柴胡疏肝散对肝气郁结证大鼠海马及下丘脑单胺类神经递质的影响

目的研究柴胡疏肝散对肝郁证大鼠行为学和大鼠海马及下丘脑单胺类神经递质的影响。方法用慢性束缚应激结合孤养法建立肝郁证大鼠模型,测评开野、蔗糖水实验,采用高效液相色谱法测定大鼠海马及下丘脑单胺类神经递质。结果模型组大鼠的行为学发生了明显变化,海马及下丘脑中5-羟色胺(5-HT)、5-羟吲哚乙酸(5-HIAA)、多巴胺(DA)含量均下降,去甲肾上腺素(NE)含量呈增加趋势,而柴胡疏肝散能调控其变化趋势。结论柴胡疏肝散能改善肝郁证大鼠行为学的变化,具有治疗肝郁证的作用,其作用机制可能与其能够调节肝郁证大鼠脑5-HT、5-HIAA、NE、DA有关,从而有效发挥抗肝郁作用。     

从“木郁克土”角度探讨围绝经期综合征肝郁证大鼠胃肠动力的改变

目的从“木郁克土”角度探讨围绝经期综合征(PPS)肝郁证大鼠胃肠动力的改变。方法选择3月龄SPF级SD雌性大鼠,分为假手术组、PPS组、PPS肝郁组和柴胡疏肝散组,采用去势法结合慢性不可预知性温和应激建立PPS肝郁证大鼠模型,用柴疏疏肝散进行干预,观察大鼠体重增长率、饲料消耗量、胃残留率及肠推进率变化。结果在体重增长率方面,PPS组显著高于假手术组(P<0.01);PPS肝郁组显著低PPS组(P<0.01);柴胡疏肝散组显著高于PPS肝郁组(P<0.01)。在饲料消耗方面,PPS组高于假手术组,PPS肝郁组低于PPS组;柴胡疏肝散组高于PPS肝郁组。在胃残留率方面,PPS肝郁组显著高于假手术组和PPS组(P<0.01);柴胡疏肝散组显著低于PPS肝郁组(P<0.01)。在肠推进率方面,PPS肝郁组显著低于假手术组和PPS组(P<0.01);柴胡疏肝散组显著高于PPS肝郁组(P<0.01)。结论PPS肝郁大鼠的体重和饲料消耗量发生了改变,体重的增长与饲料的消耗量存在一定的联系,且与大鼠胃肠动力有关。从“木郁克土”角度提示其机制可能是肝郁状态影响到了脾胃功能的正常运行。     

肝郁证与下丘脑-腺垂体-肾上腺皮质轴和肝组织过氧化损伤的实验研究

[目的]探讨肝郁证与大鼠下丘脑-腺垂体-肾上腺皮质轴(HPA)的关系和肝组织过氧化损伤的相关性.[方法]采用"颈部带枷单笼喂养法"刺激2周和4周复制大鼠肝郁证模型.检测下丘脑促.肾上腺皮质激素释放激素(CRH)、血浆促肾上腺皮质激素(ACTH)和皮质酮(CORT)水平.并取大鼠肝脏制备10%组织匀浆,检测肝组织匀浆中活性氧(OFR)、丙二醛(MDA)水平.[结果]实验大鼠呈现急性应激躁狂和慢性应激肝郁证时的抑郁状 态;肝郁证模型大鼠下丘脑CRH、血浆ACTH、CORT水平较正常对照组显著升高;并检测到肝郁证大鼠肝脏组织过氧化作用,显示肝脏组织内OFR、MDA水平增高,且肝脏组织有明显损伤.[结论]肝郁证与HPA轴有相关性,并且肝组织有过氧化损伤.     

活化的T细胞核因子对肝气郁结证模型大鼠Th细胞分化的调节及柴胡疏肝散的干预作用

目的 :探讨活化的 T细胞核因子 (NF- ATc)对肝郁证模型大鼠 Th细胞的调节及柴胡疏肝散的干预作用。方法 :应用 RT- PCR法 ,检测肝郁模型大鼠以及运用柴胡疏肝散、四君子汤治疗后 T细胞 NF- ATc、白细胞介素 4 (IL - 4 )及γ干扰素 (IFN-γ) m RNA的表达水平。结果 :与正常组比较 ,肝郁模型大鼠 NF- ATc、IL - 4 m RNA表达明显降低 (P <0 .0 5 ) ,IFN-γ m RNA表达则明显升高 (P <0 .0 5 ) ,Th细胞向 Th2的分化途径受抑制。用柴胡疏肝散治疗后 ,NF- ATc、IL- 4 m RNA表达上调 ,IFN- γm RNA表达下调 ,与正常组比较 ,基本恢复了正常水平 (P>0 .0 5 ) ,Th1、Th2趋于平衡状态 ;而四君子汤治疗后与正常组比较 ,NF- ATc、IFN-γ及 IL - 4 m RNA的表达无明显变化 (P>0 .0 5 )。结论 :肝郁证模型大鼠 NF- ATc m RNA表达下降 ,Th细胞向 Th2的分化途径受抑制 ,导致 IL - 4 m RNA表达下降 ,IFN- γ m RNA表达升高 ;柴胡疏肝散可以上调 NF- ATc m RNA表达 ,双向调节 IFN- γ、IL- 4 m RNA的表达水平 ,使 Th的分化趋于平衡。     

疏肝理气法对夹尾应激大鼠行为学及胃组织学的影响

目的: 观察疏肝理气法对夹尾应激大鼠行为学及胃组织学的影响.方法: 30只大鼠随机分为正常组、模型组、柴胡疏肝散组, 每组10只, 对后二组大鼠进行夹尾激惹刺激持续4wk, 并分别给予生理盐水、柴胡疏肝散水煎剂灌胃, 每日观察其一般情况,进行饮食饮水量的测定,每周进行体质量的测定,4wk后观察大鼠胃大体情况及进行组织学检查.结果: 夹尾激惹刺激大鼠4 wk, 模型组出现了靠边、扎堆状, 兴奋性及活跃程度下降, 打斗减弱, 活动相对迟缓、反应迟钝, 毛发蓬松枯黄、不顺等现象, 而柴胡疏肝散组上述表现则较不显著. 模型组大鼠饮水量、食量较正常对照组显著减低(第4周: 22.0±1.51 vs 25.70±1.4, 10.33±0.84 vs 11.29±0.29, 均P<0.05), 柴胡疏肝散组大鼠饮水量、食量较模型组显著增加(第4周:24.27±2.3 vs 22.0±1.51, 11.71±1.26 vs 10.33±0.84, 均P<0.05). 模型组大鼠体质量增长显著低于正常对照组( P<0.05), 柴胡疏肝散组大鼠体质量增长较模型组增加, 但无显著性差别.结论: 疏肝理气法能减轻长期夹尾应激大鼠抑郁、饮食量减低、体质量增长缓慢等情况,并改善胃组织学, 具有一定的"身心同治"的抗应激作用.     

急性和慢性束缚应激对大鼠内脏敏感性和神经内分泌的影响

目的了解急性和慢性部分束缚应激对大鼠内脏敏感性以及神经内分泌反应的影响特点和持续时间。方法成年SD大鼠分为对照组(无束缚应激)、急性组和慢性组,通过腹壁回撤反射(AWR)评分评估应激前后大鼠内脏对结直肠扩张(CRD)的敏感性;并通过放免法检测应激前后不同时间点大鼠血浆促肾上腺皮质激素(ACTH)以及皮质酮(CORT)水平。结果①20和40 mm Hg压力扩张时,急、慢性组的AWR评分均显著高于基础水平(0 d),P<0.05;但在应激后第7天AWR评分显著下降,P<0.05。②急性组血浆ACTH和CORT水平显著高于对照组[(25.35±6.03)ng/ml比(7.24±2.97)ng/ml,(312.47±50.76)pg/ml比(97.00±23.33)pg/ml],但束缚应激7 d后,激素浓度[(11.81±5.03)ng/ml和(113.73±24.58)pg/ml]下降至基础水平。③慢性组血浆ACTH和CORT水平[(20.84±2.19)ng/ml和(200.41±78.10)pg/ml]显著高于对照组,且激素水平在束缚7 d后[(19.95±5.31)ng/ml和(162.51±47.08)pg/ml)]仍维持在高水平。结论急性和慢性束缚应激都可导致大鼠内脏敏感性增高,但作用可能是短暂的。急性束缚应激短暂显著提高血浆ACTH和CORT水平,而慢性束缚应激可能长期提高激素水平。     

疏肝补肾方对肝纤维化大鼠睾丸酮及促肾上腺皮质激素的调节

目的:观察疏肝补肾方对肝纤维化大鼠睾丸酮(Te)、促肾上肾皮质激素(ACTH)的调节作用。方法:采用二甲基亚硝胺复制大鼠慢性肝损伤模型,检测不同剂量组大鼠的血清Te、ACTH水平。结果:肝纤维化大鼠血清Te、ACTH水平明显低于正常对照组(P<0.01),经中药治疗后,两组大鼠肝组织病理改变基本恢复正常,其血清Te、ACTH亦趋于正常(P>0.05)。组间差异不明显(P>0.05)。结论:疏肝补肾方在抗肝纤维化同时具有改善激素紊乱的作用。     

水通道蛋白-4在抑郁及抗抑郁大鼠模型海马区的表达

目的探讨抑郁及抗抑郁模型大鼠海马区水通道蛋白(AQP)-4的表达。方法通过采用慢性不可预见性刺激和孤养相结合的方法,在应激第21天后对大鼠称量体重、测24 h糖摄取量,灌流取脑,免疫组化观察海马区AQP-4的变化。结果抑郁大鼠体重和糖摄取量明显少于正常对照组及抗抑郁组,抑郁模型大鼠海马区神经元出现凋亡及AQP-4表达增加。结论 AQP-4在抑郁模型大鼠脑中对抑郁症的发病发挥重要作用。     

柴胡疏肝散对肝气郁结证大鼠尿液代谢组学的影响

目的:观察柴胡疏肝散对肝气郁结证模型大鼠尿液代谢组学的影响。方法:30只SD大鼠随机分为3组:正常组10只(A组)、模型组10只(B组)和给药组10只(C组)。采用夹尾法建立肝气郁结证大鼠模型,收集实验前后的大鼠尿液,通过核磁共振波谱仪检测,观察与分析各组大鼠尿液代谢组学的差异性变化。结果:与正常组相比,模型组尿液马尿酸、α-酮戊二酸、柠檬酸、异柠檬酸和乌头酸的含量降低,肌酸酐、丙酮、乙酸、肌酸、烟酸和5-羟基吲哚-3-乙酸的含量显著升高。给予柴胡疏肝散灌胃干预后,给药组大鼠尿液肌酸、丙酮、肌酸酐等含量明显下降,N-氧化三甲胺、氧化三甲胺(TMAO)、牛磺酸等含量明显增高,其尿液代谢表型有向正常范围回归的趋势,呈现代谢网络修复的结果。结论:肝气郁结证大鼠的尿液代谢组学出现变化,柴胡疏肝散能够部分调控平抑肝气郁结证中发生异常的代谢产物,促使代谢表型向正常范围回归,对肝气郁结证大鼠代谢紊乱有一定的恢复作用。     

Ucn3及其受体CRFR2在肠易激综合征大鼠模型肠神经系统中的表达

目的:探讨尿皮质素3(Urocotin3,Ucn3)及其受体促肾上腺皮质释放因子受体2(corticotrophin releasing factor receptor2,CRFR2)在肠易激综合征中的表达.方法:将36只180-220g的Wistar大鼠随机分为对照组(N)、急性应激组(A,急性束缚1h)、慢性应激组(C,28d不可预知轻度应激)、急慢性联合应激组(AC,在慢性应激基础上给予急性束缚)4组建模.采用排便粒数、敞箱行为评分和蔗糖水偏嗜度评价动物模型.建成后留取大鼠结肠组织,采用Real-timePCR方法检测各组大鼠结肠中Ucn3及其受体CRFR2表达水平的变化.结果:Ucn3在各组大鼠结肠中的表达:N组1.108±0.293,A组3.594±1.839,C组1.852±0.674,AC组3.989±1.591,各应激组Ucn3的表达均高于对照组(P<0.05),各应激组间A组vsC组(P<0.017),C组vsAC组(P<0.002),表达有统计学差异.CRFR2在各组大鼠结肠中的表达:N组1.042±0.217,A组2.119±0.468,C组1.568±0.507,AC组2.392±0.840,各应激组CRFR2的表达均高于对照组(P<0.05).各应激组之间没有统计学差异.结论:慢性应激、慢急性联合应激建立肠易激综合征大鼠模型重复性好.Ucn3及其受体CRFR2在肠易激综合征中表达升高,且Ucn3在急性应激后升高比慢性应激后更明显.     

Hypothalamic-pituitary-adrenal axis up-regulation in rats submitted to pituitary stalk compression

The present study investigated the hypothalamic-pituitary-adrenal (HPA) axis activity in response to stress in adult male rats submitted to pituitary stalk compression (PSC) or sham operation. Animals received water or oral salt loading (2% NaCl) for one or eight days before the day of the experiment. On the 14th day post-surgery rats were killed under basal conditions or after 15 min immobilization stress. In the PSC group urine output increased significantly and plasma vasopressin (AVP) levels failed to respond to osmotic stimuli. Short-term salt load induced a significant increase in AVP levels in the sham-operated group. The PSC group presented higher adrenocorticotrophin (ACTH) and corticosterone levels compared with sham-operated rats, both in water intake and salt load conditions. Immobilization stress induced a similar increase in plasma ACTH and corticosterone concentrations in sham-operated and PSC groups under water intake. However, long-term salt load blunted the ACTH and corticosterone responses to immobilization stress in sham-operated rats. PSC rats submitted to short- and long-term salt loading presented no changes in ACTH and corticosterone levels after immobilization. Immobilization stress caused neither AVP responses nor plasma osmolality changes in sham and PSC groups. There was no difference in median eminence AVP content among all groups. In conclusion, the high ACTH and corticosterone levels found in PSC rats under water intake and salt loading conditions suggest an up-regulation of the HPA axis, with a preserved adaptive mechanism to chronic stress.     

Secretion of melanocyte-stimulating hormone and adrenocorticotropin from transplanted pituitary pars intermedia in stressed and nonstressed rats

Rats bearing kidney grafts of the pituitary pars intermedia were divided into three groups: unstressed, acutely stressed, and chronically stressed. Corresponding sham-operated rats were used for comparisons. Twenty days after grafting, the rats were sacrificed and alpha-melanocyte-stimulating hormone (alpha-MSH), adrenocorticotropin (ACTH), and corticosterone were estimated in plasma. The adrenal/body weight ratio and DNA content of the glands were also investigated. The following results were obtained: MSH was found not to be increased in unstressed rats, but it was in grafted animals subjected to acute and chronic swimming stress. ACTH and corticosterone rose in all three groups. Adrenal/body weight ratio and DNA content increased only in grafted chronically stressed rats. Moreover, plasma corticosterone was found higher in grafted hypophysectomized rats than in non-grafted hypophysectomized animals. Administration of ergocryptine to nonstressed grafted rats induced a decrease in the blood content of ACTH and MSH, indicating that the grafts were the source of a part of the circulating ACTH. On the other hand, the fall in MSH levels could show the effect of the drug upon the pars intermedia. Comparison of the ratios of both hormones released in incubations showed that grafts secreted more ACTH than MSH; on the other hand, when intact neurointermediate lobes were incubated, MSH predominated over ACTH. For the first time it is demonstrated that the pars intermedia can secrete ACTH in vivo. Nevertheless, the ability to secrete this hormone is not a property of normal intact pars intermedia, but it manifests in the transplantations probably due to the overactivity of light cells induced by chronic stoppage of dopaminergic inhibition.     

Chronic stress promotes palatable feeding, which reduces signs of stress: feedforward and feedback effects of chronic stress

We suggested a new model of the effects of glucocorticoids (GCs) exerted during chronic stress, in which GCs directly stimulate activities in the brain while indirectly inhibiting activity in the hypothalamo-pituitary-adrenal (HPA) axis through their metabolic shifts in energy stores in the periphery. This study is an initial test of our model. In a 2 x 2 design, we provided ad lib access to calorically dense lard and sucrose (comfort food) + chow or chow alone, and repeatedly restrained half of the rats in each group for 5 d (3 h/d). We measured caloric intake, body weight, caloric efficiency, ACTH, corticosterone (B), and testosterone during the period of restraint and leptin, insulin, and fat depot weights, as well as hypothalamic corticotropin-releasing factor mRNA at the end of the period. We hypothesized that chronically restrained rats would exhibit a relative increase in comfort food ingestion and that these rats would have reduced HPA responses to repeated restraint. Although total caloric intake was reduced in both groups of restrained rats, compared with controls, the proportion of comfort food ingested increased in the restrained rats compared with their nonrestrained controls. Moreover, caloric efficiency was rescued in the stressed, comfort food group. Furthermore, ACTH and B responses to the repeated restraint bouts were reduced in the rats with access to comfort food. Corticotropin-releasing factor mRNA was reduced in control rats eating comfort food compared with those eating chow, but there were no differences between the stressed groups. The results of this experiment tend to support our model of chronic effects of stress and GCs, showing a stressor-induced preference for comfort food, and a comfort-food reduction in activity of the HPA axis.     

Alcohol induces liver neoplasia in a novel alcohol-preferring rat model

Background: Alcohol is a significant risk factor for the development of hepatocellular carcinoma (HCC). To date, no rodent model has demonstrated the formation of hepatic neoplasia in the setting of chronic alcohol consumption alone. Methods: We investigated whether rats selectively bred for high alcohol preference (P rats), allowed free access to water, or water and 10% (v/v) alcohol, for 6, 12, or 18 months, develop hepatic neoplasia. Results: At necropsy, liver tumor incidence and multiplicity were significantly increased in 18‐month alcohol‐consuming versus water‐consuming P rats. These data were confirmed histologically by glutathione‐S‐transferase pi‐class (GSTp) staining. Phosphorylated mitogen‐activated protein kinase/extracellular signal‐regulated kinase 1/2 (MAPK/ERK) staining was also increased in the sinusoidal lining cells within livers of alcohol‐consuming versus water only P rats. In addition, cytochrome p450IIE1 (CYP2E1) mRNA, protein expression/activity, and intrahepatic oxidative stress were significantly increased in alcohol‐consuming P rat livers versus water only. In contrast, acetaldehyde dehydrogenase expression decreased in alcohol‐consuming versus water only P rats. No significant difference in alcohol dehydrogenase expression was detected. Conclusions: These data demonstrate that chronic alcohol consumption is associated with hepatic neoplasia, MAPK/ERK activation, increased CYP2E1 activity, and intrahepatic oxidative stress in P rats. As these rats are well characterized as a model of alcoholism, these findings identify a novel rodent model of alcohol or “alcoholism”‐induced liver neoplasia.     

Nitric Oxide Donation Lowers Blood Pressure in Adrenocorticotrophic Hormone‐Induced Hypertensive Rats

Adrenocorticotrophic hormone (ACTH) elevates systolic blood pressure (SBP) and lowers plasma reactive nitrogen intermediates in rats. We assessed the ability of NO donation from isosorbide dinitrate (ISDN) to prevent or reverse the hypertension caused by ACTH. In the prevention study, male Sprague Dawley rats were treated with ACTH (0.2 mg/kg/day) or saline control for 8 days, with either concurrent ISDN (100 mg/kg/day) via the drinking water or water alone. Animals receiving ISDN via the drinking water were provided with nitrate‐free water for 8 hours every day. In the reversal study ISDN (100 mg/kg) or vehicle was given as a single oral dose on day 8. SBP was measured daily by the indirect tail‐cuff method in conscious, restrained rats. ACTH caused a significant increase in SBP compared with saline (P < 0.0015). In the prevention study, chronic administration of ISDN (100 mg/kg/day) did not affect the SBP in either group. In the reversal study, ISDN significantly lowered SBP in ACTH‐treated rats at 1 and 2.5 hours (132 ± 3 mmHg (1 h) and 131 ± 2 mmHg (2.5 h) versus 143 ± 3 mmHg (0 h), P < 0.002), but not to control levels. It had no effect in control (saline treated) rats. In conclusion, the lowering of SBP by NO donation is consistent with the notion that ACTH‐induced hypertension involves an impaired bioavailability or action of NO in vivo.     

Melatonin prevents early pituitary dysfunction induced by sucrose‐rich diets

While physiological levels of glucocorticoids are required to ensure proper functions of the body, consistently high levels may engender several deleterious consequences. We have previously shown an increase in the activity of the hypothalamic‐pituitary‐adrenal (HPA) axis in rats fed sucrose‐rich diets (SRD). The main goal of this study was to analyze the processes involved in the modulation of the pituitary production of ACTH by SRD, and to test melatonin as a possible therapeutic agent for the prevention of the HPA axis dysfunction. Male Wistar rats were fed standard chow and either SRD (30% sucrose in the drinking water) or plain water for three weeks. Melatonin was administered as subcutaneous pellets. Results showed that SRD treatment induced an increase in systemic ACTH and corticosterone levels and a decrease in melatonin levels. In the pituitary gland, we also detected an increase in the expression levels of proopiomelanocortin (POMC) that was accompanied by increased levels of: lipoperoxides, nitro‐tyrosine modified proteins, catalase, heme oxygenase‐1, interleukin‐1β mRNA, and by an increase in the tissue number of inflammatory cells (F4/80 and Iba‐1 positive cells). Melatonin treatment prevented all these systemic and pituitary changes as well as the increase in POMC expression induced by incubation of AtT‐20 corticotrophs with conditioned media obtained from stimulated macrophages. In conclusion, stimulation of POMC/ACTH production in rats fed a SRD could involve the generation of oxidative stress and inflammation in the pituitary gland. Melatonin treatment prevented these effects and normalized the activity of the HPA axis.     

Chronic stimulation of the pituitary-adrenal axis in rats by interleukin-1 beta infusion: in vivo and in vitro studies.

It has been shown that acute administration of interleukin-1 (IL-1) to rats elicits a transitory increase in plasma ACTH and corticosterone (B) levels. To investigate the effects of chronic administration of IL-1 on plasma ACTH and B levels, in the present study rats were equipped with Alzet osmotic minipumps loaded with either IL-1 (delivery rate 0.5, 2.0, or 4.0 micrograms/24 h, ip, for 1 week) or saline. At the end of the treatment the rats were decapitated, the adrenals were weighed, and the in vitro release of beta-endorphin (beta E) by the anterior pituitary and that of B by the adrenal gland were measured. Continuous administration of 2.0 and 4.0 micrograms IL-1/24 h resulted in a persistent increase in plasma ACTH and B concentrations compared to the levels in saline-infused rats, with peak levels on the first day of administration. In addition, adrenal weights of IL-1 rats were significantly higher than those of saline rats. The 4.0-micrograms IL-1/day in vivo treatment induced an increase in spontaneous in vitro secretion of beta E and B, while the in vitro responses of the pituitary (to CRF) and the adrenal (to ACTH) of animals treated in vivo with IL-1 were significantly diminished. IL-1 at a dose of 0.5 microgram failed to affect plasma ACTH and B values, adrenal weight, and in vitro beta E and B secretion. Chronic infusion of rats with 4.0 micrograms IL-1/day induced prolonged fever, whereas at lower doses of IL-1 (2.0 and 0.5 micrograms), temperatures were elevated only on the first 2 days of infusion. IL-1 at doses of 2.0 and 4.0 micrograms/day induced suppression of body weight gain on the first 2 days of the treatment period compared to saline treatment. Plasma norepinephrine and/or epinephrine concentrations were raised only on day 1 of the 2.0- and 4.0-micrograms IL-1 experiments. Thus, the observed effects of IL-1 on the hypothalamo-pituitary-adrenal axis probably do not result merely from stress induced by the treatment. Taken together, our data show the potential of IL-1 to induce a dose-dependent and long term activation of the pituitary-adrenal axis.     

ACTH and corticosterone secretion in rats following removal of the neurointermediate lobe of the pituitary gland

Surgical removal of the neurointermediate lobe of the pituitary gland (NIL-X) in the rat resulted in two abnormalities in ACTH secretion: (1) plasma ACTH and corticosterone levels were elevated in the morning and over a 24-hour period compared with levels in control (NIL-C) rats, and (2) although NIL-X and NIL-C rats had acute increases in plasma ACTH and corticosterone of equal magnitude after interoceptive stimuli (hemorrhage, surgery), NIL-X rats demonstrated markedly smaller elevations in plasma levels of these hormones after neurotropic stimuli (noise, novel environment). This subnormal adrenocortical response of NIL-X rats was not due to an impairment in perception of a neurotropic stimulus; these rats had normal latencies to paw licking and to jumping off a heated surface, yet smaller increases in plasma corticosterone after the stimulus. The impairment in ACTH response was not related to stimulus intensity, as NIL-X and NIL-C rats had equal ACTH and corticosterone secretion during both low and high levels of insulin-induced hypoglycemia. NIL-X rats demonstrated a significant elevation in daily water intake, although hematocrit, plasma Na+, K+, osmolality and protein were normal. Significant diurnal rhythms in plasma corticosterone levels and in water intake were maintained as well. The elevated morning plasma ACTH levels, the blunted hormone increases after noise, and the increase in water intake persisted in NIL-X rats 2 months after surgery. These data indicate that removal of the NIL results in (1) chronic elevations in basal ACTH and corticosterone secretion, and (2) chronic impairment in adrenocortical responses to neurotropic stimuli, but not to interoceptive stimuli. The deficit is not due to impaired perceptual capacity nor to the intensity of the stimulus.     

L-arginine partially reverses established adrenocorticotrophin-induced hypertension and nitric oxide deficiency in the rat

BACKGROUND: L-arginine treatment prevents adrenocorticotrophin (ACTH) induced hypertension in the rat. This study examined whether L-arginine treatment could reverse established ACTH hypertension and its effects on markers of decreased NO activity. METHODS: Sixty-four male Sprague-Dawley rats were randomly divided into 6 groups given 12 days of treatment: (1) sham (0.9% NaCl, 0.5 ml/kg, subcutaneously, sc, n = 16); (2) ACTH (0.5 mg/kg/day, sc, n = 16); (3) sham + L-arginine (0.6% in food, from treatment day 8 onwards, n = 10); (4) ACTH + L-arginine (n = 10); (5) sham + D-arginine (0.6% in food, from T 8 onwards) (n = 6); and (6) ACTH + D-arginine (n = 6). Systolic blood pressure, water intake, urine volume, and body weight were measured every second day. At the end of the experiments, plasma and urinary nitrate/nitrite (NOx), plasma amino acid concentrations (in groups 1-4), and urinary cyclic guanosine monophosphate (cGMP) concentrations were measured. RESULTS: Sham, sham + L-arginine, and sham + D-arginine treatments did not affect blood pressure. ACTH increased systolic blood pressure (from 121 +/- 1 to 147 +/- 2 mmHg, p < 0.001, pooled control vs treatment day 12, mean +/- sem), and this was partially reversed by L-arginine (group 4: from 141 +/- 2 on day 8 to 133 +/- 1 mmHg on day 12, n = 10, p < 0.001). In contrast, D-arginine did not affect blood pressure in ACTH-treated rats (group 6). ACTH increased water intake and urine volume and decreased body weight, and L-arginine administration did not alter these parameters. ACTH decreased plasma citrulline (group 1 vs 2: 115 +/- 7 vs 67 +/- 6 micro M/L, n = 16, p < 0.001) and NOx concentrations (group 1 vs 2: 8.3 +/- 0.8 vs 4.5 +/- 0.6 microM/L, n= 10, p < 0.001) and these decreases were reversed by L-arginine treatment (group 4: citrulline 98 +/- 9 micro M/L, NOx 9.1 +/- 1.6 micro M/L, group 2 vs 4, both p < 0.05). ACTH produced marked increases in urinary cGMP excretion (group 1 vs 2: 0.5 +/- 0.1 vs 1.9 +/- 0.4 nmol/24 h, p < 0.01). CONCLUSION: Supplementation with L-arginine partly reversed established ACTH-induced hypertension and restored plasma NOx and citrulline concentrations to levels seen in sham-treated rats. These data are consistent with previous studies suggesting that functional NO deficiency has a role in ACTH-induced hypertension in rats.     

Memantine treatment reverses anhedonia, normalizes corticosterone levels and increases BDNF levels in the prefrontal cortex induced by chronic mild stress in rats

Memantine is a N-methyl-D-aspartate (NMDA) receptor antagonist and several studies have pointed to the NMDA receptor antagonists as a potential therapeutic target for the treatment of depression. The present study was aimed to evaluate the behavioral and physiological effects of administration of memantine in rats exposed to the chronic mild stress (CMS) model. To this aim, after 40 days of exposure to CMS procedure, rats were treated with memantine (20 mg/kg) for 7 days. In this study, sweet food consumption, adrenal gland weight, corticosterone levels, and brain-derived-neurotrophic factor (BDNF) protein levels in the prefrontal cortex, hippocampus and amygdala were assessed. Our results demonstrated that chronic stressful situations induced anhedonia, hypertrophy of adrenal gland weight, and an increase of corticosterone levels in rats, but did not alter BDNF protein levels in the rat brain. Memantine treatment reversed anhedonia and the increase of adrenal gland weight, normalized corticosterone levels and increased BDNF protein levels in the prefrontal cortex in stressed rats. Finally, these findings further support the hypothesis that NMDA receptor antagonists such as memantine could be helpful in the pharmacological treatment of depression.