Properly timed exposure to central ANG II prevents behavioral sensitization and changes in angiotensin receptor expression

Abstract

Previous studies show that the angiotensin type 1 receptor (AT1R) is susceptible to rapid desensitization, but that more chronic treatments that stimulate ANG II lead to sensitization of several responses. It is unclear, however, if the processes of desensitization and sensitization interact. To test for differences in AT1R expression associated with single or repeated injections of ANG II, we measured AT1R mRNA in nuclei that control fluid intake of rats given ANG II either in a single injection or divided into three injections spaced 20 min apart. Rats given a single injection of ANG II had more AT1R mRNA in the subfornical organ (SFO) and the periventricular tissue surrounding the anteroventral third ventricle (AV3V) than did controls. The effect was not observed, however, when the same cumulative dose of ANG II was divided into multiple injections. Behavioral tests found that single daily injections of ANG II sensitized the dipsogenic response to ANG II, but a daily regimen of four injections did not cause sensitization. Analysis of (125)I-Sar(1)-ANG II binding revealed a paradoxical decrease in binding in the caudal AV3V and dorsal median preoptic nucleus after 5 days of single daily injections of ANG II; however, this effect was absent in rats treated for 5 days with four daily ANG II injections. Taken together, these data suggest that a desensitizing treatment regimen prevents behavior- and receptor-level effects of repeated daily ANG II.

Associative learning contributes to the increased water intake observed after daily injections of angiotensin II

“…Additionally, the 3-h, 1-h, and 30-min delay groups drank less across all induction days when compared to intake of the no-delay group. Consistent with previous studies [14, 23], when no delay was imposed, rats drank more water on the fifth day of AngII than they drank on the first day of injections (t(8) = −6.34, p < 0.01; Figure 1b). …”

“…Alternatively, the increased intake could be due to a learned association between the injection of AngII and the resultant water intake after several pairings of AngII and drinking [23]. To test these competing hypotheses, we added a delay period (30 min, 1 h, or 3 h) between AngII and drinking during 4 consecutive induction days to remove or reduce the behavioral response, and tested the effect of this delay on AngII-induced intake on a fifth day of treatment.…”

“…Injections given within a relatively short period decrease the response to subsequent AngII [29]; however, daily injections of AngII increase water intake [14, 23]. More specifically, the drinking response to AngII by the fifth day of testing was significantly greater than the intake after AngII on the first day [14, 23]. The mechanism underlying the increased intake remains unclear, but the pattern of intake resembles a classical non-associative sensitization.…”

“…Analysis of receptor binding produced results that may be inconsistent with this hypothesis. Specifically, a reduction in AT 1 R binding was observed in the caudal AV3V and dMnPO, but not in other areas known to be targets of AngII for the control of drinking behavior, after daily exposure to AngII [23]. This could be consistent with sensitization if the receptor or its downstream signaling somehow becomes more efficient, but it also could indicate that the changes in intake require changes beyond a simple receptor-level sensitization, and may instead involve a form of associative learning.…”

Activation of G protein-coupled estrogen receptor 1 (GPER-1) decreases fluid intake in female rats

“…; 4.6 mg/kg; Akron Inc., Decatur, Il) and underwent bilateral ovariectomy surgery (OVX) as previously described (Santollo et al, 2013). In the same surgery, a chronic cannula was implanted (coordinates: 0.9 mm posterior and 1.4 mm lateral to bregma and 2.8 mm ventral to the surface of the skull) to allow delivery of substances to the right lateral ventricle as described previously (Santollo et al, 2013; Santollo et al, 2014) (rats in Experiment 5A were OVX, but not implanted with cannula). After surgery, all rats received a single injection of carprofen (sc, 5 mg/kg; Pfizer Animal Health, New York, NY) as a perioperative analgesic.…”