Modulatory action of environmental enrichment on hormonal and behavioral responses induced by chronic stress in rats: Hypothalamic renin-angiotensin system components.

Environmental enrichment (EE) has been studied as a protocol that can improve brain plasticity and may protect against negative insults such as chronic stress. The aim of this study was to evaluate the effects of EE on the hormonal and behavioral responses induced by chronic mild unpredictable stress (CMS) in rats, considering the involvement of the renin-angiotensin system. Male adult rats were divided into 4 groups: control, CMS, EE, and CMS + EE, and the experimental protocol lasted for 7 weeks. EE was performed during 7 weeks, 5 days per week, 2 h per day. CMS was applied during weeks 3, 4, and 5. After the CMS (week 6), depression-like behavior was evaluated by forced swimming and sucrose consumption tests, anxiety level was evaluated using the elevated plus-maze test, and memory was evaluated using the Y-maze test. On week 7, the animals were euthanized and basal plasma levels of corticosterone and catecholamines were determined. The hypothalamus was isolated and tissue levels of angiotensin peptides were evaluated. CMS increased plasma corticosterone, norepinephrine, and epinephrine basal concentrations, induced depression-like behaviors, impaired memory, and increased hypothalamic angiotensin I, II, and IV concentrations. EE decreased stress hormones secretion, depression-like behaviors, memory impairment, and hypothalamic angiotensin II induced by stress. Reductions of anxiety-like behavior and norepinephrine secretion were observed in both stressed and unstressed groups. The results indicated that EE seemed to protect adult rats against hormonal and behavioral CMS effects, and that the reduction of angiotensin II could contribute to these effects.

Tactile stimulation of adult rats modulates hormonal responses, depression-like behaviors, and memory impairment induced by chronic mild stress: Role of angiotensin II.

Physical touch can help to decrease the effects of stress. The aim of this study was to evaluate the influence of tactile stimulation on the hormonal and behavioral responses of young adult rats submitted to chronic mild unpredictable stress (CMS), considering the role of angiotensin II (Ang II). In Experiment 1, male rats were divided into 4 groups: control, stress, tactile stimulation (TS), and stress + TS. CMS was applied for three weeks. Tactile stimulation was applied for seven weeks, five days a week. After the CMS protocol, depression-like behaviors were evaluated by forced swimming and sucrose consumption tests. Learning and memory were evaluated using the Y-maze test. Fifteen days after the CMS procedure, the animals were euthanized and the levels of stress hormones were determined. The hypothalamus was isolated for determination of the Ang II concentration. In Experiment 2, control and stressed rats, with or without treatment using losartan (angiotensin II type 1 receptor blocker), were evaluated using the same behavioral tests and the hypothalamus Ang II concentration was also determined. CMS increased plasma corticosterone, norepinephrine, and epinephrine concentrations, induced depression-like behaviors, impaired learning and memory, and increased the Ang II concentration in the hypothalamus. Tactile stimulation attenuated these stress-induced effects. Losartan treatment effectively prevented increase of the hypothalamic Ang II concentration and the development of depression-like behavior, and also reduced the impairment of learning and memory in the stressed animals. The results indicated that tactile stimulation seemed to protect adult rats against hormonal and behavioral chronic stress effects, and that Ang II could be involved in the CMS effects.

Brain angiotensin-converting enzymes: role of angiotensin-converting enzyme 2 in processing angiotensin II in mice.

Angiotensin (Ang)-converting enzyme 2 (ACE2) metabolizes Ang II to the vasodilatory peptide Ang(1-7), while neprilysin (NEP) generates Ang(1-7) from Ang I. Experiments used novel Surface Enhanced Laser Desorption Ionization-Time of Flight (SELDI-TOF) mass spectroscopic (MS) assays to study Ang processing. Mass spectroscopy was used to measure proteolytic conversion of Ang peptide substrates to their specific peptide products. We compared ACE/ACE2 activity in plasma, brain and kidney from C57BL/6 and NEP(-/-) mice. Plasma or tissue extracts were incubated with Ang I or Ang II (1296 or 1045, m/z, respectively), and generated peptides were monitored with MS. Angiotensin-converting enzyme 2 activity was detected in kidney and brain, but not in plasma. Brain ACE2 activity was highest in hypothalamus. Angiotensin-converting enzyme 2 activity was inhibited by the specific ACE2 inhibitor, DX600 (10 microm, 99% inhibition), but not by the ACE inhibitor, captopril (10 microm). Both MS and colorimetric assays showed high ACE activity in plasma and kidney with low levels in brain. To extend these findings, ACE measurements were made in ACE overexpressing mice. Angiotensin-converting enzyme four-copy mice showed higher ACE activity in kidney and plasma with low levels in hypothalamus. In hypothalamus from NEP-/- mice, generation of Ang(1-7) from Ang I was decreased, suggesting a role for NEP in Ang metabolism. With Ang II as substrate, there was no difference between NEP-/- and wild-type control mice, indicating that other enzymes may contribute to generation of Ang(1-7). The data suggest a predominant role of hypothalamic ACE2 in the processing of Ang II, in contrast to ACE, which is most active in plasma.