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 (AV3V) region 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.

Keywords: AV3V; Angiotensin; Desensitization; Thirst.

Figure 1

Injection of a low dose of AngII into the AV3V stimulated water intake. A) When given icv, AngII stimulated a significant increase in 30-min water intake at the 10 ng dose (p<0.05 vs all other groups), but 1 ng AngII did not stimulate intake (p>0.05 vs vehicle). B) When cannulae terminated in the AV3V, rats drank significantly more water to injection of 1 ng AngII than did rats with cannulae that terminated outside of the AV3V (p<0.05). C) Illustration depicting cannula placement in rats from panel B. Closed circles represent accurate cannula placements (hits) and open circles represent placements outside of the AV3V (misses).

Figure 2

Repeated AngII injections in the AV3V resulted in behavioral desensitization. A) Timeline of the experiment showing treatment regimen (TR) injections and the test injection that immediately preceded the intake measures. B) Rats were given an icv treatment regimen (TR) of either vehicle (TBS) or AngII (300 ng or 100 ng) prior to all rats receiving an icv AngII (100 ng) test injection. Rats that received a 300 ng AngII TR drank less to the test injection than did rats given either a vehicle or a 100 ng AngII TR (p<0.05). A 100 ng AngII TR did not reduce intake stimulated by the test injection (p>0.05 vs vehicle TR). C) When rats were given either an AngII (100 ng) or a vehicle (TBS) TR into the AV3V, rats given an AngII TR drank less water 5 min after an AngII (100 ng) test injection in the AV3V (p<0.05).

Figure 3

Repeated AngII administration in the AV3V caused reduced water intake stimulated by an icv AngII challenge. A) When cannulae terminated in the AV3V, rats given an AngII (100 ng) treatment regimen (TR) drank less water 10 min after an icv AngII (100 ng) test injection than did rats given a vehicle (TBS) TR prior to the same test injection (p<0.05). B) When cannulae terminated outside the AV3V, there was no difference in intake between rats that received either an AngII (100 ng) or a vehicle (TBS) TR in the parenchyma prior to an icv AngII (100 ng) test injection (p>0.05).

Figure 4

AT₁ receptor activation in the AV3V was required for the reduced water intake observed after repeated icv AngII administration. Rats were given pretreatment (PreTR) of either vehicle (TBS) or losartan (1 μg) into the AV3V prior to receiving an icv treatment regimen (TR) of either AngII (300 ng) or vehicle (TBS). All rats then received an icv test injection of AngII (100 ng). A) There was a significant Time × PreTR × TR interaction 10 min after the test injection (p<0.05). B) At 10 min after the test injection, rats pretreated with vehicle had reduced water intake after an AngII TR (p<0.05). PreTR with losartan reduced water intake after a vehicle TR (p<0.05 vs veh/veh), but losartan PreTR blocked the desensitizing effect of the AngII TR (p>0.05 vs veh/veh). Bars with different letters are significantly different from each other (p<0.05).