Acute repeated intracerebroventricular injections of angiotensin II reduce agonist and antagonist radioligand binding in the paraventricular nucleus of the hypothalamus and median preoptic nucleus in the rat brain

Abstract

Angiotensin II (Ang II) stimulates water and saline intakes when injected into the brain of rats. This arises from activation of the AT1 Ang II receptor subtype. Acute repeated injections, however, decrease the water intake response to Ang II without affecting saline intake. Previous studies provide evidence that Ang II-induced water intake is mediated via the classical G protein coupling pathway, whereas the saline intake caused by Ang II is mediated by an ERK 1/2 MAP kinase signaling pathway. Accordingly, the different behavioral response to repeated injections of Ang II may reflect a selective effect on G protein coupling. To test this hypothesis, we examined the binding of a radiolabeled agonist (125I-sarcosine1 Ang II) and a radiolabeled antagonist (125I-sarcosine1, isoleucine8 Ang II) in brain homogenates and tissue sections prepared from rats given repeated injections of Ang II or vehicle. Although no treatment-related differences were found in hypothalamic homogenates, a focus on specific brain structures using receptor autoradiography, found that the desensitization treatment reduced binding of both radioligands in the paraventricular nucleus of the hypothalamus (PVN) and median preoptic nucleus (MnPO), but not in the subfornical organ (SFO). Because G protein coupling is reported to have a selective effect on agonist binding without affecting antagonist binding, these findings do not support a G protein uncoupling treatment effect. This suggests that receptor number is more critical to the water intake response than the saline intake response, or that pathways downstream from the G protein mediate desensitization of the water intake response.

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

“…Additionally, in the kidney, losartan increases AT 1 R mRNA, but decreases AT 1 R binding (36). Moreover, recent studies from our laboratory found that repeated injections of large doses of ANG II (the doses used in experiment 1 here) decreased radioligand binding (27), whereas the repeated injections here produced no difference in mRNA levels. As such, a change in mRNA should be interpeted with caution, and these examples highlight the importance of measuring levels of the relevant protein whenever possible.…”

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

“…Moreover, although our presentation of these studies may give the sense that we see a dichotomy between a learned behavior and a pharmacological effect of AngII at its receptor, these studies do not rule out a role for altered AT 1 R expression or signaling in the behavioral effects observed here. Indeed, our previous studies using daily injections of AngII, and our studies of the desensitizing effect of more acute repeated injections, found AngII-induced changes in receptor binding and expression [23, 27]. In addition, studies in mice have shown that AngII-sensitive SFO neurons fall into at least two categories of cells, glutamatergic or GABAergic, and that these cells can promote or inhibit drinking, respectively [18].…”

“…In addition, studies in mice have shown that AngII-sensitive SFO neurons fall into at least two categories of cells, glutamatergic or GABAergic, and that these cells can promote or inhibit drinking, respectively [18]. Although this may not occur similarly in rats, it opens the intriguing possibilities that repeated exposure to AngII either causes a shift in the relative proportion of these cell types, or shifts the receptor expression from one cell type to the other; a change that would not be detected by our previous studies testing for changes in receptor binding [23, 27]. These and other receptor-level changes may certainly be related to the appetition observed here.…”

Sodium appetite elicited by low‐sodium diet is dependent on p44/42 mitogen‐activated protein kinase (extracellular signal‐regulated kinase 1/2) activation in the brain

“…Diverse studies have shown that an increase in RAAS activity leads to the activation of PKC, which appears to mediate the dipsogenic effect of Ang II . Furthermore, repeated exposure to Ang II leads to the desensitisation of water intake behaviour but not sodium appetite; some studies suggest that these differential responses are the result of a divergent signalling mechanism by which different signalling pathways could lead to specific behaviours such as ingesting either water or sodium . Thus, because the literature has indicated that Ang II‐induced sodium appetite is dependent on MAPK pathway activation by AT1R, we assessed the activation of this pathway by the degree of ERK phosphorylation in brain tissues after the consumption of a low‐sodium diet, a condition whereby Ang II levels are higher in plasma …”