Angiotensin (1–7) through modulation of the NMDAR–nNOS–NO pathway and serotonergic metabolism exerts an anxiolytic-like effect in rats

Abstract

Although recent studies have shown that angiotensin (1–7) (Ang [1–7]) exerts anti-stress and anxiolytic-like effects, the underlying mechanisms remain elusive. The ventral hippocampus (VH) is proposed to be a critical brain region for mood and stress management through the N-methyl-d-aspartate receptor (NMDAR) signaling pathway. However, the role of VH NMDAR signaling in the effects of Ang (1–7) remains unclear. In the present study, Ang (1–7) was injected into the bilateral VH of stressed rats, or in combination with a Fyn kinase inhibitor, NMDAR antagonist, neuronal nitric oxide synthase (nNOS) inhibitor, or nitric oxide (NO) scavenger. Anxiety-like behaviors were assessed using the open field test and elevated plus maze test, while alterations in NMDAR–nNOS–NO signaling and serotonergic metabolism were examined in the VH. After 21 days of chronic restraint stress, anxiety-like behaviors were evident. Levels of phosphorylated NR2B (a key NMDAR subunit), its upstream kinase Fyn, as well as activity of nNOS and monoamine oxidase (MAO) were markedly reduced. In contrast, levels of serotonin were increased. Bilateral VH infusion of Ang (1–7) recovered NMDAR–nNOS–NO signaling and MAO-mediated serotonin metabolism, as well as reducing anxiety-like behaviors in stressed rats. These effects were diminished by blockade of MasR (Ang [1–7]-specific receptor), Fyn kinase, NMDAR, nNOS, or NO production. Altogether, these findings indicate that Ang (1–7) exerts anxiolytic effects through modulation of the NMDAR–nNOS–NO pathway and serotonergic metabolism. Future translational research should focus on the relationship between Ang (1–7), glutamatergic neurotransmission, and serotonergic neurotransmission in the VH.