Rationale-Chronic stress perturbs modulatory brain neurotransmitter systems, including serotonin (5-HT), and is a risk factor for psychiatric disorders such as depression. Deficits in cognitive flexibility, reflecting prefrontal cortical dysfunction, are prominent in such disorders. Orbitofrontal cortex (OFC) has been implicated specifically in reversal learning, a form of cognitive flexibility modulated by 5-HT.Objectives-Assess the effects of chronic intermittent cold (CIC) stress, a potent metabolic stressor, on performance of rats in an attentional set shifting test (AST). Assess a possible role for serotonin in CIC-induced deficits, and test the effects of acute serotonin reuptake blockade. Methods-MaleSprague-Dawley rats were exposed to CIC stress (14 days × 6 hr/day at 4 °C) before testing on the AST. In subsequent experiments, brain 5-HT was depleted in naïve rats with para-chlorophenylalanine, or 5-HT release was increased acutely in CIC-stressed rats with citalopram (5 mg/kg, s.c.) given 30 min prior to the first reversal task. Microdialysis was used to assess CICinduced changes in 5-HT release in OFC during testing.Results-CIC-stressed rats exhibited a selective impairment on the first reversal task in the AST. 5-HT depletion induced a similarly selective deficit in reversal learning. The CIC-induced impairment in reversal learning was attenuated by acute 5-HT reuptake blockade. 5-HT release was reduced in OFC of CIC-stressed rats during behavioral testing.Conclusions-The CIC stress-induced impairment of cognitive flexibility may involve dysregulation of 5-HT modulatory function in OFC. Such deficits may thus model relevant symptoms of neuropsychiatric disorders that respond positively to SSRI treatment.

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Introduction. Breast cancer is the most frequently diagnosed malignancy in women, and comorbidities like hypertension and obesity diminish their quality of life and negatively affect their response to chemotherapy. Furthermore, inulin supplementation is associated with the reduction of cardiovascular diseases (CVD) risk. Objective. To determine whether inulin supplementation prevents the elevation of blood pressure in women with breast cancer undergoing neoadjuvant therapy with cyclophosphamide and doxorubicin. Methods. This was a randomized, double-blind placebo controlled trial which included women with early-stage breast cancer undergoing neoadjuvant therapy (n=38). Patients were randomly assigned to participate in two different groups to receive either 15 g of inulin or 15 g of placebo (maltodextrin) for 21 days. Body composition and blood pressure were evaluated before and after the supplementation period. Results. Women in the inulin group showed a lower systolic blood pressure (SBP) after the supplementation (-4.21 mmHg, p<0.001). However, SBP increased in the placebo supplemented group. Diastolic blood pressure (DBP) nonsignificantly decreased in the inulin group. Inulin supplementation also increased BMI (p<0.001) but reduced BFP (p=0.288). Furthermore, confounding variables, such as BMI, baseline fasting glucose, age, menopause status, vomiting, constipation, and chronic medication did not have a statistical influence over the inulin effect on SBP. Conclusion. Inulin supplementation reduces SBP and prevents increases in DBP in women with breast cancer. This could be an innovative nutraceutical approach to prevent hypertension present in women with this type of cancer at an early stage and may improve the quality of life of the patients and their prognostic development through chemotherapy. Trial Registration Number. This trial is registered with ACTRN12616001532493.

Our objective was to study hypertension induced by chronic administration of synthetic glucocorticoid, dexamethasone (DEX), under nonstressful conditions and examine the role of catecholamine biosynthesis. To achieve this, we did the following: 1) used radiotelemetry to record mean arterial pressure (MAP) and heart rate (HR) in freely moving rats, and 2) administered different doses of DEX in drinking water. To evaluate the involvement of tyrosine hydroxylase (TH), the rate-limiting step in catecholamine biosynthesis, we treated rats with the TH inhibitor, a-methyl-paratyrosine (a-MPT), for 3 days prior to administration of DEX and assessed TH mRNA and protein expression by quantitative realtime polymerase chain reaction and Western blot in the adrenal medulla. We observed a dose-dependent elevation in blood pressure with a DEX dose of 0.3 mg/kg administered for 10 days, significantly increasing MAP by 115.0 6 1.1 mm Hg, while concomitantly reducing HR. Although this DEX treatment also significantly decreased body weight, pair-fed animals that showed similar decreases in body weight due to lowered food intake were not hypertensive, suggesting that body weight changes may not account for DEX-induced hypertension. Chronic DEX treatment significantly increased the TH mRNA and protein levels in the adrenal medulla, and a-MPT administration not only reduced DEX pressor effects, but also inhibited TH (serine 40 ) phosphorylation. Our study thus validates a novel model to study hypertension induced by chronic intake of DEX in freely moving rats not subject to the confounding factors of previous models and establishes its dependence on concomitant activation of peripheral catecholamine biosynthesis.

The human tyrosine hydroxylase (hTH) gene has a 42 bp evolutionarily conserved region designated (CR) II at À7.24 kb, which bears 93% homology to the region we earlier identified as containing the glucocorticoid response element, a 7 bp activator protein-1 (AP-1)-like motif in the rat TH gene. We cloned this hTH-CRII region upstream of minimal basal hTH promoter in luciferase (Luc) reporter vector, and tested glucocorticoid responsiveness in human cell lines. Dexamethasone (Dex) stimulated Luc activity of hTH-CRII in HeLa cells, while mifepristone, a glucocorticoid receptor (GR) antagonist, prevented Dex stimulation. Deletion of the 7 bp 5′-TGACTAA at À7243 bp completely abolished the Dex-stimulated Luc activity of hTH-CRII construct. The AP-1 agonist, tetradeconoyl-12,13-phorbol acetate (TPA), also stimulated hTH promoter activity, and Dex and TPA together further accentuated this response. Chromatin immunoprecipitation assays revealed the presence of both GR and AP-1 proteins, especially Jun family members, at this hTH promoter site. Dex did not stimulate hTH promoter activity in a catecholaminergic cell line, which had low endogenous GR levels, but did activate the response when GR was expressed exogenously. Thus, our studies have clearly identified a glucocorticoidresponsive element in a 7 bp AP-1-like motif in the promoter region at À7.24 kb of the human TH gene.