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  • Other reports however have indicated that all components


    Other reports, however, have indicated that all components of RAS are produced within the central nervous system (CNS) (Saavedra, 2005). Thus, AGTR1 and AGTR2 in circumventricular organs and in cerebrovascular endothelial cells may respond to circulating ANG2 of peripheral origin, whereas neural receptors inside the blood Cy5 Firefly Luciferase mRNA barrier respond to RAS of brain origin (Saavedra, 2005). AGTR1 and AGTR2 are expressed inside blood brain barrier structures such as the hippocampus and frontal cortex (Bunnemann et al., 1992; Tsutsumi and Saavedra, 1991), which are both considered crucial limbic structures associated with the neurobiology of depression (Krishnan and Nestler, 2008). In fact, several pieces of evidence suggest that ANG2 is a hormone regulator of peripheral and central physiological changes regarding stress exposure, including behavioral consequences. For instance, both acute and chronic stress increased ANG2 and AGTR1 expression levels in the hypothalamic-pituitary-adrenal axis (HPA axis) (Castren and Saavedra, 1988; Saavedra et al., 2004; Yang et al., 1993). Moreover, candesartan (an AGTR1 antagonist) treatment prevented the stress effect of increasing pituitary adrenocorticotropic and corticosterone hormone levels (Armando, 2001), and treatment with ACE inhibitors (ACEi) or AGTR1 antagonists reversed or prevented animal behavioral responses to stress (Gard et al., 1999; Giardina and Ebert, 1989; Martin et al., 1990a, 1990b; Ping et al., 2014; Vijayapandi and Nagappa, 2005). Similarly, animals lacking angiotensinogen showed an antidepressant-like phenotype (Okuyama et al., 1999). The neurotrophin brain-derived neurotrophic factor (BDNF) is found mostly in the central nervous system and is important for neural plasticity, including synapse formation, neuronal differentiation, and growth (Park and Poo, 2013). The functional role of BDNF and its receptor (tropomyosin-related kinase B receptor, TRKB) has been linked to the pathophysiology of psychiatric disorders (such as depression) and with the mechanism of action of antidepressant drugs (Castrén, 2014). RAS may modulate BDNF and TRKB brain levels. For instance, candesartan treatment prevented both infarct volume and neurological deficits in animals submitted to middle cerebral artery occlusion, and increased TRKB protein and mRNA levels in the brain (Krikov et al., 2008). In addition, telmisartan (an AGTR1 antagonist) chronic treatment prevented retinal damage and decrease of BDNF levels in a diabetic animal model (Ola et al., 2013). Valsartan, another AGTR1 antagonist, counteracted the consequences of stress on depressive and anxiogenic-like behavior and on BDNF levels in the hippocampus and frontal cortex (Ping et al., 2014). Moreover, some case reports describe relief of depressive symptoms in hypertensive patients treated with the ACEi captopril (Deicken, 1986; Germain and Chouinard, 1988; Zubenko and Nixon, 1984). Despite scarce evidence, it is plausible that drugs acting on the RAS promote antidepressant-like effects. However, such properties have not been linked to modulation of the BDNF/TRKB system. In the present work, we investigated the behavioral effects of the AGTR1 antagonist losartan and ACEi in a model predictive of antidepressant-like effect (i.e., forced swimming test) and the requirement of BDNF/TRKB for such effect. Since AGTR1 activation is related to brain injury (Saavedra, 2012) and activation of AGTR2 induces neuroprotective outcomes, especially when AGTR1 is blocked (Mogi and Horiuchi, 2013; Zhao et al., 2005), we hypothesized that activation of AGTR2 mediates the antidepressant-like effects of losartan. We also performed a series of in vitro analysis to provide a mechanistic insight to the behavioral data.
    Material and methods
    Discussion The present study indicates that systemic treatment with angiotensin receptor blocker (ARB) losartan and imipramine (used as positive control), but not with the ACE inhibitors captopril or enalapril, promoted an antidepressant-like effect in the FST. Losartan infusion into vHC or into PL, but not into dHC, was sufficient to mimic the antidepressant-like effect of systemic injection. Both the hippocampus and vmPFC are core structures that modulate motivational and emotional behavioral consequences of stress exposure, including depressive disorders (Castrén, 2005; Nestler et al., 2002). Consistent with our data, vHC is suggested to be mainly related to behavioral and physiological consequences of stress exposure, while dHC engages cognitive and learning processes concerning spatial navigation (Fanselow and Dong, 2010). The antidepressant-like effect of losartan probably relies on TRK signaling acting in the hippocampus and vmPFC prelimbic aspects, whereas AGTR2 activation is required only in PL, since an inhibitor of TRK in vHC and PL, and an AGTR2 antagonist in PL decreased such effect. Moreover, we can rule out any nonspecific effect on locomotion, a common misleading factor in FST, since no change was observed in this parameter following the pharmacological treatments (Fig. S1). The differences between these two structures can be explained by the higher levels of AGTR2 found in medial aspects of prefrontal cortex than in hippocampus. The study from De Kloet and colleagues (de Kloet et al., 2016), using GFP expression to report for AGTR2 expression, demonstrated positive labelling for the fluorescent protein in the medial prefrontal cortex of mice. The same study found very low levels of GFP in the hippocampus of these animals. In line with this observation, the levels of Agtr2 in mouse hippocampus are found below the cutoff used in Gregg and cols. study (Gregg et al., 2010). However, using a functional approach it was observed that ANG2 amnesic effect is counteracted by the AGTR2 antagonist PD123319 in the hippocampus (Kerr et al., 2005).