Angiotensin-(1-7)-induced plasticity changes in the lateral amygdala are mediated by COX-2 and NO

Abstract

It is known from studies outside the brain that upon binding to its receptor, angiotensin-(1-7) elicits the release of prostanoids and nitric oxide (NO). Cyclooxygenase (COX) is a key enzyme that converts arachidonic acid to prostaglandins. Since there are no data available so far on the role of COX-2 in the amygdala, in a first step we demonstrated that the selective COX-2 inhibitor NS-398 significantly reduced the probability of long-term potentiation (LTP) induction in the lateral nucleus of the amygdala. Similarly, in COX-2 −/− mice, LTP induced by external capsule (EC) stimulation was impaired. Second, we evaluated the action of angiotensin-(1-7) in the amygdala. In wild-type mice, angiotensin-(1-7) increased LTP. This LTP-enhancing effect of Ang-(1-7) was not observed in COX-2 +/− mice. However, in COX-2 −/− mice, Ang-(1-7) caused an enhancement of LTP similar to that in wild-type mice. The NO synthetase inhibitor L-NAME blocked this angiotensin-(1-7)-induced increase in LTP in COX-2 −/− mice. Low-frequency stimulation of external capsule fibers did not cause long-term depression (LTD) in drug-free and angiotensin-(1-7)-treated brain slices in wild-type mice. In contrast, in COX-2 −/− mice, angiotensin-(1-7) caused stable LTD. Increasing NO concentration by the NO-donor SNAP also caused LTD in wild-type mice. Our study shows for the first time that LTP in the amygdala is dependent on COX-2 activity. Moreover, COX-2 is involved in the mediation of angiotensin-(1-7) effects on LTP. Finally, it is recognized that there is a molecular cross-talk between COX-2 and NO that may regulate synaptic plasticity.

Different Isoforms of Nitric Oxide Synthase Are Involved in Angiotensin-(1–7)-Mediated Plasticity Changes in the Amygdala in a Gender-Dependent Manner

“…As described previously in male mice [14], the pretreatment of slices with Ang-(1–7) significantly enhanced LA-LTP (males: 173.3 ± 8.8%, n = 6 slices; p < 0.05). The same enhancement was also observed in slices derived from female wt mice (females: 173.3 ± 4.8%, n = 9 slices; p < 0.05; fig.…”

“…Angiotensin-(1–7) (Ang-(1–7)) is an endogenous peptide in the brain RAS with several beneficial effects that are often the opposite of those attributed to angiotensin II (Ang II) [10,11,12]. Recently, we showed that Ang-(1–7) increases long-term potentiation (LTP) not only in the CA1 region of the hippocampus [13], but also in the lateral nucleus of the amygdala (LA) [14], which is in contrast to the LTP suppression mediated by Ang II [15]. A G-protein-coupled receptor, Mas, encoded by the Mas proto-oncogene, has been identified as a possible receptor for Ang-(1–7) [16].…”

Immunohistochemical localization of the angiotensin-(1–7) receptor Mas in the murine forebrain

“…However, Mas may not only lead to the release of nitric oxide by interacting with AT1 receptors but also be capable of directly acting on nitric oxide (NO) formation (Gwathmey et al 2010). Within the amygdala, Ang-(1-7) is capable of increasing LTP and data hint that this effect is mediated by nitric oxide, since blockage of NO-synthesis with L-NAME resulted in a blockage of the Ang-(1-7)-mediated increase in LTP (Albrecht 2007). Within the hippocampus, strong Mas immunoreactivity has been detected in the DG.…”

Angiotensin-converting enzyme 2, angiotensin-(1–7) and Mas: new players of the renin–angiotensin system

“…These conflicting findings are probably due to differences in the models used and to cell-specific Ang-(1-7) signaling in the kidney, for example the dependency of each model on COX-2-mediated events, which can be differentially modulated by Ang-(1-7) (Albrecht 2007, Menon et al 2007, and highlight the need for further in vivo studies related to the RAS and its novel axis in kidney disease.…”