Role of serotonergic 5-HT1A and oxytocinergic receptors of the lateral septal area in sodium intake regulation

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Adrenergic mechanisms of the Kölliker-Fuse/A7 area on the control of water and sodium intake

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Central angiotensin II induces sodium bicarbonate intake in the rat

The aim of this work was to test mineral preference in hydrated rats that received a pulse intracerebroventricular (icv(p)) injection of ANG II at a dipsogenic dose (50 ng). The icv(p) ANG II induced a four-fold higher ingestion of 0.15 M NaHCO(3) than of other mineral solutions at palatable concentrations (0.15 M NaCl, 0.05 mM CaCl(2) and 0.01 M KCl) in a five-bottle test with water available in a fifth bottle; water intake was not consistently high in this test. Contrary to what is predicted by the mineralocorticoid/angiotensin II synergy hypothesis, the 0.15 M NaCl intake in the five-bottle test was not enhanced by icvp ANG H preceded by deoxycorticosterone (DOCA) treatment (2.5 mg/day for 3 days); neither was the NaHCO(3) intake. This result contrasted with the vigorous ingestion of both isotonic sodium solutions, but mostly of NaCl, rather than of other fluids, by sodium-depleted (furosemide 10 mg sc + 24 h removal ambient sodium) rats in a sodium appetite test. The results suggest that mineralocorticoid combined to icv(p) ANG II does not simulate the sodium preference shown during sodium appetite. The results also show that a dipsogenic dose of central ANG II induces a reliable ingestion of isotonic sodium bicarbonate in the rat. (C) 2007 Elsevier Ltd. All rights reserved.

Mineral intake independent from gastric irritation or pica by cell-dehydrated rats

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Central serotonergic and adrenergic/imidazoline inhibitory mechanisms on sodium and water intake

Recent studies have shown the existence of two important inhibitory mechanisms for the control of NaCl and water intake: one mechanism involves serotonin in the lateral parabrachial nucleus (LPBN) and the other depends on alpha(2)-adrenergic/imidazoline receptors probably in the forebrain areas. In the present study we investigated if alpha(2)-adrenergic/imidazoline and serotonergic inhibitory mechanisms interact to control NaCl and water intake. Male Holtzman rats with cannulas implanted simultaneously into the lateral ventricle (LV) and bilaterally into the LPBN were used. The ingestion of 0.3 M NaCl and water was induced by treatment with the diuretic furosemide (10 mg/kg of body weight)+the angiotensin converting enzyme inhibitor captopril (5 mg/kg) injected subcutaneously 1 h before the access of rats to water and 0.3 M NaCl. Intracerebroventricular (i.c.v.) injection of the alpha(1)-adrenergic/imidazoline agonist clonidine (20 nmol/l RI) almost abolished water (1.6 +/- 1.2, vs. vehicle: 7.5 +/- 2.2 ml/2 h) and 0.3 M NaCl intake (0.5 +/- 0.3, vs. vehicle: 2.2 0.8 ml/2 h). Similar effects were produced by bilateral injections of the 5HT(2a/2b) serotonergic agonist 2,5-dimetoxy-4-iodoamphetamine (DOI, 5 mug/0.2 mul each site) into the LPBN on water (3.6 +/- 0.9 ml/2 h) and 0.3 M NaCl intake (0.4 +/- 0.2 m1/2 h). Injection of the (alpha(2)-adrenergic/imidazoline antagonist idazoxan (320 nmol) i.c.v. completely blocked the effects of clonidine on water (8.4 +/- 1.5 ml/2 h) and NaCl intake (4.0 +/- 1.2 ml/2 h), but did not change the effects of LPBN injections of DOI on water (4.2 +/- 1.0 ml/2 h) and NaCl intake (0.7 +/- 0.2 ml/2 h). Bilateral injections of methysergide (4 mug/0.2 mul each site) into the LPBN increased 0.3 M NaCl intake (6.4 +/- 1.9 ml/2 h), not water intake. The inhibitory effect of i.c.v. clonidine on water and 0.3 M NaCl was still present after injections of methysergide into the LPBN (1.5 +/- 0.8 and 1.7 +/- 1.4 ml/2 h, respectively). The results show that the inhibitory effects of the activation of a,-adrenergic/imidazoline receptors in the forebrain are still present after blockade of the LPBN serotonergic mechanisms and vice versa for the activation of serotonergic mechanisms of the LPBN. Therefore, each system may act independently to inhibit NaCl and water intake. (C) 2002 Elsevier B.V. B.V. All rights reserved.

Idazoxan and the effect of intracerebroventricular oxytocin or vasopressin on sodium intake of sodium-depleted rats

The alpha(2)-adrenergic agonist clonidine and the neuropeptide oxytocin, inhibit sodium intake when injected intracerebroventricularly (i.c.v.). The present work investigates whether (1) vasopressin also inhibits sodium intake when injected i.c.v., and (2) the effect of oxytocin and of vasopressin on sodium intake is affected by i.c.v. injection of idazoxan, an alpha(2)-adrenergic antagonist. Clonidine (30 nmol), oxytocin (40, 80 nmol) and vasopressin (40, 80 nmol) were injected i.c.v. 20 min prior to a 1.5% NaCl appetite test, in rats depleted of sodium for 24 h by a combination of a single s.c. injection of furosemide (10 mg/rat) and removal of ambient sodium. Every dose of clonidine, oxytocin and vasopressin inhibited the 1.5% NaCl intake. Seizures were observed with the higher dose of vasopressin, but not with either dose of oxytocin. The effect of i.c.v. injection of clonidine (30 nmol), oxytocin (80 nmol) or vasopressin (40 nmol) was partially inhibited by prior i.c.v. injection of idazoxan (160, 320 nmol). The results suggest that the inhibition of 1.5% NaCl intake induced by i.c.v. injection of neuropeptides in sodium-depleted rats depends, in part, on the activation of central alpha(2)-adrenoceptors. (C) 1997 Elsevier B.V. B.V. All rights reserved.

Serotonergic mechanisms of the lateral parabrachial nucleus and cholinergic-induced sodium appetite

Central cholinergic mechanisms are suggested to participate in osmoreceptor-induced water intake. Therefore, central injections of the cholinergic agonist carbachol usually produce water intake (i.e., thirst) and are ineffective in inducing the intake of hypertonic saline solutions (i.e., the operational definition of sodium appetite). Recent studies have indicated that bilateral injections of the serotonin receptor antagonist methysergide into the lateral parabrachial nucleus (LPBN) markedly increases salt intake in models involving the activation of the renin-angiotensin system or mineralocorticoid hormones. The present studies investigated whether sodium appetite could be induced by central cholinergic activation with carbachol (an experimental condition where only water is typically ingested) after the blockade of LPBN serotonergic mechanisms with methysergide treatment in rats. When administered intracerebroventricularly in combination with injections of vehicle into both LPBN, carbachol (4 nmol) caused water drinking but insignificant intake of hypertonic saline. In contrast, after bilateral LPBN injections of methysergide (4 mug), intracerebroventricular carbachol induced the intake of 0.3 M NaCl. Water intake stimulated by intracerebroventricular carbachol was not changed by LPBN methysergide injections. The results indicate that central cholinergic activation can induce marked intake of hypertonic NaCl if the inhibitory serotonergic mechanisms of the LPBN are attenuated.

Paraventricular nucleus administration of DuP753 or PD123319 inhibits the effects of angiotensin on water and sodium intake

We determined the effects of DuP753 and PD123319 (both nonpeptides and selective antagonists of the AT(1) and AT(2) angiotensin receptors, respectively), and [Sar(1), Ala(8)]ANG II (a non-selective peptide antagonist of angiotensin receptors) on water and 3%NaCl intake induced by administration of angiotensin II (ANG II) into the paraventricular nucleus (PVN) of sodium-depleted Holtzman rats weighing 250-300 g. Twenty hours before the experiments, the rats were depleted of sodium using furosemide (10 ng/rat, sc). The volume of drug solution injected was 0.5 mu l over a period of 10-15 sec. Water and sodium intake were measured at 0.25, 0.5, 1.0 and 2.0 h. Pre-treatment with DuP753 (14 rats) at a dose of 60 ng completely abolished the water intake induced by injection of 12 ng of ANG II (15 rats) (6.4 +/- 0.6 vs 1.4 +/- 0.3 ml/2 h), where [Sar(1), Ala(8)]ANG II (12 rats) and PD123319 (10 rats) at the doses of 60 ng partially blocked water intake (6.4 +/- 0.6 vs 2.9 +/- 0.5 and 2.7 +/- 0.2 ml/2 h, respectively). In the same animals, [Sar(1), Ala(8)]ANG II, DuP753, and PD123319 blocked the sodium intake induced by ANG II (9.2 +/- 1.6 vs 3.3 +/- 0.6, 1.8 +/- 0.3, and 1.4 +/- 0.2 ml/2 h, respectively). These results indicate that both DuP753 and PD123319, administered into the PVN, blocked the water and sodium intake induced by administration of ANG II into the same site.

Antagonism of clonidine injected intracerebroventricularly in different models of salt intake

Clonidine, an alpha 2-adrenergic agonist, injected into the brain inhibits salt intake of animals treated by the diuretic model of sodium depletion. In the present study, we address the question of whether central injection of clonidine also inhibits salt intake in animals deprived of water or in the need-free state. Saline or clonidine (30 nmol) was injected into the anterior third ventricle of 24-h sodium-depleted (furosemide + removal of ambient sodium), of 24-h water-deprived and of normovolemic (need-free state) adult male rats, Clonidine injected intracerebroventricularly (icv) inhibited the 1.5% NaCl intake for 120 min by 50 to 90% in every model tested. Therefore, different models of salt intake are inhibited by icv injection of clonidine, Idazoxan, an alpha 2-adrenergic antagonist, injected icy at a dose of 160 nmol, inhibited the effect of clonidine only in the furosemide + removal of ambient sodium model of salt intake. This indicates that the antagonism of this effect by idazoxan is dependent on the body fluid/sodium status of the animal.

Sedation and need-free salt intake in rats treated with clonidine

The effect of intraperitoneal injection of clonidine (9-72 mu g/kg) on need-free 1.5% NaCl intake and on performance (defined as percent of a complete trial) in the rotarod test, was studied in normovolemic adult male rats. Clonidine (18 and 36 mu g/kg) inhibited the 1.5% NaCl intake in a 2-h test at doses that did not alter the performance in the rotarod test. The dose of 36 mu g/kg did not inhibit 10% sucrose intake. Only the highest dose (72 mu g/kg) of clonidine inhibited the 1.5% NaCl intake and the performance in the rotarod test, and produced signs of sedation. Sedation was determined either by change in posture (immobility or lack of postural tonus) of the animals during the ingestive test or by their performance in the rotarod test. The results suggest that sedation is not a determinant effect on the inhibition of 1.5% NaCl intake induced by clonidine. (C) 1999 Elsevier B.V.

PROGESTERONE ADMINISTRATION TO OVARIECTOMIZED RATS REDUCES WATER AND SALT INTAKE INDUCED BY CENTRAL ADMINISTRATION OF ANGIOTENSIN-II

We tested the effects of estradiol, progesterone and testosterone on water and salt intake induced by angiotensin II (ANG II) injected into the third ventricle of female Holtzman rats weighing 250-300 g. The water and salt ingestion observed after 120 min in the control experiments (injection of 0.5 mu l of 0.15 M NaCl into the third ventricle) was 1.6 +/- 0.3 ml (N = 10) and 0.3 +/- 0.1 ml (N = 8) in intact rats, respectively, and 1.4 +/- 0.3 ml (N = 10) and 0.2 +/- 0.1 (N = 8) in ovariectomized rats, respectively. ANG II injected in intact rats (4, 6, 12, 25, and 50 ng, icv, in 0.5 mu l saline) induced an increase in water intake (4.3 +/- 0.6, 5.4 +/- 0.7. 7.8 +/- 0.8, 10.4 +/- 1.2, 11.2 +/- 1.4 ml/120 min, respectively) (N = 43). The same doses of icv ANG II in intact rats increased the 3% NaCl intake (0.9 +/- 0.2; 1.4 +/- 0.3, 2.3 +/- 0.4, 2.2 +/- 0.3. and 2.5 +/- 0.4 ml/120 min, respectively) (N = 42). When administered to ovariectomized rats ANG II induced comparable amounts of water intake (4.0 +/- 0.5, 4.8 +/- 0.6, 6.9 +/- 0.7. 9.6 +/- 0.8, and 10.9 +/- 1.2 ml/120 min, respectively) (N = 43) but there was a significant decrease of 3% NaCl solution ingestion (0.3 +/- 0.1, 0.4 +/- 0.1, 0.8 +/- 0.2, 0.7 +/- 0.2, and 0.6 +/- 0.2 ml/120 min, respectively) (N = 44). Estrogen (50 mu g), progesterone (25 ng), and testosterone (300 mu g) were injected daily into ovariectomized rats for 21 days. Treatment with estrogen decreased the water intake and abolished the saline ingestion induced by icy injection of ANG II (12 ng (2.8 +/- 1.2 and 0.3 +/- 0.1 ml/120 min, respectively) (N = 8). Treatment with progesterone also reduced the water intake (3.3 +/- 0.6 ml/120 min) (N = 8) and abolished the ANG II-induced saline ingestion (0.4 +/- 0.1 ml/120 min) (N = 8), but these effects were not observed with testosterone (6.4 +/- 0.8 and 2.2 +/- 0.3 ml/120 min, respectively) (N = 8). These results indicate that ANG II induces a greater increase in sodium intake in intact female rats than in ovariectomized rats and that estrogen and progesterone impair water and sodium intake in ovariectomized rats.

Hindbrain serotonin and the rapid induction of sodium appetite

Both systemically administered furosemide and isoproterenol produce water intake (i.e., thirst). Curiously, however, in light of the endocrine and hemodynamic effects produced by these treatments, they are remarkably ineffective in eliciting intake of hypertonic saline solutions (i.e., operationally defined as sodium appetite). Recent work indicates that bilateral injections of the serotonin receptor antagonist methysergide into the lateral parabrachial nuclei (LPBN) markedly enhance a preexisting sodium appetite. The present studies establish that a de novo sodium appetite can be induced with LPBN-methysergide treatment under experimental conditions in which only water is typically ingested. The effects of bilateral LPBN injections of methysergide were studied on the intake of water and 0.3 M NaCl following acute (beginning 1 h after treatment) diuretic (furosemide)-induced sodium and water depletion and following subcutaneous isoproterenol treatment. With vehicle injected into the LPBN, furosemide treatment and isoproterenol injection both caused water drinking but essentially no intake of hypertonic saline. In contrast, bilateral treatment of the LPBN with methysergide induced the intake of 0.3 M NaCl after subcutaneous furosemide and isoproterenol. Water intake induced by subcutaneous furosemide or isoproterenol was not changed by LPBN-methysergide injections. The results indicate that blockade of LPBN-serotonin receptors produces a marked intake of hypertonic NaCl (i.e., a de novo sodium appetite) after furosemide treatment as well as subcutaneous isoproterenol.

Periodontal disease reduces water and sodium intake induced by injection of muscimol into the lateral parabrachial nucleus

Objective: Gamma-aminobutyric acid A (GABAA) receptor activation with muscimol in the lateral parabrachial nucleus (LPBN) induces water and 0.3 M NaCl intake. The purpose of this study was to investigate whether a local inflammatory event, such as periodontal disease (PD), is able to alter the effects of muscimol on water and 0.3 M NaCl intake in fluid-replete rats and in rats treated with furosemide (FURO) combined with captopril (CAP) injected subcutaneously. Design: Male Wistar rats were divided into two groups: with PD and those without PD (control condition). Fifteen days after PD, both groups had cannulas implanted bilaterally into the LPBN. Results: In fluid-replete rats without PD, injections of muscimol (0.5 nmol/0.2 μl) into the LPBN induced 0.3 M NaCl and water intake and a pressor response. In fluid-replete rats with PD, a decrease was observed in water intake and pressor response but not in 0.3 M NaCl intake. In control rats with FURO + CAP treatment, injections of muscimol into the LPBN increased 0.3 M NaCl and water intake. In PD rats with FURO + CAP treatment, a decrease was observed in 0.3 M NaCl and water intake after muscimol in the LPBN. Alveolar bone loss and interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) plasmatic concentration were higher in PD rats in comparison with controls. Conclusion: These results suggest that PD is able to reduce the pressor response and the dipsogenic and natriorexigenic effects induced by the activation of GABAA receptors in the LPBN, probably due to the elevation of the plasmatic concentration of pro-inflammatory cytokines IL-6 and TNF-α. © 2013 Elsevier Ltd. All rights reserved.

Facilitation of sodium intake by combining noradrenaline into the lateral parabrachial nucleus with prazosin peripherally

Injections of noradrenaline into the lateral parabrachial nucleus (LPBN) increase arterial pressure and 1.8% NaCl intake and decrease water intake in rats treated with the diuretic furosemide (FURO) combined with a low dose of the angiotensin converting enzyme inhibitor captopril (CAP). In the present study, we investigated the influence of the pressor response elicited by noradrenaline injected into the LPBN on FURO + CAP-induced water and 1.8% NaCl intake. Male Holtzman rats with bilateral stainless steel guide-cannulas implanted into LPBN were used. Bilateral injections of noradrenaline (40 nmol/0.2 μl) into the LPBN increased FURO + CAP-induced 1.8% NaCl intake (12.2 ± 3.5, vs., saline: 4.2 ± 0.8 ml/180 min), reduced water intake and strongly increased arterial pressure (50 ± 7, vs. saline: 1 ± 1 mm Hg). The blockade of the α1 adrenoceptors with the prazosin injected intraperitoneally abolished the pressor response and increased 1.8% NaCl and water intake in rats treated with FURO + CAP combined with noradrenaline injected into the LPBN. The deactivation of baro and perhaps volume receptors due to the cardiovascular effects of prazosin is a mechanism that may facilitate water and NaCl intake in rats treated with FURO + CAP combined with noradrenaline injected into the LPBN. Therefore, the activation of α2 adrenoceptors with noradrenaline injected into the LPBN, at least in dose tested, may not completely remove the inhibitory signals produced by the activation of the cardiovascular receptors, particularly the signals that result from the extra activation of these receptors with the increase of arterial pressure. © 2013 Elsevier Inc.

Participação dos receptores purinérgicos do núcleo do trato solitário no controle da ingestão hidro-mineral

Pós-graduação em Ciências Fisiológicas - FOAR