Role of various types of serotonin receptors in regulation of drinking behavior and salt appetite in vasopressin-deficient brattleboro rats

Serotonin 5-HT_1A receptor agonist 8-OH DPAT suppressed drinking behavior in Brattleboro and Wistar rats. 5-HT_1B agonist CGS-12066A and 5-HT_2A antagonist ketanserin did not affect drinking behavior in Brattleboro rats; 5-HT₃ antagonist ondansetron suppressed water consumption and 5-HT_1A agonist stimulated salt appetite in Brattleboro, but not in Wistar rats. Presumably, vasopressin regulates thirst and salt appetite by modulating sensitivity/density of various types of 5-HT receptors.     

Excessive drinking by rats with septal lesions during hypovolemia induced by subcutaneous colloid treatment

Rats with septal lesions consumed much more water than control rats did during a 24-hr test after subcutaneous administration of polyethylene glycol solution. Previous experiments have demonstrated that plasma renin activities are 35 to 70 times greater than basal levels after this treatment, and that rats with septal lesions overdrink when comparable levels are produced by systemic administration of renin. Thus, it seems likely that angiotensin was largely responsible for the exaggerated intakes that were elicited by the colloid. However, given their special sensitivity to the thirst-inducing effects of angiotensin, it is noteworthy that the brain-damaged animals drank normally during the first 8 hr of the test period because by then plasma renin activities should have been increased to values 20 to 40 times greater than basal levels. These findings therefore suggest that angiotensin usually contributes little as a dipsogen to thirst, even during such extensive hyperreninemia, and that it is only when angiotensin levels are higher still that drinking is stimulated.     

Ontogenetic role of angiontensin-converting enzyme in rats: Thirst and sodium appetite evaluation

We investigated the influence of captopril (an angiotensin converting enzyme inhibitor) treatment during pregnancy and lactation period on hydromineral balance of the male adult offspring, particularly, concerning thirst and sodium appetite. We did not observe significant alterations in basal hydromineral (water intake, 0.3 M NaCl intake, volume and sodium urinary concentration) or cardiovascular parameters in adult male rats perinatally treated with captopril compared to controls. However, male offspring rats that perinatally exposed to captopril showed a significant attenuation in water intake induced by osmotic stimulation, extracellular dehydration and beta-adrenergic stimulation. Moreover, captopril treatment during perinatal period decreased the salt appetite induced by sodium depletion. This treatment also attenuated thirst and sodium appetite aroused during inhibition of peripheral angiotensin II generation raised by low concentration of captopril in the adult offspring. Interestingly, perinatal exposure to captopril did not alter water or salt intake induced by i.c.v. administration of angiotensin I or angiotensin II. These results showed that chronic inhibition of angiotensin converting enzyme during pregnancy and lactation modifies the regulation of induced thirst and sodium appetite in adulthood.     

Thirst and sodium appetite after colloid treatment in rats: role of the renin-angiotensin-aldosterone system

Recent experiments indicated that rats usually develop sodium appetite 5 hr after subcutaneous injection of polyethylene glycol (PEG) solution. However, sodium appetite appeared within 30 to 60 min if the rats had been maintained on sodium-deficient diet instead of Purina chow for 2-4 days previously. Elevated levels of aldosterone paralleled the appearance of NaCl consumption in both circumstances. In the present experiments, sodium appetite was no longer potentiated by pretreatment maintenance on sodium-deficient diet when the hypersecretion of aldosterone after PEG administration was prevented by prior hypophysectomy. Conversely, sodium appetite was enhanced in PEG-treated rats when angiotensin II (AII) was produced in unusually large amounts in the brain, owing to the systemic administration of captopril. This latter effect occurred even when drinking water was withheld and plasma sodium concentrations were markedly elevated. These and other findings raise the possibility that the normal secretion of aldosterone in rats after PEG treatment might permit physiological amounts of AII to be effective in stimulating sodium appetite. Such actions would complement the accepted physiological role of the renin-angiotension-aldosterone system in the maintenance of blood pressure and sodium balance.     

Inhibition of food deprivation induced hypovolemia by saline consumption in rats

Food deprivation hypovolemia has been observed in a variety of mesic and desert adapted rodents. Xeric adapted rodent species appear to lose intravascular volume in proportion with body weight loss during food restriction, while mesically adapted rodent species lose intravascular volume at a rate much in excess to body weight loss. The laboratory rat was chosen as a representative mesically adapted rodent species for the purpose of investigating this phenomenon. Acute isotonic saline stomach loads had no appreciable influence upon intravascular volume reparation induced by either 2 or 4 days of food deprivation. Free and forced choice saline solutions presented during starvation were noted to significantly inhibit hypovolemia, however, there was no evidence for reparation of carcass water losses. It is suggested that the availability of only water during fasting results in the premature termination of drinking due to cellular over-hydration. When water and a source of sodium are available the food deprived rat can more adequately maintain ad lib intravascular volume. There is presently no explanation for the absence of repaired carcass water.     

Plasma hyperosmolality at the onset of drinking during starvation induced hypovolemia

Elevations of 2–4% in plasma osmolality were noted at the initiation of drinking following 4 days of fasting in rats. Paired animals food deprived for identical time periods but not drinking when blood sampled revealed ad lib levels of osmolality. Drinking initiation by 4 day food deprived rats following access to dry food was also accompanied by 2–4% elevations in plasma osmotic pressure. Substantial decreases in daily water consumption were observed during the 4 day food deprivation period accompanied by a mean plasma volume loss of 32% determined by T-1824 dye injection. Total blood volume loss was estimated to by 27%. Hematocrit was found to be the best estimator of plasma volume in starved rats. The elevations in plasma osmolality did not appear to be the result of uremia due to starvation induced protein catabolism. The data support the position that elevated plasma osmolality accompanies the initiation of drinking during extended fasting while return to ad lib set point osmolality accompanies cessation of drinking.     

Central kappa opioid receptors modulate salt appetite in rats

The role of the central opioid system in the control of water and salt intake is complex, with both stimulatory and inhibitory effects having been observed. The aim of the present study was to investigate the participation of the central κ-opioid receptors in the control of salt appetite. Male Wistar rats were submitted to two different experimental protocols: sodium deficit produced by the diuretic, furosemide, and brain angiotensinergic stimulation in rats under normal sodium balance. Lateral ventricle (LV) injections of Nor-binaltorphimine (Nor-BNI) at different doses (5, 10 and 20 nmol) inhibited hypertonic saline solution (1.5%) intake in sodium-depleted rats. The salt appetite induced by an LV injection of angiotensin II (Ang II) (10 ng) was also blocked by Nor-BNI injections into the LV, while no significant change was observed in water intake. Furthermore, the decrease in salt intake seems not to have been due to a general inhibition of locomotor activity or to any change in palatability, since central administration of Nor-BNI failed to modify the intake of a 0.1% saccharin solution when the animals were submitted to a "dessert test" or to induce any significant locomotor deficit in the open-field test. Also the central administration of Nor-BNI was unable to modify blood pressure in sodium-depleted animals. The present results suggest that activation of endogenous κ-opioid receptors modulates salt appetite induced by sodium depletion and by central angiotensinergic stimulation in rats.     

Forebrain sites of action for drinking and salt appetite to angiotensin or captopril

Three-hour infusions of angiotensin II (ANG II) agonists and antagonists were used to determine the relative sites of action of ANG in producing water drinking and salt appetite. In the first experiment, lateral ventricular (LV) but not fourth ventricular (4V) ANG II elicited water and saline intake, and LV but not 4V sarile, a competitive ANG II receptor blocker, reduced saline intake aroused by ip injections of 10 mg/kg furosemide and 6 mg/kg captopril. In the second experiment, water, but not saline, intake to furosemide-captopril treatment was reduced by sarile infusions into the subfornical organ (SFO). It is concluded that (a) brain ANG receptors for water and saline intakes are more accessible from the forebrain than the hindbrain ventricles and (b) receptors for water drinking, but not saline intake, after captopril reside in part in the SFO. Salt appetite appears to be dependent on ANG II receptors somewhere in the forebrain other than in the SFO.     

Change in salt appetite due to rehydration level in rats

Thermally dehydrated rats were given a choice of tap water and saline (0.9% or 1.8% NaCl), and the change in the salinity of their choice during rehydration was measured up to 15 hr. The rats consumed more water than saline for about 2 hr after the start of fluid replacement (about 55 mEq/l), while they consumed more saline than tap water (about 120 mEq/l) thereafter. Urine output and urinary Na output were only about 20% of their intake during the initial 4 hr of rehydration, while after 4 hr the output became almost equal with the intake. The change in salt intake occurred when about 90% of Na loss and 60% of fluid loss was regained. The results indicate that rats choose dilute salt solution to lower plasma osmolality during the initial period of the rehydration and then regain body fluid isotonically. Urine volume and urinary Na output increased only after volume repletion. Thus, osmoregulation with salt appetite has priority over fluid volume regulation in restitution from thermal dehydration.     

Angiotensin and salt appetite: physiological amounts of angiotensin given peripherally increase salt appetite in the rat

Two experiments were conducted in which adrenalectomized male Sprague-Dawley rats were maintained ad lib on distilled water, 3% saline, and sodium-free food. In Experiment 1, 45 rats were given 100, 200, 400, 800, and 1,000 micrograms/kg/day desoxycorticosterone acetate (DOCA) im for 5 days to determine the dose of DOCA that would produce the lowest voluntary saline intake, and 800 micrograms/kg/day was found to produce the nadir in saline intake. In Experiment 2, 40 rats were placed ad lib on distilled water, saline, and sodium-free food as described above, maintained on 800 micrograms/kg/day DOCA, and infused with 4, 25, 100 micrograms/kg/day angiotensin II (A II) or 0.9% saline. The three A II groups showed significant percentage changes in their saline intake above pre-A II levels; the saline control group showed no change in saline intake from pre-A II level. These results are interpreted to demonstrate the production of salt appetite in rats by peripheral administration of physiological doses of angiotensin II.     

Sodium appetite induced in rats by chronic administration of a thiazide diuretic

Characteristics of hydrochlorothiazide (HCZ)-induced sodium appetite were examined in rats fed with low sodium diet to which HCZ was added. Compared with controls, HCZ induced a robust appetite for 0.1 and 0.3 M NaHCO3. The intake of 0.3 M NaCl was only about one half that of NaHCO3, but was still greatly above control. In both cases, the intake of the sodium solution exceeded that of water, so the rats were taking a hypertonic mixture. The appetite was evident in both Sprague-Dawley and Long-Evans rats, but appeared to be more stable in the latter strain over at least 1 month. The diuretic and natriuretic effect of HCZ was sustained over this period. Plasma renin activity was elevated substantially in HCZ-treated rats, but aldosterone concentration was decreased. Administration of HCZ in food is a simple and reliable method for inducing a sustained, substantial, and need-based salt appetite in rats.     

Effects of bile duct ligation and captopril on salt appetite and renin-aldosterone axis in rats.

A ligation of the common bile duct (BDL) produces cholestasis and hypotension and increases the daily ingestion of sodium chloride solutions in rats. Low-dose captopril (CAP) treatment also modifies the ingestion of water and sodium in naive rats, and may do so in cholestatic rats. This study examined whether the elevated ingestion of saline by Long-Evans rats after BDL is associated with increased plasma renin activity (PRA), and whether treatment with a low dose of the angiotensin converting-enzyme inhibitor CAP further exacerbates fluid intake and PRA after BDL. In these experiments water and 0.3 M saline intake and PRA and plasma aldosterone (PA) were measured in naive and CAP-treated BDL and sham-ligated rats. We found that BDL elevated rats' daily saline intake 2 weeks after the ligation procedure but had no effect on PRA. CAP (0.1 mg/mL) placed in the drinking water of some BDL rats further increased saline intake. Both PA and hematocrits tended to be reduced in BDL rats, whereas PRA was elevated in both BDL and sham-ligated rats receiving CAP in the drinking water or by gavage (0.1 mg/mL in 10 mL/kg). The data suggest that the ingestion of saline by rats can be modified by BDL and CAP administration, but that exaggerated saline intake in BDL rats is not associated with excessive renin secretion.     

Postingestional modulation of drinking induced in rats by angiotensin II: intragastric infusion and sham drinking studies

The dipsogenic potency of angiotensin II (ANGII, 200 micrograms/kg, SC) was examined after the removal of various postingestional factors. In the first experiment, rats with intragastric catheters were injected SC with ANGII and allowed water to drink. During the induced drinking, either NaCl (1.5 M) or water was injected into the stomach via the catheter at a rate of 0.1 ml for each ml water ingested orally. The water intake was identical in the two conditions. In a second experiment, rats, fitted with gastric fistulas, were administered ANGII and subsequent water intake with fistulas open was compared to that occurring with the fistulas closed. Rats drank more water during the first trial with fistulas open than with fistulas closed. Water intake during subsequent trials with an open fistula rose above that observed on the first trial. In a third experiment, rats with gastric fistulas were offered 0.15 M NaCl to drink. Intake was greater when the fistula was open than when it was closed. Intake of 0.15 M NaCl increased during the second trial with fistula open. Rats drank more 0.15 M NaCl during the first trial with an open fistula in Experiment 3 than those rats given water to drink on their first trial with fistula open in Experiment 2. These data suggest both oropharyngeal and postingestional factors interact in the control of ANGII-induced fluid intake.     

Centrally administered ghrelin potently inhibits water intake induced by angiotensin II and hypovolemia in rats

Ghrelin is a potent, centrally acting orexigenic hormone. Recently, we showed that centrally administered ghrelin is a potent antidipsogenic hormone in 24-h water deprived rats. In this study, we examined the effect of intracerebroventricular (icv) injection of ghrelin on angiotensin II (AII)-induced water intake in rats. We also examined the effects of icv injection of ghrelin on drinking induced by intraperitoneal injection of an isotonic polyethylene glycol (PEG) solution that causes isotonic hypovolemia. Water intake induced by the icv injection of AII or ip injection of PEG was significantly reduced after icv injection of ghrelin, although food intake was stimulated by the hormone. The drinking induced by AII was also inhibited by the icv administration of 4α-phorbol 12, 13-didecanoate, an agonist of the osmosensitive TRPV4 channel. This study showed that ghrelin is a potent antidipsogenic peptide by antagonizing general dipsogenic mechanisms including those activated by AII and hypovolemia in rats.     

Thirst and saccharin preference in rats

Three experiments with 112 water-deprived rats initially showed higher water than saccharin consumption regardless of whether the liquids were presented singly or as a choice, and whether food was available or withheld during testing. More saccharin than water was consumed later. The reversal from water to saccharin was positively related to hours of water deprivation and per cent saccharin concentration and occurred with either continuous or interrupted exposure. It was concluded that rats must first drink water in order to reduce their water deficit to some threshold before saccharin is drunk. Postingestional and oral factors then become responsible for ingestion of large quantities of saccharin.     

Tolerance to appetite suppression induced by peptidoglycan.

Physiologically realistic peptidoglycan (PG) fragments, derived from Neisseria gonorrhoeae, were shown previously to dose-dependently suppress food consumption and body weight gain in rats following single intraperitoneal injections. The present study, examining the effects of repeated daily injection of PG, provides additional support to our underlying hypothesis, i.e., that soluble PG fragments contribute to the loss of appetite commonly associated with bacterial infections. An initial intraperitoneal injection of purified, soluble, macromolecular, extensively O-acetylated PG fragments (S-O-PG) (240 micrograms/kg of body weight) decreased overnight food consumption in male Lewis rats (150 g) by approximately 35% relative to animals receiving diluent alone (P < 0.05). However, subsequent daily injections of S-O-PG resulted in progressively smaller effects on food consumption until, by the fourth day, rats were completely nonresponsive (tolerant) to S-O-PG-induced hypophagia. Rats that developed tolerance to the effects of S-O-PG on appetite were also tolerant to three other known hypophagic agents, lipopolysaccharide (LPS), muramyl dipeptide, and interleukin-1, when challenged one day after establishment of S-O-PG tolerance. Similarly, rats developed tolerance to repeated injections of muramyl dipeptide or LPS and were cross-tolerant to S-O-PG when challenged 1 day later. However, 30 days after establishment of S-O-PG tolerance, rats remained nonresponsive to S-O-PG but regained full responsiveness to LPS-mediated hypophagia. Thus, at least two mechanisms of tolerance to S-O-PG hypophagia exist: an early tolerance which is nonspecific and a late tolerance which is specific for S-O-PG. Late, but not early, tolerance to S-O-PG-mediated suppression of appetite was associated with an increase in specific anti-PG antibody activity as measured in an enzyme-linked immunosorbent assay.     

The ontogeny of salt appetite aroused by depletion in the rat

The emergence of the rat's ability to respond behaviorally to a bodily sodium deficit was examined. Sucklings were depleted of bodily sodium by furosemide injections and their ability to replenish sodium by imbibing 3% NaCl solution was measured at different ages. The results suggest that the appetite for salt, as a response to sodium deficit, matures at weaning age.