Anxiolytic-like effects of nociceptin/orphanin FQ in the elevated plus maze and in the conditioned defensive burying test in rats

Different reports suggest that nociceptin/orphanin FQ (N/OFQ) may have either anxiolytic- or anxiogenic-like effect in rodents. Since N/OFQ elicits hypolocomotion, which undergoes rapid tolerance, and hypolocomotion may be associated to emotional consequences, the present study was designed to investigate the effect of N/OFQ on anxiety after development of tolerance to its hypolocomotor effect. The effect of single or double intracerebroventricular (i.c.v.) injection of N/OFQ was evaluated on anxiety-related behaviors in rats, in the elevated plus maze (EPM) and conditioned defensive burying (CDB) tests. After single administration, N/OFQ displayed an anxiogenic-like pattern of response on the elevated plus maze but hypolocomotion was also observed. Conversely, in the CDB test, N/OFQ induced a clear-cut anxiolytic pattern. To produce tolerance to N/OFQ-induced hypolocomotion the peptide was administered by two i.c.v. injections separated by 120 min; in these conditions it decreased the expression of anxiety-related behaviors in both tests without affecting locomotor activity. The nociceptin/orphanin FQ peptide (NOP) receptor antagonist UFP-101 significantly reduced the effects of N/OFQ to control values in either tests. Corticosterone levels were significantly increased after a single N/OFQ administration (not in a dose-dependent manner) but this increase did not reach significance after double administration (1 nmol/rat). Our results support the idea that N/OFQ may act as an anxiolytic-like agent in the rat; the apparent anxiogenic-like effect observed following its single administration in the EPM may be consequent to its, effect on locomotion. (c) 2006 Elsevier Inc. All rights reserved

Mixed modeling for large-eddy simulation: The single-layer and two-layer minimum-dissipation-Bardina models

Predicting the behavior of turbulent flows using large-eddy simulation requires modeling of the subgrid-scale stress tensor. This tensor can be approximated using mixed models, which combine the dissipative nature of functional models with the capability of structural models to approximate out-of-equilibrium effects. We propose a mathematical basis to mix (functional) eddy-viscosity models with the (structural) Bardina model. By taking an anisotropic minimum-dissipation (AMD) model for the eddy viscosity, we obtain the (single-layer) AMD-Bardina model. In order to also obtain a physics-conforming model for wall-bounded flows, we further develop this mixed model into a two-layer approach: the near-wall region is parameterized with the AMD-Bardina model, whereas the outer region is computed with the Bardina model. The single-layer and two-layer AMD-Bardina models are tested in turbulent channel flows at various Reynolds numbers, and improved predictions are obtained when the mixed models are applied in comparison to the computations with the AMD and Bardina models alone. The results obtained with the two-layer AMD-Bardina model are particularly remarkable: both first- and second-order statistics are extremely well predicted and even the inflection of the mean velocity in the channel center is captured. Hence, a very promising model is obtained for large-eddy simulations of wall-bounded turbulent flows at moderate and high Reynolds numbers.Comment: 29 pages, 14 figures, 3 tables; revised, accepted manuscrip

CDC in brief 2013

With the start of the 113th Congress, we\u2019d like to take an opportunity to (re)introduce the Centers for Disease Control and Prevention (CDC), and provide some helpful information about our agency and its work. This E-Brief contains links to useful information about CDC\u2019s science, budget, and presence on the ground. For quick access to additional information about CDC\u2019s work, please contact the CDC Washington Office at (202) 245-0600, and see below for information about how CDC Washington can help you.CS238048-6What CDC does -- Fast facts -- CDC on the ground -- How can CDC Washington help you?201

EXTRA-HYPOTHALAMIC CRF-1 RECEPTOR MECHANISMS IN A MODEL OF BINGE-LIKE PALATABLE FOOD CONSUMPTION IN FEMALE RATS

Purpose: The present study evaluated the effect of the corticotrophin releasing factor (CRF)1 receptor antagonist R121919 and the corticosterone synthesis inhibitor metyrapone in female rats, in which binge eating for highly palatable food was evoked by frustration stress and cycles of food restrictions. Methods: We used 4 groups of rats that were first exposed or not exposed to repeated intermittent cycles of regular chow food restriction during which they were also given intermittent access to high-caloric palatable food. On the test day, we either exposed or did not expose the rats to the sight of the palatable food for 15 min, without allowing access to it (frustration stress) before assessing food consumption for 2 h. Results: We found that systemic injections of the CRF1 receptor antagonist R121919 but not of the metyrapone blocked binge-like eating behavior. Moreover, corticosterone injection did not induce binge eating in non-stressed rats. Restricted and stressed rats showed up regulation of CRH1 receptor mRNA signal in dorsal BNST and in CeA but not in PVN. Injection of CRF receptor antagonist D-Phe-CRF(12– 41) in CeA blocked binge-like eating behavior. Conclusions: These findings demonstrate that extra-hypothalamic CRF1 receptors, rather than those involved in endocrine functions, are involved in binge eating. Selective antagonism at CRF1 receptor may represent a novel pharmacological treatment for bingeing-related eating disorders

Pharmacological Inhibition of FAK-Pyk2 Pathway Protects Against Organ Damage and Prolongs the Survival of Septic Mice

Sepsis and septic shock are associated with high mortality and are considered one of the major public health concerns. The onset of sepsis is known as a hyper-inflammatory state that contributes to organ failure and mortality. Recent findings suggest a potential role of two non-receptor protein tyrosine kinases, namely Focal adhesion kinase (FAK) and Proline-rich tyrosine kinase 2 (Pyk2), in the inflammation associated with endometriosis, cancer, atherosclerosis and asthma. Here we investigate the role of FAK-Pyk2 in the pathogenesis of sepsis and the potential beneficial effects of the pharmacological modulation of this pathway by administering the potent reversible dual inhibitor of FAK and Pyk2, PF562271 (PF271) in a murine model of cecal ligation and puncture (CLP)-induced sepsis. Five-month-old male C57BL/6 mice underwent CLP or Sham surgery and one hour after the surgical procedure, mice were randomly assigned to receive PF271 (25 mg/kg, s.c.) or vehicle. Twenty-four hours after surgery, organs and plasma were collected for analyses. In another group of mice, survival rate was assessed every 12 h over the subsequent 5 days. Experimental sepsis led to a systemic cytokine storm resulting in the formation of excessive amounts of both pro-inflammatory cytokines (TNF-α, IL-1β, IL-17 and IL-6) and the anti-inflammatory cytokine IL-10. The systemic inflammatory response was accompanied by high plasma levels of ALT, AST (liver injury), creatinine, (renal dysfunction) and lactate, as well as a high, clinical severity score. All parameters were attenuated following PF271 administration. Experimental sepsis induced an overactivation of FAK and Pyk2 in liver and kidney, which was associated to p38 MAPK activation, leading to increased expression/activation of several pro-inflammatory markers, including the NLRP3 inflammasome complex, the adhesion molecules ICAM-1, VCAM-1 and E-selectin and the enzyme NOS-2 and myeloperoxidase. Treatment with PF271 inhibited FAK-Pyk2 activation, thus blunting the inflammatory abnormalities orchestrated by sepsis. Finally, PF271 significantly prolonged the survival of mice subjected to CLP-sepsis. Taken together, our data show for the first time that the FAK-Pyk2 pathway contributes to sepsis-induced inflammation and organ injury/dysfunction and that the pharmacological modulation of this pathway may represents a new strategy for the treatment of sepsis

Modulation of pain sensitivity by chronic consumption of highly palatable food followed by abstinence: emerging role of fatty acid amide hydrolase

There is a strong relationship between palatable diet and pain sensitivity, and the cannabinoid and opioid systems might play an important role in this correlation. The palatable diet used in many animal models of obesity is the cafeteria (CAF) diet, based on human food with high sugar, salt, and fat content. In this study, we investigated whether long-term exposure to a CAF diet could modify pain sensitivity and explored the role of the cannabinergic system in this modification. Male Sprague–Dawley rats were divided into two groups: one fed with standard chow only (CO) and the other with extended access (EA) to a CAF diet. Hot plate and tail flick tests were used to evaluate pain sensitivity. At the end of a 40-day CAF exposure, EA rats showed a significant increase in the pain threshold compared to CO rats, finding probably due to up-regulation of CB1 and mu-opioid receptors. Instead, during abstinence from palatable foods, EA animals showed a significant increase in pain sensibility, which was ameliorated by repeated treatment with a fatty acid amide hydrolase inhibitor, PF-3845 (10 mg/kg, intraperitoneally), every other day for 28 days. Ex vivo analysis of the brains of these rats clearly showed that this effect was mediated by mu-opioid receptors, which were up-regulated following repeated treatment of PF-3845. Our data add to the knowledge about changes in pain perception in obese subjects, revealing a key role of CB1 and mu-opioid receptors and their possible pharmacological crosstalk and reinforcing the need to consider this modulation in planning effective pain management for obese patients

Depressive-like behavior is paired to monoaminergic alteration in a murine model of Alzheimer's disease

Background: Neuropsychiatric signs are critical in primary caregiving of Alzheimer patients and have not yet been fully investigated in murine models. Methods: 18-month-old 3.Tg-AD Male mice and their wild-type Male littermates (non-Tg) were used. The open field test and the elevated plus maze test were used to evaluate anxiety-like behaviors, whereas the Porsolt forced swim test, the tail suspension test, and the sucrose preference test for antidepressant/depression-coping behaviors. Neurochemical study was conducted by microdialysis in freely-moving mice, analyzing the basal and K+-stimulated monoamine output in the frontal cortex and ventral hippocampus. Moreover by immunohistochemistry, we analysed the expression of Tyrosin hydroxylase and Tryptophan hydroxylase, which play a key role in the synthesis of monoamines. Results: Aged 3.Tg-AD mice exhibited a higher duration of immobility in the forced swim and tail suspension tests (predictors of depression-like behavior) which was not attenuated by a noradrenaline reuptake inhibitor, desipramine. In the sucrose preference test, 3.Tg-AD mice showed a significantly lower sucrose preference compared to the non-Tg group, without any difference in total fluid intake. In contrast, the motor functions and anxiety-related emotional responses of 3.Tg-AD mice were normal, as detected by the open-field and elevated plus-maze tests. To strengthen these results, we then evaluated the monoaminergic neurotransmissions by in vivo microdialysis and immunohistochemistry. In particular, with the exception of the basal hippocampal dopamine levels, 3.Tg-AD mice exhibited a lower basal extracellular output of amines in the frontal cortex and ventral hippocampus and also a decreased extracellular response to K+ stimulation. Such alterations occur with obvious local amyloid-β and tau pathologies and without gross alterations in the expression of Tyrosin and Tryptophan hydroxylase. Conclusions: These results suggest that 3.Tg-AD mice exhibit changes in depression-related behavior involving aminergic neurotrasmitters and provide an animal model for investigating AD with depression