Enhanced self-administration of the CB1 receptor agonist WIN55,212-2 in olfactory bulbectomized rats: evaluation of possible serotonergic and dopaminergic underlying mechanisms

Depression has been associated with drug consumption, including heavy or problematic cannabis use. According to an animal model of depression and substance use disorder comorbidity, we combined the olfactory bulbectomy (OBX) model of depression with intravenous drug self-administration procedure to verify whether depressive-like rats displayed altered voluntary intake of the CB1 receptor agonist WIN55,212-2 (WIN, 12.5 μg/kg/infusion). To this aim, olfactory-bulbectomized (OBX) and sham-operated (SHAM) Lister Hooded rats were allowed to self-administer WIN by lever-pressing under a continuous [fixed ratio 1 (FR-1)] schedule of reinforcement in 2 h daily sessions. Data showed that both OBX and SHAM rats developed stable WIN intake; yet, responses in OBX were constantly higher than in SHAM rats soon after the first week of training. In addition, OBX rats took significantly longer to extinguish the drug-seeking behavior after vehicle substitution. Acute pre-treatment with serotonin 5HT1B receptor agonist, CGS-12066B (2.5-10 mg/kg), did not significantly modify WIN intake in OBX and SHAM Lister Hooded rats. Furthermore, acute pre-treatment with CGS-12066B (10 and 15 mg/kg) did not alter responses in parallel groups of OBX and SHAM Sprague Dawley rats self-administering methamphetamine under higher (FR-2) reinforcement schedule with nose-poking as operandum. Finally, dopamine levels in the nucleus accumbens (NAc) of OBX rats did not increase in response to a WIN challenge, as in SHAM rats, indicating a dopaminergic dysfunction in bulbectomized rats. Altogether, our findings suggest that a depressive-like state may alter cannabinoid CB1 receptor agonist-induced brain reward function and that a dopaminergic rather than a 5-HT1B mechanism is likely to underlie enhanced WIN self-administration in OBX rats

How does the quality of surveys for nutrient intake adequacy assessment compare across Europe? A scoring system to rate the quality of data in such surveys

Research was conducted within the EURopean micronutrient RECommendations Aligned (EURRECA) Network of Excellence, to find the best practice in assessing nutrient intakes. Objectives include: to search for and use data on individual nutrient intake adequacy (NIA) assessment collected in twenty-eight European countries and the four European Free Trade Association countries: to design and test innovative tools for data quality analysis. The information was obtained using the method described by Blanquer et al. in the present issue. The best-practice criteria were devised to select the most appropriate survey in each country. Then a survey quality scoring system was developed in consultation with experts and tested on these surveys. Weights were allocated according to a variable priority order agreed by consultation. The thirty-two Countries yielded twenty-four national surveys (eight countries excluded). Data collection techniques: eleven countries/surveys used personal interviews only; six used combinations of techniques. Dietary assessment methods: two used repeated 24h recalls only: eleven used combinations. NIA assessment methods: two used probabilistic approach and SD/Z-scores only; eleven used comparison with estimated average requirements/RDA only. Countries were ranked according to the survey quality scoring, but careful interpretation is needed because of incomplete data from some surveys bearing this in mind, the information quality is high in 37.5% countries, medium in 50.0% and low in 12.5%. Although there is room for improvement and caution should be taken when drawing conclusions and recommendations from these results, the lessons learned and tools developed at this first attempt form the basis for future work within the EURRECA framework for aligning European micronutrient recommendations

Loss of DPP4 activity is related to a prothrombogenic status of endothelial cells: implications for the coronary microvasculature of myocardial infarction patients

Pro-coagulant and pro-inflammatory intramyocardial (micro)vasculature plays an important role in acute myocardial infarction (AMI). Currently, inhibition of serine protease dipeptidyl peptidase 4 (DPP4) receives a lot of interest as an anti-hyperglycemic therapy in type 2 diabetes patients. However, DPP4 also possesses anti-thrombotic properties and may behave as an immobilized anti-coagulant on endothelial cells. Here, we studied the expression and activity of endothelial DPP4 in human myocardial infarction in relation to a prothrombogenic endothelial phenotype. Using (immuno)histochemistry, DPP4 expression and activity were found on the endothelium of intramyocardial blood vessels in autopsied control hearts (n = 9). Within the infarction area of AMI patients (n = 73), this DPP4 expression and activity were significantly decreased, coinciding with an increase in Tissue Factor expression. In primary human umbilical vein endothelial cells (HUVECs), Western blot analysis and digital imaging fluorescence microscopy revealed that DPP4 expression was strongly decreased after metabolic inhibition, also coinciding with Tissue Factor upregulation. Interestingly, inhibition of DPP4 activity with diprotin A also enhanced the amount of Tissue Factor encountered and induced the adherence of platelets under flow conditions. Ischemia induces loss of coronary microvascular endothelial DPP4 expression and increased Tissue Factor expression in AMI as well as in vitro in HUVECs. Our data suggest that the loss of DPP4 activity affects the anti-thrombogenic nature of the endothelium

Prevalence of physical activity through the practice of sports among adolescents from Portuguese speaking countries

This study evaluated the prevalence of physical activity through the practice of sports in adolescents from schools in two Brazilian cities and a Portuguese school, and its association with independent variables, such as gender and age. A cross-sectional study was conducted of schoolchildren from two cities in Brazil and one in Portugal. The total study sample was 3694 subjects (1622 males and 1872 females). Physical activity levels were assessed using Baecke's questionnaire. Body weight was measured on electronic scales and stature was measured with a portable wooden stadiometer. Numerical variables were expressed as mean, categorical variables were expressed as percentages and the chi-square test analyzed associations. The prevalence of no sport was high (39.7%), being higher in the Portuguese school than in the Brazilian schools (p < 0.001). Irrespective of being an adolescent in a Brazilian or Portuguese school, boys showed higher engagement in sports practice than girls (p < 0.001). In both, differences were identified between adolescents aged 13 to 15 (P = 0.001) and 16 to 17 (P = 0.001). The prevalence of physical inactivity among schoolchildren from two cities in Brazil and a school in Portugal was high, with the girls practicing less sport than the boys and with this imbalance likely to be higher in adolescents

Effect of a peptide antagonist of the F11 Receptor on platelet adhesion to the vascular walls

We examined various parameters of platelet adhesion to the vascular walls in mice in both in the arterioles and venules in the presence of a peptide antagonist of the F11 Receptor (peptide 4D), utilizing the intravital microscopy system. To induce an inflammatory phenotype of the vascular endothelium, mice were injected intraperitoneally with both murine recombinant TNF-alpha and murine recombinant IFN-gamma prior to the initiation of the measurement of platelet adhesion. The F11R peptide 4D was injected to the peptide-treated group of animals in 3 consecutive applications. The control, vehicle- treated animal group received injections of equal volumes of saline at each time point. At the time of measurements conducted to assess platelet adhesion to the vasculature, mice were anesthetized and injected with the platelet-specific fluorescent anti-GPIbβ antibody. Video imaging was carried out at the magnification of 200x for 40 s with an exposure time of 200 ms in at least three venules and at least three arterioles in each mouse. The analysis of platelets tethering to the endothelium cells in the recorded movies was performed with the use of TrackMate plugin that is implemented in FIJI software. Three parameters, each characterizing platelet interactions with the vascular wall, were calculated: 1. the time of interaction (referred to as the ‘adhesion time’), 2. the reciprocal distance (i.e. the distance in a given view field that was overcome by a rolling platelet), which may be regarded as a measure of an overall platelet ‘immobilization’ on endothelium integrated through time, and 3. the integrated measure of these two parameters, the so called reciprocal ‘velocity’ of a platelet sliding on the vessel wall (referred to as ‘adhesion time*distance-1’). These results demonstrate that the platelets were sliding with a higher velocity in the arterioles of the peptide-treated group and suggest that peptide 4D significantly inhibits platelets’ ability to interact with endothelial layer of arterioles (Representative video is shown in Film 1, 2 and 3). In contrast to the statistically-significant differences in platelet-arteriole wall interactions observed between the peptide 4D treated group and the nontreated group, we observed that peptide 4D treatment did not have an effect on the interaction times of platelets within venules (Representative video is shown in Film 4, 5 and 6). Data from intravital microscopy demonstrate that peptide 4D blocks the adhesion of platelets to inflamed arterioles suggesting a critical role of F11R in the adhesion of platelets to cytokine-inflamed endothelium