genotype analyses yielded significant association between CRH binding protein (CRHBP) and suicide attempt (P = 0.035). The genotype analysis for quantitative measures of suicidal behaviour showed no association. The interaction analysis showed a significant interaction between CRH receptor type 1 (CRHR1) and CRH binding protein (CRHBP) in influencing suicide attempt and the severity of suicidal behaviour. Current results show that genetic variation in HPA axis genes could be associated with suicidal behaviour in schizophrenia. This is to our knowledge the first study on suicidal behaviour investigating the interaction among the HPA axis genes.     

Depression and alterations in hypothalamic–pituitary–adrenal and hypothalamic–pituitary–thyroid axis function in male abstinent methamphetamine abusers

The present study was to investigate depression and alterations in the hypothalamic–pituitary–adrenal (HPA) and hypothalamic–pituitary–thyroid (HPT) axis function in methamphetamine (METH) abusers after abstinence. Depression was assessed using the 13‐item Beck Depression Inventory (BDI‐13) scale; blood samples from in‐patients who were METH abusers and age‐matched and sex‐matched healthy controls were collected. The demographic characteristics and history of METH abuse also was assessed. We found that serum levels of adrenocorticotropic hormone (ACTH) and thyroxine were increased; and serum levels of cortisol, triiodothyronine, and thyroid‐stimulating hormone were decreased; and the BDI score was higher in METH abusers compared with control. In addition, there was no correlation between the BDI‐13 score and any of hormones of HPA and HPT axis was found. Particularly, we found abnormally higher ACTH level and mismatched with lower cortisol level in abstinent METH abusers. These results indicate that METH abusers and that their HPA and HPT functions are all altered after abstinence. Chronically using METH may destroy the regulatory function of the HPA axis, especially the feedback regulation of cortisol to ACTH. Copyright © 2013 John Wiley & Sons, Ltd.     

Multiple feedback mechanisms activating corticotropin-releasing hormone system in the brain during stress

Stress-associated disorders such as melancholic depression are characterized by persistent hypothalamic-pituitary-adrenocortical (HPA) axis activation and intensive anxiety. Corticotropin-releasing hormone (CRH) appears to play an essential role in pathophysiology of such disorders. In an attempt to elucidate possible mechanisms underlying persistent activation of CRH in the central nervous system (CNS), we examined responses of hypothalamic and extrahypothalamic CRH systems to the stressors (immobilization stress or psychological stress) and interactions between these CRH systems and glucocorticoids in rats. We propose multiple feedback loops activating central CRH system: (1) attenuation of glucocorticoid-induced negative feedback on the activity of the hypothalamic and brainstem nuclei during chronic stress, (2) autoregulation of CRH biosynthesis in the hypothalamic paraventricular nucleus (PVN) through up-regulation of Type-1 CRH receptor (CRHR-1), and (3) glucocorticoid-mediated positive effects on the amygdaloid CRH system. Stress initially activates the hypothalamic CRH system, resulting in the hypersecretion of glucocorticoids from the adrenal gland. In addition, the psychological component of the stressor stimulates the amygdaloid CRH system. In the chronic phase of stress, down-regulation of GR in the PVN and other brain structures such as the locus coeruleus (LC) fails to restrain hyperfunction of the HPA axis, and persistent activation of the HPA axis further up-regulates the amygdaloid CRH system. Thus, the hypothalamic and the amygdaloid CRH systems cooperatively constitute stress-responsive, anxiety-producing neurocircuitry during chronic stress, which is responsible for the clinical manifestations of stress-associated disorders. Effects of tricyclic antidepressants (TCAs), which appear to mitigate the above mentioned multiple feedback loop forming the vicious circle to activate central CRH systems, will also be discussed.     

苏郁胶囊对双侧嗅球损伤抑郁模型大鼠行为学及下丘脑-垂体-肾上腺轴的影响

目的：探讨苏郁胶囊对双侧嗅球损伤抑郁模型大鼠行为学及下丘脑-垂体-肾上腺（HPA）轴的影响。方法：48只雄性大鼠随机分为假手术组、模型组、苏郁胶囊高、中、低剂量组（22．8、11．4、5．7g／kg）及氯米帕明组（0．02g／kg）。应用双侧嗅球损伤复制大鼠抑郁模型,敞箱法及跳台法测定大鼠的行为学指标;放射免疫方法测定大鼠血浆促肾上腺皮质素释放激素（CRH）、促肾上腺皮质激素（ACTH）及皮质醇（CORT）的水平。结果：苏郁胶囊可不同程度降低双侧嗅球损伤大鼠敞箱实验的水平运动次数与垂直运动次数;增加双侧嗅球损伤大鼠跳台实验的潜伏期及减少错误次数;同时降低双例嗅球损伤大鼠血浆CRH、ACTH和CORT含量。结论：苏郁胶囊能逆转双侧嗅球损伤抑郁模型大鼠的行为异常,其可能与苏郁胶囊有效地拮抗HPA轴功能亢进相关。     

Evidence for arginine vasopressin as the primary activator of the HPA axis during adjuvant-induced arthritis.

1. Adjuvant-induced arthritis (AA) is an experimental inflammation of the joints that results in chronic activation of the hypothalamo-pituitary-adrenal (HPA) axis. 2. In this study the role of hypothalamic corticotrophin-releasing factor (CRF) and arginine vasopressin (AVP) in the regulation of the HPA axis in this condition both in Sprague-Dawley (SD), and Piebald-Viral-Glaxo (PVG) rats has been further characterized. 3. The increase in AVP peptide content of portal blood (as early as day 11), just prior to the onset of arthritis is confirmed and further increases, peaking at day 16 are shown, coincident with the progression of inflammation in the PVG rats. 4. The increase in AVP is associated with a significant increase in the expression of AVP but not CRF mRNAs in the medial parvocellular division of the hypothalamic paraventricular nucleus (PVN) of arthritic SD rats. 5. In the presence of maximal inflammation of SD rats there was a significant decrease in the maximum binding of [125I]-Tyr-oCRF to anterior pituitary membranes, whereas AVP receptor concentration in anterior pituitary membranes from both PVG and SD rats showed a significant increase with respect to controls. 6. The basal adrenocorticotrophin (ACTH) secretion in vitro was similar in both control and arthritic SD rats but that from arthritic PVG rat pituitaries was significantly greater than the respective controls (436 +/- 91 v 167 +/- 23 pg/tube). The ACTH response of pituitaries of arthritic PVG rats to CRF or the combination of CRF and AVP was significantly higher compared with the controls, although the ACTH response of arthritic SD rat pituitaries was unchanged. 7. The results are consistent with the view that activation of the parvocellular vasopressin system has an important role in the adaptation of the HPA axis to experimentally-induced chronic stress of arthritis.     

A preliminary study of dexamethasone treatment on pituitary–adrenal responsivity in major depression

Major depression is characterized by overactivity of the hypothalamic–pituitary–adrenal (HPA) axis. Dexamethasone (DEX), the glucocorticoid agonist, has been shown to be effective in the treatment of depression. We chose to examine the impact of a short course of DEX treatment on depressive symptomatology, and on the pituitary‐adrenal response to CRH administration. In this preliminary study, five subjects with major depression were treated for 4 days with 3 mg DEX; a CRH test was performed before and after treatment. Four subjects showed a reduction in ACTH (p=0·01) and cortisol output (p<0·01) following DEX treatment. All subjects showed a drop in depression scores after treatment; the Hamilton Depression score fell by 11·4±1·7 (mean±SEM) from baseline (p=0·01) and the Beck Depression score by 9·2±2·5 (mean±SEM) from baseline (p=0·01); this represented a reduction by almost 50 per cent from baseline levels on both depression indices. We suggest that the impact of DEX treatment on depressive symptoms may reflect a restraining influence on an overactive HPA, with a normalization of pituitary–adrenal response to CRH drive. Larger studies are required to investigate this further and to ascertain whether the mood and neuroendocrine changes induced by dexamethasone are sustained. Copyright © 1999 John Wiley & Sons, Ltd.     

Strain and sex alter effects of stress and nicotine on feeding, body weight, and HPA axis hormones

Gender and genotype result in differential sensitivity to stress and to nicotine. Male and female Sprague–Dawley and Long–Evans rats exhibit different behavioral responses to immobilization stress and to chronically-administered nicotine, suggesting that these animals may be useful to model human variability in stress and nicotine sensitivity. It is possible that differences in sensitivity of the hypothalamo–pituitary–adrenocortical (HPA) axis might account for these sex and strain differences. This experiment examined corticosterone (CORT) and adrenocorticotropin hormone (ACTH) responses of male and female Sprague–Dawley (n=117) and Long–Evans (n=120) rats administered 0, 6, or 12 mg/kg/day nicotine for 14 days; half of each treatment group was exposed to immobilization stress (20 min/day). Feeding and body weight also were measured. Nicotine increased CORT and ACTH levels of Sprague–Dawley females only. Stress increased CORT and ACTH levels of all groups except for Long–Evans females. Nicotine and stress decreased feeding and body weight with greatest effects in Long–Evans females. CORT, feeding, and body weight were positively correlated among stressed females. These findings suggest that strain differences in HPA axis, body weight, and feeding responses to nicotine and to stress are robust among females but not among males. CORT reactivity and female sex hormones may explain these differences.