Overexpression of Adenosine A2A receptors in rats: effects on depression, locomotion, and anxiety

Copyright: © 2014 Coelho, Alves, Canas, Valadas, Shmidt, Batalha, Ferreira, Ribeiro, Bader, Cunha, do Couto and Lopes. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Adenosine A2A receptors (A2AR) are a sub-type of receptors enriched in basal ganglia, activated by the neuromodulator adenosine, which interact with dopamine D2 receptors. Although this reciprocal antagonistic interaction is well-established in motor function, the outcome in dopamine-related behaviors remains uncertain, in particular in depression and anxiety. We have demonstrated an upsurge of A2AR associated to aging and chronic stress. Furthermore, Alzheimer's disease patients present A2AR accumulation in cortical areas together with depressive signs. We now tested the impact of overexpressing A2AR in forebrain neurons on dopamine-related behavior, namely depression. Adult male rats overexpressing human A2AR under the control of CaMKII promoter [Tg(CaMKII-hA2AR)] and aged-matched wild-types (WT) of the same strain (Sprague-Dawley) were studied. The forced swimming test (FST), sucrose preference test (SPT), and the open-field test (OFT) were performed to evaluate behavioral despair, anhedonia, locomotion, and anxiety. Tg(CaMKII-hA2AR) animals spent more time floating and less time swimming in the FST and presented a decreased sucrose preference at 48 h in the SPT. They also covered higher distances in the OFT and spent more time in the central zone than the WT. The results indicate that Tg(CaMKII-hA2AR) rats exhibit depressive-like behavior, hyperlocomotion, and altered exploratory behavior. This A2AR overexpression may explain the depressive signs found in aging, chronic stress, and Alzheimer's disease.Joana E. Coelho, Vânia L. Batalha and Diana G. Ferreira were supported by a grant from Fundação para a Ciência e Tecnologia (FCT); Paula M. Canas and Rodrigo A. Cunha were supported by FCT (PTDC/SAU-NSC/122254/2010) and Defense Advanced Research Projects Agency (DARPA, grant 09-68-ESR- FP-010). Luísa V. Lopes is an Investigator FCT, funded by Fundação para a Ciência e Tecnologia (PTDC-099853/2009) and Bial.info:eu-repo/semantics/publishedVersio

Brain renin angiotensin system in cardiac hypertrophy and failure

Brain renin-angiotensin system (RAS) is significantly involved in the roles of the endocrine RAS in cardiovascular regulation. Our studies indicate that the brain RAS participates in the development of cardiac hypertrophy and fibrosis through sympathetic activation. Inhibition of sympathetic hyperactivity after myocardial infarction through suppression of the brain RAS appears beneficial. The brain RAS is involved in the modulation of circadian rhythms of arterial pressure, contributing to nondipping hypertension. We conclude that the brain RAS in pathophysiological states interacts synergistically with the chronically overactive RAS through a positive biofeedback in order to maintain a state of alert diseased conditions, such as cardiac hypertrophy and failure. Therefore, targeting brain RAS with drugs such as angiotensin converting inhibitors or receptor blockers having increased brain penetrability could be of advantage. These RAS-targeting drugs are first-line therapy for all heart failure patients. Since the RAS has both endocrine and local tissue components, RAS drugs are being developed to attain increased tissue penetrability and volume of distribution and consequently an efficient inhibition of both RAS components

Effect of angiotensin(1-7) on heart function in an experimental rat model of obesity

Aim: Obesity is a risk factor for the development of cardiovascular diseases. Recently it was shown that overexpression of the Mas- receptor antagonist angiotensin(1-7) could prevent from diet- induced obesity. However, it remained unclear whether diet-induced obesity and angiotensin(1-7) overexpression might also have effects on the cardiovascular system in these rats.Methods: 23 male Sprague Dawley rats were fed with standard chow (SD+chow, n=5) or a cafeteria diet (SD+CD, n=6) for five months. To investigate the effect of angiotensin(1-7) transgenic rats, expressing an angiotensin(1-7)-producing fusion protein in testis were used. These transgenic rats also received a five month’s feeding period with either chow (TGR+chow, n=6) or cafeteria diet (TGR+CD, n=6), respectively. Hemodynamic measurements (pressure-volume loops) were carried out to assess cardiac function and blood pressure. Subsequently, hearts were explanted and investigated according to the Langendorff technique. Furthermore, cardiac remodeling in these animals was investigated histologically.Results: After five months cafeteria diet feeding rats showed a significantly increased body weight, which could be prevented in transgenic rats. However, there was no effect on cardiac performance after cafeteria diet in non-transgenic and transgenic rats. Moreover, overexpression of angiotensin(1-7) deteriorated cardiac contractility as indicated by impaired dp/dt. Furthermore, histological analysis revealed that cafeteria diet led to myocardial fibrosis in both, control and transgenic rats and this was not inhibited by an overproduction of angiotensin(1-7).Conclusion: These results indicate that an overexpression of circulating angiotensin(1-7) prevents a cafeteria diet-induced increase in body weight, but does not affect cardiac performance in this experimental rat model of obesity. Furthermore, overexpression of angiotensin(1-7) alone resulted in an impairment of cardiac function

Promoting coordinated development of community-based information standards for modeling in biology: the COMBINE initiative

The Computational Modeling in Biology Network (COMBINE) is a consortium of groups involved in the development of open community standards and formats used in computational modeling in biology. COMBINE's aim is to act as a coordinator, facilitator, and resource for different standardization efforts whose domains of use cover related areas of the computational biology space. In this perspective article, we summarize COMBINE, its general organization, and the community standards and other efforts involved in it. Our goals are to help guide readers toward standards that may be suitable for their research activities, as well as to direct interested readers to relevant communities where they can best expect to receive assistance in how to develop interoperable computational models