Drinking Response Research Articles

Obestatin Inhibits Vasopressin Release and Thirst

We have previously reported that obestatin, a product of post-translational processing of the ghrelin prohormone, significantly inhibits thirst in a variety of animal models (AJP 292:, 2007). To further investigate potential CNS actions of obestatin on fluid and electrolyte homeostasis, we examined the effects of i.c.v. administration of the peptide on salt appetite and vasopressin (AVP) secretion. Saline drinking in response to polyethylene glycol-induced hypovolemia was not altered by obestatin in a dose that did significantly reduced water drinking in this and previously reported models. On the other hand, i.c.v. administration of obestatin in overnight water restricted rats significantly reduced AVP levels in peripheral plasma in a time and dose-dependent fashion. Our previous patch clamp recordings have shown that subfornical organ neurons respond to the direct application of obestatin, and thus the actions of the peptide may occur as a consequence of actions at circumventricular organs and not the hypothalamus. These results further our hypothesis that obestatin acts within the CNS to modulate the behavioral and endocrine mechanisms controlling fluid balance.

Role of brain angiotensin AT1 receptor in the carbachol-induced natriuresis and expression of nNOS in the locus coeruleus and proximal convoluted tubule.

Central administration of losartan effectively blocked the increase of blood pressure and drinking response induced by angiotensin II (Ang II) or carbachol. However, the relationship between angiotensin AT(1) receptors and the natriuresis induced by brain cholinergic stimuli is still not clear. The purpose of the study is to reveal the role of brain angiotensin AT(1) receptor in the carbachol-induced natriuresis and expression of neuronal nitric oxide synthase (nNOS) in the locus coeruleus (LC) and proximal convoluted tubule (PCT). Our results indicated that 40 min after intracerebroventricular (ICV) injection of carbachol (0.5 microg), urinary sodium excretion was significantly increased to 0.548+/-0.049 micromol x min(-1) x 100 g(-1). Immunohistochemistry showed that carbachol induced an increase of neuronal nitric oxide synthase immunoreactivity (nNOS-IR) in the LC and renal proximal tubular cells. After pretreatment with losartan (20 microg), carbachol-induced urinary sodium excretion was reduced to 0.249+/-0.067 micromol x min(-1) x 100 g(-1). The same was true for carbachol-induced increase of nNOS-IR in the LC and PCT. The present data suggest that ICV cholinergic stimulation could induce a natriuresis and upregulate the activity of nNOS in the LC and PCT. The blockade of AT(1) receptors might downregulate the effects induced by carbachol in the LC and PCT. Consequently, we provide a new evidence that brain angiotensinergic pathway and NO-dependent neural pathway contribute to the natriuresis following brain cholinergic stimulation and thus play an important role in the regulation of fluid homeostasis. Furthermore, the final effect of nitric oxide on proximal tubular sodium reabsorption participated in the natriuresis induced by brain cholinergic stimulation.

The Role of Medication Use and Health on the Decision to Quit Drinking Among Older Adults

To determine the extent to which changes in medication use and health influence the decision to quit drinking among older adults. The sample consisted of 8,883 elderly enrolled in Pennsylvania's Pharmaceutical Assistance Contract for the Elderly (PA-PACE) program who completed surveys in 2000 and 2002. Survey data were linked with prescription claims to examine medication and health factors associated with drinking cessation between baseline and follow-up. Overall, 3.9% of those using alcohol at baseline quit drinking during the study period. Logistic regression results showed that individuals who initiated antipsychotic (OR = 2.92) and antineoplastic therapies (OR = 2.67) were the most likely to quit drinking. These findings support the hypothesis that elderly quit drinking in response to ill health. Results have implications for alcohol interventions in older adults and underscore the importance of separating former drinkers from lifetime abstainers in the study of alcohol-health relationships.

Impaired drinking response in histamine H3 receptor knockout mice following dehydration or angiotensin-II challenge

Histamine H3 receptors (H3Rs) are presynaptic receptors that negatively regulate the release of histamine. The present study examined the physiological role of H3Rs in drinking behavior. In water-replete rats, intracerebroventricular (i.c.v.) administration of R-α-methylhistamine (RαMeHA), an H3R agonist, elicited drinking behavior. In contrast, i.c.v. administration of thioperamide, an H3R inverse agonist, significantly attenuated the drinking behavior elicited by either overnight dehydration or i.c.v. administration of angiotensin-II (AT-II). Inhibition of histamine release with α-fluoromethylhistidine, an inhibitor of histidine decarboxylase, did not elicit drinking behavior. Moreover, the inhibitory effects of thioperamide on drinking behavior in water-depleted rats were not mimicked by i.c.v. administration of histamine. These results suggest that the predominant effects of H3Rs on drinking behavior are not mediated by the modulation of histamine release. In H3R-deficient (H3RKO) mice, drinking behavior induced by overnight dehydration or i.c.v. administration of AT-II was significantly impaired compared to wild type mice. Collectively, these observations suggest that brain H3Rs play a pivotal role in drinking behavior in response to dehydration and AT-II, and these effects may be largely independent of the modulation of histaminergic tone.

Differential effects of aging on fluid intake in response to hypovolemia, hypertonicity, and hormonal stimuli in Munich Wistar rats

A significant proportion of aged humans may have impaired thirst and inadequate fluid intake after a period of fluid deprivation. We have studied the water drinking responses, relative to body weight, of Munich Wistar (MW) rats in response to osmotic, hypovolemic, dehydrational, and angiotensin (Ang)-related stimuli as they aged from 3 to 24 months. Young 3-months-old (m.o.) rats had the largest daily fluid intakes and drinking responses to hypertonic and dehydrational stimuli, suggesting that they have accentuated thirst in comparison with older age groups. There were no differences in daily fluid intake from 6-24 m.o.; however, drinking responses to i.p. injection of hypertonic 0.4 mol/liter NaCl gradually declined over this period so that in 24-m.o. rats the response was only half that of 6-m.o. rats. Water intake after 24-h water deprivation also declined gradually over 24 months. Drinking responses to hypovolemia induced by s.c. injection of colloid (polyethylene glycol) were unchanged in 6- to 15-m.o. rats, then declined precipitously in 18- to 24-m.o. rats. Drinking responses to s.c. Ang II or s.c. isoproterenol were not reduced in 24-m.o. rats, nor was the drinking associated with feeding. Therefore, there are specific impairments of water intake in response to hypertonicity and hypovolemia in aged MW rats, but Ang-related drinking is not reduced. Like aged humans, aged MW rats exhibit high plasma atrial natriuretic peptide levels and impaired cardiovascular reflexes that could contribute to the impairment of thirst with age.

Insulin action in the brain contributes to glucose lowering during insulin treatment of diabetes

To investigate the role of brain insulin action in the pathogenesis and treatment of diabetes, we asked whether neuronal insulin signaling is required for glucose-lowering during insulin treatment of diabetes. Hypothalamic signaling via the insulin receptor substrate-phosphatidylinositol 3-kinase (IRS-PI3K) pathway, a key intracellular mediator of insulin action, was reduced in rats with uncontrolled diabetes induced by streptozotocin (STZ-DM). Further, infusion of a PI3K inhibitor into the third cerebral ventricle of STZ-DM rats prior to peripheral insulin injection attenuated insulin-induced glucose lowering by approximately 35%-40% in both acute and chronic insulin treatment paradigms. Conversely, increased PI3K signaling induced by hypothalamic overexpression of either IRS-2 or protein kinase B (PKB, a key downstream mediator of PI3K action) enhanced the glycemic response to insulin by approximately 2-fold in STZ-DM rats. We conclude that hypothalamic insulin signaling via the IRS-PI3K pathway is a key determinant of the response to insulin in the management of uncontrolled diabetes.

Targeting Brain AT 1 Receptors By RNA Interference

The dipsogenic and pressor actions of angiotensin II (Ang II) in the central nervous system (CNS) have been well documented in many species and are now accepted as dogma. The major central cardiovascular effects of Ang II are elicited by a complex receptor-dependent signaling cascade initiated by the detection of circulating Ang II in regions of the brain lacking a blood brain barrier (BBB) through local production of Ang II in regions outside and inside the BBB or through the neurotransmitter actions of Ang II. It is generally accepted that most of the central neurocardiovascular actions of Ang II occur through the activation of intracellular signaling cascades that originate at the Ang II type 1 (AT1) receptor. A second Ang II receptor, termed AT2, has been implicated in some cardiovascular and behavioral responses. However, the AT2 receptor is distantly related to AT1 and can be effectively distinguished from AT1 pharmacologically. In humans, a single gene encodes the AT1 Ang II receptor, whereas in rodents a duplication resulted in 2 AT1 receptor genes, located on different chromosomes, each known to encode 1 of 2 distinct subtypes of the receptor, AT1a and AT1b. Both receptors are highly homologous, use the same signaling mechanisms, and cannot be distinguished using currently available pharmacological reagents or antisera. Despite their high similarity at the protein level, sufficient divergence is present in the sequence of the mRNA that allows them to be distinguished by RT-PCR and in situ hybridization. Through

A new way of looking at eating

the analysis of meals, especially of spontaneous meals, has long had a problematic place in the behavioral neuroscience of eating. Only a small minority of eating researchers now, or ever, have concerned themselves with meal patterns. On first glance this seems paradoxical. After all, eating occurs

Influence of Changes of Blood Pressure on Vascular Angiotensin II Receptor Subtype Expression

The evolving complexity associated with the renin-angiotensin cascade has been the focus of increasingly sophisticated pharmacological experimentation. The identification of at least 2 angiotensin II (Ang II) receptor subtypes led to functional subclassification of their activity. Activation of the type 1 (AT1) receptor is associated with the vasopressive and aldosterone-secreting effects of Ang II. Mice that lack the gene that encodes the AT2 receptor demonstrate normal development but an impaired drinking response to water deprivation and a reduction in spontaneous movements.1 Basal blood pressure is higher, and sensitivity to the pressor actions of exogenously delivered Ang II is increased.1,2 Differences in diastolic blood pressure persist even when AT1 receptors are blocked by losartan, indicating that this effect is independent of AT1. The greater pressor response to Ang II requires AT1 receptor activation and therefore, normally, AT2 receptors may serve to limit this.3 As a consequence, the concept of a vasodilator role for this receptor was introduced. See p 1006 Subsequently, a variety of reports have emerged linking the stimulation of AT2 with vasodilation in small resistance arteries in normotensive rats. The mechanism invoked usually is associated with nitric oxide (NO) production by endothelial cells and cGMP production …

Older adults’ health and changes in late-life drinking patterns

This study focused on the prospective associations between older adults’ health-related problems and their late-life alcohol consumption and drinking problems. A sample of 1,291 late-middle-aged community residents (55–65 years old at baseline) participated in a survey of health and alcohol consumption, and was followed one year, four years, and 10 years later. Health-related problems increased and alcohol consumption and drinking problems declined over the 10-year interval. Medical conditions, physical symptoms, medication use, and acute health events predicted a higher likelihood of abstinence and less frequent and lower alcohol consumption. However, overall health burden predicted more subsequent drinking problems, even after controlling for alcohol consumption and a history of heavy drinking and increased drinking in response to stressors. Among older adults, increased health problems predict reduced alcohol consumption but more drinking problems. Older adults with several health problems who consume more alcohol are at elevated risk for drinking problems and should be targeted for brief interventions to help them curtail their drinking.

Dipsogenic stimulation in ibotenic DRN-lesioned rats induces concomitant sodium appetite

The main purpose of this study was to investigate whether dipsogenic stimuli influences the sodium appetite of rats with ibotenic acid lesion of the dorsal raphe nucleus (IBO-DRN). Compared to control, rats microinjected with phosphate buffer (PB-DRN), the ingestion of 0.3 M NaCl was enhanced in IBO-DRN at 21 and 35 days after DRN lesion under a protocol of fluids and food deprivation. Despite of similar dipsogenic response observed both in IBO-DRN and PB-DRN treated with isoproterenol (ISO, 300 μg/kg, sc), the 0.3 M NaCl intake was again significantly enhanced in IBO-DRN at 21 and 35 days post-lesion. Finally, treatment with polyethylene glycol (PEG, MW = 20,000, 20%, w/v, 16.7 ml/kg, sc) induced higher dipsogenic response in IBO-DRN than PB-DRN at 21 day after lesion. In addition, IBO-DRN also expressed higher sodium appetite than PB-DRN, concomitantly with a drinking response. These results suggest that ibotenic lesion of DRN promote an increase of the brain angiotensinergic response, possibly settled within the subfornical organ, through paradigms which increase circulating ANG II levels. The current paper supports the hypothesis that the ibotenic lesion of DRN suppresses a serotonergic component implicated on the modulation of the sodium appetite and, therefore, furthering homeostatic restoration of extracellular fluid volume.

Role of angiotensin in body fluid homeostasis of mice: effect of losartan on water and NaCl intakes

It is known that mice injected peripherally with ANG II do not show a drinking response but that cFos immunoreactivity (ir) is induced in brain regions similar to those in rats. We now show in Crl:CD1(ICR) mice that peripheral injection of the ANG II type 1 receptor antagonist losartan was sufficient to prevent this induction of Fos-ir in the subfornical organ (SFO). Injection of ANG II into the lateral cerebral ventricle produced a robust water intake in mice and induced Fos-ir in SFO, as well as in median preoptic (MnPO) and paraventricular (PVN) nuclei. Peripheral injection of losartan blocked this drinking response and prevented the induction of Fos-ir in each of these brain regions. Hypovolemia produced by polyethylene glycol (PEG) produced a robust water intake but no evidence of sodium appetite, and it induced Fos-ir in SFO, MnPO, and PVN. Peripheral injection of losartan did not affect this drinking response. Fos-ir induced by PEG in SFO and MnPO was reduced by treatment with losartan, while that induced in the PVN was further increased by losartan. Sodium depletion with furosemide and low-sodium diet produced a strong sodium appetite and induced Fos-ir in SFO and MnPO. Treatment with losartan completely blocked the sodium appetite, as well as the induction of Fos-ir in these brain regions. These data indicate that endogenous production of ANG II and action at forebrain receptors is critically involved in depletion-related sodium appetite in mice. The absence of an effect of losartan on PEG-induced drinking suggests the critical involvement of other factor(s) such as arterial or venous baroreceptor input, and we discuss how this factor could also explain why peripheral ANG II is not dipsogenic in mice.

Ten‐year patterns of alcohol consumption and drinking problems among older women and men

This study focused on changes in 10-year patterns of alcohol consumption among older women and men, late-life and life history predictors of drinking problems, and gender differences in these predictors. A sample of late-middle-aged community residents (N = 1291) who had consumed alcohol in the past year or shortly before was surveyed at baseline and 1 year, 4 years and 10 years later. At each contact point, participants completed an inventory that assessed their alcohol consumption, drinking problems and health-related and life context factors. Participants also provided information about their life history of drinking. Over the 10 years, the proportion of individuals who consumed alcohol declined. Among individuals who continued to drink, women and men showed comparable declines in alcohol consumption, minor concomitants of alcohol consumption and drinking problems. In addition to the amount of alcohol consumption, smoking, friends' approval of drinking and avoidance coping consistently predicted late-life drinking problems. With respect to life history factors, heavy drinking, drinking problems and increased drinking in response to life events were related to a higher likelihood of late-life drinking problems; obtaining help from family members and friends and, among men, participation in Alcoholics Anonymous, were related to a lower likelihood of problems. Older women and men show comparable declines in alcohol consumption and drinking problems. Specific late-life social context and coping variables, and life history indices, are risk factors for late-life drinking problems among both women and men.

Labor and Beer in the Transkei, South Africa: Xhosa Work Parties in Historical and Contemporary Perspective

The paper examines cooperative labor and its relationship with beer drinking rituals in South Africa’s Transkei. The analysis is placed within a historical context and the evolution of both cooperative labor and beer drinking in response to specific political, ecological, and socioeconomic circumstances. This facilitates a critique of the conventional approach to work parties and the standard typology of cooperative work in Africa and has important implications for one of anthropology’s major concerns over the past decade—the study of commodities and consumption.

Influence of arginine vasopressin receptors and angiotensin receptor subtypes on the water intake and arterial blood pressure induced by vasopressin injected into the lateral septal area of the rat

In this study we investigated the influence of d(CH 2) 5-Tyr(Me)-[Arg 8]vasopressin (AAVP) and [adamanteanacetyl 1,0-ET- d-Tyr 2,Val 4,aminobutyryl 6,Arg 8,9]-[Arg 8]vasopressin (ATAVP), which are antagonists of vasopressin V 1 and V 2 receptors, and the effects of losartan, a selective angiotensin AT 1 receptor antagonist, and CGP42112A, a selective AT 2 receptor antagonist, injected into the lateral septal area (LSA) on thirst and hypertension induced by [Arg 8]vasopressin (AVP). AAVP and ATAVP injected into the LSA reduced the drinking responses elicited by injecting AVP into the LSA. Both the AT 1 and AT 2 ligands administered into the LSA elicited a concentration-dependent decrease in the water intake induced by AVP injected into the LSA, but losartan was more effective than CGP42112A. The increase in MAP, due to injection of AVP into the LSA, was reduced by prior injection of AAVP from 18±1 to 6±1 mm Hg. Losartan injected into the LSA prior to AVP reduced the increase in MAP to 7±0.8 mm Hg. ATAVP and CGP42112A produced no changes in the pressor effect of AVP. These results suggest that the dipsogenic effects induced by injecting AVP into the LSA were mediated primarily by AT 1 receptors. However, doses of losartan were more effective when combined with CGP42112A than when given alone, suggesting that the thirst induced by AVP injections into LSA may involve activation of multiple AVP and angiotensin II receptor subtypes. The pressor response of AVP was reduced by losartan and by AAVP. CGP42112A and ATAVP did not change the AVP pressor response. These results suggest that facilitator effects of AVP on water intake are mediated through the activation of V 1 receptors and that the inhibitory effect requires V 2 receptors. The involvement of AT 1 and AT 2 receptors can be postulated. Based on the present findings, we suggest that the AVP in the LSA may play a role in the control of water and arterial blood pressure balance.

The α 1D-adrenergic receptor modulates cardiovascular and drinking responses to central salt loading in mice

To characterize the involvement of specific α 1-adrenergic receptor (α 1-AR) subtypes in hypertension, parameters related to central salt- or angiotensin II (ANG II)-induced hypertension were investigated in α 1D-AR-deficient mice (knockout). Baseline daily water intake and food intake were larger in α 1D −/− mice than in α 1D +/+ mice. Intracerebroventricular (i.c.v.) administration of NaCl (0.67 M NaCl, 1 μl) elicited smaller increases in mean arterial blood pressure (MABP), heart rate, and water intake in α 1D −/− mice than it did in α 1D +/+ mice. I.c.v. administration of ANG II (10 pmol) resulted in increases in MABP and water intake that were similar in α 1D −/− mice and α 1D +/+ mice. These results suggest that α 1D-AR is, at least in part, involved in central salt-induced but not ANG II-induced hypertension and water intake.

GABAergic modulation of the ANG II-induced drinking response in the rat medial preoptic nucleus

The present study was designed to examine the participation of γ-aminobutyric acid (GABA) receptor mechanisms in the medial preoptic nucleus (MPO) in the drinking response caused by angiotensin II (ANG II) activation of the subfornical organ (SFO) in the awake rat. Local administration of ANG II (5 pmol, 50 nl) into the SFO elicited drinking. The water intake induced was significantly attenuated by previous injections (50 nl) into the MPO of the GABA A agonist muscimol (0.5, 5 and 50 pmol), but not by the GABA B agonist baclofen (0.5, 5 and 50 pmol) or vehicle, into the MPO. On the other hand, the ANG II-induced water intake was significantly enhanced by previous injections (50 nl) into the MPO of the GABA A antagonist bicuculline (0.5 and 5 pmol), but not the GABA B antagonist phaclofen (0.05, 0.5 and 5 pmol). Muscimol (50 nmol) injected into the MPO significantly reduced the water intake elicited by intracellular fluid depletion (i.e., hypertonic saline: 2 M, 2 ml/kg bw ip), whereas bicuculline (5 pmol) was without effect. These results show the involvement of the GABAergic system within the MPO in the dipsogenic responses induced by ANG II acting at the SFO and intracellular fluid depletion, and suggest that the system may serve to attenuate the ANG II-induced dipsogenic response through GABA A receptors.

Effects of V 1 and angiotensin receptor subtypes of the paraventricular nucleus on the water intake induced by vasopressin injected into the lateral septal area

In this study, we investigated the influence of d(CH 2) 5-Tyr (Me)-AVP (AAVP) an antagonist of V 1 receptors of arginine 8-vasopressin (AVP) and the effects of losartan and CGP42112A (selective ligands of the AT 1 and AT 2 angiotensin receptors, respectively) injections into the paraventricular nucleus (PVN) on the thirst effects of AVP stimulation of the lateral septal area (LSA). AVP injection into the LSA increased the water intake in a dose-dependent manner. AAVP injected into the PVN produced a dose-dependent reduction of the drinking responses elicited by LSA administration of AVP. Both the AT 1 and AT 2 ligands administered into the PVN elicited a concentration-dependent inhibition in the water intake induced by AVP injected into the LSA, but losartan was more effective than CGP42112A the increase in the AVP response. These results indicate that LSA dipsogenic effects induced by AVP are mediated primarily by PVN AT 1 receptors. However, doses of losartan were more effective when combined with CGP42112A than when given alone, suggesting that the thirst induced by AVP injections into LSA may involve activation of multiple angiotensin II (ANG II) receptor subtypes. These results also suggests that facilitatory effects of AVP on water intake into the LSA are mediated through the activation of V 1-receptors and that the inhibitory effect requires V 2-receptors. Based on the present findings, we suggest that the administration of AVP into the LSA may play a role in the PVN control of water control.

Body sodium and volume homeostasis.

maintenance of a “milieu interieur,” which allows our cells to function away from the ancient sea, is one of the most important functions of the body. Maintenance of constant extracellular osmolarity and sodium concentration depends on a precise balance between intake and excretion of sodium and

Effects of Microcystis cells, cell extracts and lipopolysaccharide on drinking and liver function in rainbow trout Oncorhynchus mykiss Walbaum

Liver mass (hepatosomatic index, HSI) increased by approximately 18% and water content in the gut by approximately 13 ml kg −1 in freshwater rainbow trout exposed for 24 h to intact cells of a microcystin-producing cyanobacterium ( Microcystis PCC 7813) together with administration of heterotrophic bacterial LPS. Exposure to broken (ultrasonicated) cyanobacterial cells together with administration of bacterial LPS increased HSI by approximately 50% and water content in the gut by almost 30 ml kg −1. Exposure to broken or unbroken Microcystis cells without administration of bacterial LPS resulted in increased water content of the gut (by approximately 13 ml kg −1) with insignificant changes in HIS. Drinking rate increased with increasing dosage of bacterial LPS alone. The increased volume of water in the gut potentially increases the opportunity for uptake of waterborne toxins, including microcystins, and increased liver mass is a symptom consistent with the toxic effects of microcystins. It is concluded that exposure of fish to the cell contents of cyanobacteria (e.g. Microcystis PCC 7813) promotes osmoregulatory imbalance resulting from stimulation of the drinking response, increased volume of fluid in the gut and inability to remove excess water.