L. Castro

Central 5-HT2B/2C and 5-HT3 receptor stimulation decreases salt intake in sodium-depleted rats

In the present study, we investigated the participation of central 5-HT(2B/2C) and 5-HT(3) receptors in the salt intake induced by sodium depletion in Wistar male rats. Sodium depletion was produced by the administration of furosemide associated with a low salt diet. Third ventricle injections of mCPP, a 5-HT(2B/2C) agonist, at doses of 80, 160 and 240 nmol, promoted a dose-dependent reduction in salt intake in sodium-depleted rats. The inhibitory effect produced by central administration of mCPP was abolished by the central pretreatment with SDZ SER 082, a 5-HT(2B/2C) antagonist. Similar results were obtained with third ventricle injections of m-CPBG (80, 160 and 240 nmol), a selective 5-HT(3) agonist that also induced a dose-related decrease in salt intake in sodium-depleted rats. The central pretreatment with LY-278,584, a selective 5-HT(3) receptor antagonist, was able to impair the salt intake inhibition elicited by third ventricle injections of m-CPBG. Central administration of each one of the antagonists alone or a combination of both antagonists together did not significantly change salt intake after sodium depletion. On the other hand, the central administration of both mCPP and m-CPBG, in the highest dose used to test their effect on salt intake (240 nmol), was unable to modify blood pressure in sodium-depleted rats. It is concluded that: (1) pharmacological activation of central 5-HT(2B/2C) and 5-HT(3) receptors diminishes salt intake during sodium depletion, (2) an inhibitory endogenous drive exerted by central 5-HT(2B/2C) and 5-HT(3) receptors does not seem to exist and (3) the reduction in salt intake generated by the pharmacological activation of these central receptors is not produced by an acute hypertensive response.

Central administration of mCPP, a serotonin 5-HT2B/2C agonist, decreases water intake in rats

In the present study, we investigated in rats the effect of third ventricle injections of 1-(3-chlorophenyl)piperazine (mCPP), a 5-HT(2) receptor agonist, on water intake induced by three different physiological stimuli: fluid deprivation, acute salt load and hypovolemia. Injections of mCPP in the doses of 80 and 160 nmol/rat were able to decrease water intake in all three conditions studied. Third ventricle injections of mCPP (160 nmol/rat) were no longer able to diminish water intake in the groups of rats pretreated with central injections of an equimolar amount of (+)-cis-4,5,7a,8,9,10,11,11a-octahydro-7H-10-methylindolo[1,7-bc][2,6]-naphthyridine (SDZ SER 082), a selective 5-HT(2B/2C) antagonist. The central administration of mCPP (160 nmol/rat) was not able to modify the intake of a 0.1% saccharin solution. It is suggested that the central activation of a 5-HT(2B/2C) component is able to impair the drive for water intake induced by the physiological stimuli represented by fluid deprivation, acute salt load and hypovolemia. This effect seems not to be consequent on a general nonspecific central nervous system depression or on a locomotor deficit, because saccharin intake is not affected by third ventricle injections of mCPP.

Central 5-HT4 Receptors and Drinking Behavior

The aim of the present study was to investigate the effect of acute third ventricle injections of two different 5-HT(4) receptor antagonists, GR 113808 and SB 204070, on water intake in different situations. Injections of 80 nmol/rat of both GR 113808 and SB 204070 were unable to modify water intake in normohydrated rats. Pretreatment with GR 113808 (40 and 80 nmol/rat) and SB 204070 (80 and 160 nmol/rat) blunted water intake after third ventricle injections of angiotensin II (9.6 pmol/rat) compared to saline-pretreated controls. Pretreatment with 80 nmol/rat of both antagonists potentiated drinking induced by third ventricle injections of carbachol (11.0 nmol/rat) compared to saline-pretreated control. In all doses employed, none of the compounds was able to modify water intake in dehydrated rats. A separate control test using one-bottle taste aversion paradigm indicated that the reduction in water intake observed in some of the present experiments could not be attributed to a drug-induced malaise. It is suggested that central 5-HT(4) receptors exert a dualistic role on the control of water intake potentiating angiotensin II-induced drinking and inhibiting thirst induced by central cholinergic activation

Zinc and water intake in rats: investigation of adrenergic and opiatergic central mechanisms

We have demonstrated that central administration of zinc in minute amounts induces a significant antidipsogenic action in dehydrated rats as well as in rats under central cholinergic and angiotensinergic stimulation. Here we show that acute third ventricle injections of zinc also block water intake induced by central ss-adrenergic stimulation in Wistar rats (190-250 g). Central inhibition of opioid pathways by naloxone reverses the zinc-induced antidipsogenic effect in dehydrated rats. After 120 min, rats receiving third ventricle injections of isoproterenol (160 nmol/rat) exhibited a significant increase in water intake (5.78 +/- 0.54 ml/100 g body weight) compared to saline-treated controls (0.15 +/- 0.07 ml/100 g body weight). Pretreatment with zinc (3.0, 30.0 and 300.0 pmol/rat, 45 min before isoproterenol injection) blocked water intake in a dose-dependent way. At the highest dose employed a complete blockade was demonstrable (0.54 +/- 0.2 ml/100 g body weight). After 120 min, control (NaAc-treated) dehydrated rats, as expected, exhibited a high water intake (7.36 +/- 0.39 ml/100 g body weight). Central administration of zinc blocked this response (2.5 +/- 0.77 ml/100 g body weight). Naloxone pretreatment (82.5 nmol/rat, 30 min before zinc administration) reverted the water intake to the high levels observed in zinc-free dehydrated animals (7.04 +/- 0.56 ml/100 g body weight). These data indicate that zinc is able to block water intake induced by central ss-adrenergic stimulation and that zinc-induced blockade of water intake in dehydrated rats may be, at least in part, due to stimulation of central opioid peptides.

Lead (Pb2+) and cadmium (Cd2+) inhibit the dipsogenic action of central beta-adrenergic stimulation by isoproterenol

We have previously demonstrated that acute third ventricle injections of both Pb2+ and Cd2+ impair the dipsogenic response elicited by three different situations: dehydration and central cholinergic or angiotensinergic stimulation. beta-Adrenergic activation is part of the multifactorial integrated systems operating in drinking behavior control in the central nervous system. In the present study acute third ventricle injections of Pb2+ (3, 30 and 300 pmol/rat) or Cd2+ (0.3, 3 and 30 pmol/ rat) blocked the dipsogenic response induced by third ventricle injections of isoproterenol (ISO; 160 nmol/rat) in a dose-dependent manner. Normohydrated animals receiving ISO + NaAc (sodium acetate) or saline (controls) displayed a high water intake after 120 min (ISO+saline = 5.78 +/- 0.54 ml/100 g; ISO+NaAc = 6.00 +/- 0.6 ml/100 g). After the same period, animals receiving ISO but pretreated with PbAc at the highest dose employed (300 pmol/rat) drank 0.78 +/- 0.23 ml/100 g while those receiving ISO and pretreated with the highest dose of CdCl2 (30 pmol/rat) presented a water intake of 0.7 +/- 0.30 ml/100 g. Third ventricle injections of CdCl2 (3 nmol/rat) or PbAc (3 nmol/rat) did not modify food intake in rats deprived of food for 24 h. Thus, general central nervous system depression explaining the antidipsogenic action of the metals can be safely excluded. It is concluded that both Pb2+ and Cd2+ inhibit water intake induced by central beta-adrenergic stimulation.

Natriuretic and kaliuretic effects of central acute cadmium administration in rats

We studied the acute effects of cadmium third ventricle injections on renal excretion of water, sodium and potassium in rats previously submitted to an oral water load equivalent to 10% of their body weight. Injections of cadmium chloride (0.03, 0.3, and 3.0 nmol/rat) significantly increased sodium and potassium renal excretion without changing urine flow. Pretreatment with losartan, an angiotensin II AT1 receptor antagonist (10.8 nmol/rat into the third ventricle 10 min before central cadmium administration) inhibits the natriuretic effect of this metal, being unable to reverse its kaliuretic effect. Pretreatment with gadolinium, a calcium-channel blocker (0.3 nmol/rat into the third ventricle 20 min before central cadmium administration) abolishes both the natriuretic and the kaliuretic response of cadmium. The data clearly show that cadmium injections into the third ventricle disturb central regulation of renal function leading to an increased renal loss of sodium and potassium. It is also evident that the natriuretic action of the metal depends on an increase in brain angiotensin II release. Also, the functional integrity of calcium channels is required for the expression of both the natriuretic and the kaliuretic effects of the metal.

Central lead administration induces natriuretic and kaliuretic effects in rats

The aim of the present experiments was to discern whether central acute lead injections affect brain control of renal function. Adult Wistar male rats received third-ventricle injections of lead acetate in three different doses (0.03, 0.3, and 3.0 nmol/rat). Lead acetate induced a significant increase in renal excretion of sodium and potassium. Pretreatment with losartan, a selective angiotensin II AT1 receptor antagonist (10.8 nmol/rat into the third ventricle 10 min before central lead injection), inhibits lead-induced natriuretic and kaliuretic effects. In addition, pretreatment with gadolinium, a calcium-channel blocker (0.3 nmol/rat into the third ventricle 20 min before central lead administration), reversed the increase in renal excretion of sodium and potassium provoked by central lead administration. Taken together, the data presented here suggest that lead injected into the third ventricle increases renal excretion of sodium and potassium by a mechanism that depends on the functional integrity of central angiotensin II AT1 receptors and calcium channels.

Effect of the intracerebroventricular administration of GR 113808, a selective 5-HT4 antagonist, on water intake during hyperosmolarity and hypovolemia

We demonstrate here that acute third ventricle injections of GR 113808, a highly selective 5-HT4 antagonist, decrease water intake induced by a previous salt load while potentiating drinking elicited by hypovolemia induced by previous subcutaneous administration of polyethylene glycol in male Wistar rats (200 +/- 20 g). At the dose of 160 nmol/rat, third ventricle injections of GR 113808 induced a significant reduction of water intake in salt-loaded animals after 120 min as compared to salt-loaded animals receiving third ventricle injections of saline (salt load + GR = 3.44 +/- 0.41 ml, N = 12; salt load + saline = 5.74 +/- 0.40 ml, N = 9). At the dose of 80 nmol/rat, GR 113808 significantly enhanced water intake in hypovolemic animals after 120 min as compared to hypovolemic animals receiving third ventricle injections of saline (hypovol + GR = 4.01 +/- 0.27 ml, N = 8; hypovol + saline = 2.41 +/- 0.23 ml, N = 12). We suggest that central 5-HT4 receptors may exert a positive drive on water intake due to hyperosmolarity and a negative input on drinking provoked by hypovolemia.

Central administration of zinc increases renal sodium and potassium excretion in rats.

The aim of the present study was to investigate the effect of acute third ventricle injections of zinc on the brain control of renal sodium and potassium excretion. Adult Wistar male rats received third ventricle injections of zinc acetate in three different doses (0.03, 0.3 and 3.0 nmol/rat). Third ventricle administration of zinc acetate provoked a significant intensification of natriuresis and kaliuresis as compared to sodium acetate-treated controls. When rats were pretreated with losartan, a selective angiotensin II AT1 receptor antagonist (10.8 nmol/rat into the third ventricle 10 min before central zinc injection) the increase in both natriuresis and kaliuresis was abolished. Furthermore, pretreatment with gadolinium, a calcium channel blocker (0.3 nmol/rat into the third ventricle 20 min before central zinc injection), also blunted the increase in renal sodium and potassium excretion seen in animals receiving zinc alone. In a group of rats receiving the same water load used in the previous experiments, the injection of zinc acetate into the third ventricle (3.0 nmol/rat) did not modify arterial blood pressure. It is suggested that zinc in the central nervous system may be involved in the control of renal sodium and potassium excretion by a mechanism unrelated to blood pressure increase. It is also shown that both natriuretic and kaliuretic actions of zinc depend on AT1 receptor activation. Whatever should be the mechanism(s) related to the central effects of zinc here evidenced, the functional integrity of calcium channels is required.

Central lead administration inhibits water intake and sodium appetite in rats

We have demonstrated that acute third ventricle injections of lead acetate (PbAc) exert a powerful antidipsogenic effect and induce a significant increase in renal sodium excretion. In the present study we confirm the antidipsogenic effect of lead and demonstrate that central administration of this metal, in minute amounts, significantly reduces salt intake both during dehydration and after central angiotensinergic stimulation. Adult male Wistar rats had the third ventricle cannulated seven days before the experiments. During this period they had free access to distilled water and hypertonic saline solution (1.5%). After a 24-h period of fluid deprivation, experimental animals received third ventricle injections of PbAc (0.3, N = 8 and 3.0 nmol/rat, N = 14) while controls received sodium acetate (NaAc; 3.0 nmol/rat, N = 10). Rats treated with PbAc at the highest dose showed a significant reduction (P<0.05) both in water and hypertonic saline intake when compared to controls. When the effect of lead administration on angiotensin II-induced water and salt intake was studied, normohydrated animals received third ventricle injections of angiotensin II (9.6 nmol/rat) after pretreatment with 3.0 nmol/rat of PbAc (experimental group, N = 10) or NaAc (controls, N = 8). The group pretreated with PbAc presented a significant reduction (P<0.05) in both water and salt intake compared to controls. Thus, this study confirms the antidipsogenic effect of central lead injections and demonstrates that the presence of lead in the brain exerts a significant inhibition of sodium appetite.