The anteroventral third ventricle region is critical for the behavioral desensitization caused by repeated injections of angiotensin II

Abstract

A single central injection of angiotensin II (AngII) potently increases water intake; however, a growing body of research suggests that repeated, acute intracerebroventricular injections of AngII cause a reduction in the dipsogenic response to subsequent AngII. This AngII-induced behavioral desensitization is specific to the effects of angiotensin and mediated by the angiotensin type-1 (AT1) receptor. The neuroanatomical substrate for this phenomenon, however, remains unknown. The anteroventral third ventricle region (AV3V) is an important site for the behavioral and physiological actions of AngII. Therefore, we hypothesized that this region also mediates the effects of repeated central AngII administration. In support of this hypothesis, we found that repeated injections of AngII into the AV3V reduced water intake stimulated by a test injection of AngII given into this region. Moreover, repeated AngII injections in the AV3V reduced water intake after AngII was injected into the lateral ventricle. These studies also demonstrate that activation of the AT1 receptor within the AV3V is required for AngII-induced behavioral desensitization because direct injection of the AT1 receptor antagonist, losartan, into the AV3V blocked the desensitizing effect of repeated AngII injections into the lateral ventricle. These findings provide additional support for a role of the AV3V in the dipsogenic actions of AngII, and suggest that this region is critical for the desensitization that occurs after acute repeated central injections of AngII.

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

“…Previous studies show that repeated treatment of ANG II desensitizes the AT 1 R Water Intake (ml) as quickly as 1 min in vitro and reduces the dipsogenic potency of ANG II (7,21,28,29,(32)(33)(34). On the basis of these findings, we hypothesized that repeated ANG II treatment would influence AT 1 R gene expression within nuclei involved in the control of fluid intake.…”

“…On the basis of these results, we hypothesized that the timing of ANG II administration could influence the development of sensitization. To test this hypothesis, we administered ANG II to rats, using a dose shown previously to cause sensitization (32)(33)(34)(35), but with a timing of administration more similar to our studies of desensitization (19). To this end, we gave rats daily injections of vehicle, 10 ng ANG II, 40 ng ANG II, or a total of 40 ng ANG II/day in four 10-ng injections with 20 min between each.…”

“…This experiment was performed to evaluate changes in AT1R mRNA caused by doses and administration paradigms used previously to show desensitization (32)(33)(34)(35) and to compare these effects to administration of the same amount of ANG II given in a single bolus. To this end, 24 rats were divided into one of three groups.…”

“…To evaluate changes in AT 1 R after doses of ANG II used previously to produce desensitization, we injected rats intracerebroventricularly with a treatment regimen of three 300-ng injections, each given 20 min apart (32)(33)(34) and compared them with rats given the same cumulative dose in a single intracerebroventricular bolus and rats given an injection of vehicle. ANG II treatment appeared to increase AT 1 R mRNA expression in a brain region-specific manner ( Fig.…”

“…Previous in vivo studies from our laboratory and in vitro studies by others demonstrate that the angiotensin type 1 receptor (AT 1 R) is susceptible to rapid desensitization if there is repeated exposure to ANG II within a short time frame (7,28,29,(32)(33)(34)(35). Behaviorally, this decreases the dipsogenic potency of ANG II treatment (21,(32)(33)(34)(35).…”