Alamandine, a peptide hormone, was described in 2013 by our group (Lautner et al., 2013). It can be generated from the catalytic action of angiotensin-converting enzyme 2 (ACE2) on angiotensin (Ang)-A or directly through enzymatic decarboxylation of aspartic acid from Ang-(1–7). This peptide interacts specifically with MrgD, which is a Mas-related G-protein coupled receptor that is part of a subfamily of receptors (Mrgprs or Mas-related genes) (Zylka et al., 2005; Bader et al., 2014).

The effects of alamandine are extinguished with D-Pro7-Ang-(1–7), an antagonist of both Mas and MrgD receptors (Lautner et al., 2013; Almeida-Santos et al., 2021). However, its effects are not altered in mice lacking Mas receptor or after treatment with a selective Mas receptor antagonist, A779 (Lemos et al., 2005; Lautner et al., 2013). The MrgD was previously reported as a neuron-specific receptor of dorsal root (spinal) ganglia (Dong et al., 2001). Noteworthy is the fact that the presence and actions of MrgD have been found in different organs and tissues including the brain (Bader et al., 2014; Jackson et al., 2018).

Like Ang-(1–7) (Kangussu et al., 2013; Almeida-Santos et al., 2016; Kangussu et al., 2017), a previous study of our group showed that alamandine, through MrgD, induces antidepressant-like effects in transgenic rats with low brain angiotensinogen [TGR(ASrAOGEN)680] (TGR) (Almeida-Santos et al., 2021). In this study, we aimed to investigate whether a lack of this peptide causes the anxiety-like behavior in TGR. We hypothesized that alamandine by activating MrgD can mediate anxiolytic effects in this animal model.