The Neuroendocrinology of Thirst and Salt Appetite: Visceral Sensory Signals and Mechanisms of Central Integration

FRONTIERS IN NEUROENDOCRINOLOGY ARTICLE NO.

18, 292–353 (1997)

FN970153

The Neuroendocrinology of Thirst and Salt Appetite: Visceral Sensory Signals and Mechanisms of Central Integration Alan Kim Johnson and Robert L. Thunhorst Departments of Psychology and Pharmacology and The Cardiovascular Center, University of Iowa, Iowa City, Iowa 52242

This review examines recent advances in the study of the behavioral responses to deficits of body water and body sodium that in humans are accompanied by the sensations of thirst and salt appetite. Thirst and salt appetite are satisfied by ingesting water and salty substances. These behavioral responses to losses of body fluids, together with reflex endocrine and neural responses, are critical for reestablishing homeostasis. Like their endocrine and neural counterparts, these behaviors are under the control of both excitatory and inhibitory influences arising from changes in osmolality, endocrine factors such as angiotensin and aldosterone, and neural signals from low and high pressure baroreceptors. The excitatory and inhibitory influences reaching the brain require the integrative capacity of a neural network which includes the structures of the lamina terminalis, the amygdala, the perifornical area, and the paraventricular nucleus in the forebrain, and the lateral parabrachial nucleus (LPBN), the nucleus tractus solitarius (NTS), and the area postrema in the hindbrain. These regions are discussed in terms of their roles in receiving afferent sensory input and in processing information related to hydromineral balance. Osmoreceptors controlling thirst are located in systemic viscera and in central structures that lack the blood–brain barrier. Angiotensin and aldosterone act on and through structures of the lamina terminalis and the amygdala to stimulate thirst and sodium appetite under conditions of hypovolemia. The NTS and LPBN receive neural signals from baroreceptors and are responsible for inhibiting the ingestion of fluids under conditions of increased volume and pressure and for stimulating thirst under conditions of hypovolemia and hypotension. The interplay of multiple facilitory influences within the brain may take the form of interactions between descending angiotensinergic systems originating in the forebrain and ascending adrenergic systems emanating from the hindbrain. Oxytocin and serotonin are additional candidate neurochemicals with postulated inhibitory central actions and with essential roles in the overall integration of sensory input within the neural network devoted to maintaining hydromineral balance. KEY WORDS: Angiotensin II; anteroventral third ventricle (AV3V); baroreceptors; circumventricular organs; ingestive behaviors; parabrachial nucleus. r 1997 Academic Press

Address correspondence and reprint requests to Alan Kim Johnson, Department of Psychology, University of Iowa, 11 Seashore Hall E, Iowa City, IA 52242-1407, fax: 319/335-0191.

0091-3022/97 $25.00 Copyright r 1997 by Academic Press All rights of reproduction in any form reserved.

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INTRODUCTION

The major components of body fluids are in a state of constant flux. Even in benign environments, terrestrial animals constantly lose water and sodium. Reflex and behavioral responses are both necessary to correct water and sodium imbalances and maintain body fluid homeostasis. Reflex mechanisms employ the autonomic nervous system and endocrine responses [e.g., aldosterone; vasopressin (VP)] to modify renal losses of sodium and water in states of dehydration. Behavioral responses include the seeking out and drinking of water and the ingestion of sodium-containing foods or fluids. The ingestion of water and sodium is the only means to repair deficiencies of body water and body sodium. Thirst and salt appetite are the motivational states that drive animals to find and consume water and salty substances and are defined operationally by measuring this consumption under appropriate experimental conditions. The autonomic and endocrine reflexes and the behaviors that minimize the consequences of body fluid deficits take effect with different latencies. At the onset of an imbalance of body fluids, sympathetic reflexes exert their actions within seconds, and significant endocrine effects are felt within minutes. In contrast, the consequences of behavioral mechanisms at the cellular level are realized only tens of minutes to hours later. Reflex mechanisms, in essence, serve to maintain cardiovascular function until behaviors can be mobilized for the ultimate restoration of homeostasis. The activation and coordination of reflexive and behavioral responses that maintain body fluid homeostasis require the integrative action of the central nervous system (CNS). The brain must be informed second by second of the balance and distribution of body fluids. Although the reflexes and behaviors that maintain body fluid homeostasis differ in their forms of expression, they employ common mechanisms. Autonomic/endocrine reflexes and hydromineral-related ingestive behaviors are activated by similar afferent signals to the brain. The same CNS structures and neurochemical systems process information from the afferent signals. For example, circulating angiotensin II (ANG II) increases sympathetic outflow, stimulates VP release, and causes drinking and sodium ingestion via actions in overlapping, if not identical, areas of the brain. The purpose of this review is to summarize the current state of understanding of the stimuli and signaling mechanisms that apprise the CNS of body fluid status and to discuss how the brain processes such information to generate thirst and salt appetite. The neural and endocrine mechanisms that activate thirst and salt appetite to maintain body fluid and cardiovascular homeostasis are viewed as complementary to reflex hormonal and autonomic mechanisms. There are now numerous examples of how cardiovascular reflex mechanisms are relevant to the afferent control of thirst and salt appetite and vice versa.

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JOHNSON AND THUNHORST BACKGROUND Body Fluid Compartments and Their Experimental Manipulation

Water accounts for approximately 60% of the body’s weight (122), with two-thirds of body water within cells and one-third in interstitial spaces and plasma. The 2:1 ratio of intracellular to extracellular water largely reflects an osmotic equilibrium achieved by the relative concentrations of impermeable ions found in the two compartments. The concentration of extracellular sodium is the primary ionic factor determining this osmotic equilibrium. Thus, the addition (through ingestion) or loss (through excretion, salivary loss, respiration, perspiration, etc.) of either water or sodium to/from the body alters not only net fluid balance but also osmotic equilibrium, thereby changing the relative distribution of fluid between the compartments. Some disturbances of body water and sodium give rise to the general sensation of thirst and to drinking behavior. The double depletion hypothesis, proposed by Alan Epstein and James Fitzsimons (79, 105), incorporated the idea that loss of water from either the intracellular or the extracellular compartment is sufficient to generate sensations of thirst and drinking behavior. Losses of water from the two compartments are hypothesized to generate different classes of sensory signals (e.g., osmotic, hormonal, neural) that utilize different afferent pathways (e.g., blood, nerves) to inform the brain of the status of body water. There are continuous demands placed on body fluids by obligatory water and sodium losses from normal renal excretory functions and ‘‘insensible’’ loss of water from respiration and transpiration through the skin. Feeding places demands on body water reflecting the need to dilute ingested solutes and other products of digestion and absorption (glucose, amino acids, etc.). Thirst caused by loss of fluid from the intracellular space occurs, for example, after the ingestion of salty foods or fluids. The sodium in salty substances causes an osmotically driven loss of water from cells into the extracellular space creating a deficit of intracellular water. Thirst caused by depletion primarily of extracellular fluid occurs after hemorrhage, vomiting, diarrhea, and sweating. The extracellular fluid lost in these circumstances is dilute with respect to intracellular fluid, so there is some shifting of water from the intracellular compartment to the extracellular compartment. Pure water loss occurs through respiration and by transpiration of water through the skin (i.e., ‘‘insensible’’ loss), resulting in losses of water from both compartments. Thirst from insensible loss occurs under arid conditions, such as breathing dry heated air. Although physiological disturbances may sometimes selectively deplete only one compartment to yield a single stimulus culminating in drinking, it is likely that day-to-day thirst results from the central integration of multiple stimuli of different classes. The loss of extracellular fluid results in deficiences of sodium as well as water. The condition of sodium deficiency is associated with a ‘‘peculiar sensa-

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tion in the mouth’’ (205) that is sometimes interpreted as thirst, but is not relieved by drinking water (206). This sensation is called salt appetite. Recent evidence suggests that humans express salt appetite after reductions in plasma volume and sodium concentration by indicating increased palatability of hypertonic sodium chloride solutions (311). However, humans do not couple the unique sensations of salt appetite with the need to ingest sodium as strongly as they do thirst with the need to ingest water. For example, people who excrete large quantities of sodium in their urine due to adrenal insufficiency (e.g., Addison’s disease) or to salt-wasting renal disorders are more likely to develop a craving for salty foods than for salt itself (261, 291, 315, 356). They may simply report that the salty foods have a pleasant taste (261). Anorexia, aberrations of taste, and fatigue are also common symptoms of sodium deficiency in humans (20, 201, 205–207, 231, 276). The ability to selectively deplete the intracellular and extracellular fluid compartments has greatly advanced understanding of the afferent signaling mechanisms responsible for generating the CNS states associated with the motivation to ingest water and sodium. Thirst caused by depletion of the intracellular compartment is achieved by introducing into the extracellular space substances, such as NaCl (127), that are excluded from cells by the semipermeable properties of the cell plasma membrane, thus drawing water out of cells. Relative depletion of the extracellular compartment, or hypovolemia, is produced by experimental procedures that remove isotonic extracellular fluid so as to reduce circulating blood volume without causing loss of fluid from cells. For example, Fitzsimons (102) produced thirst in rats by injecting large molecular weight substances (e.g., polyethylene glycol, gum acacia) under the skin. The oncotic pressure at the injection site of such colloids progressively sequesters extracellular fluid. Since the sequestered fluid is isotonic, osmotic equilibrium is not affected, and there is no movement of intracellular water. Extracellular fluid depletion can also be produced by removal of sodium from the extracellular spaces by glucose dialysis (50, 88), thus diluting the extracellular fluid and shifting water into the cells. Similar shifts in body fluid are produced by maintaining animals on sodium-deficient diets (141, 310). It has been recognized for several decades that individuals suffering dehydration from heat or exercise stop drinking water before blood volume is fully restored. In order to restore blood volume, it is necessary to also provide a source of sodium ions. The phenomenon of ceasing to drink water before extracellular volume is restored was first defined as voluntary dehydration by Adolph and associates (3), but has also been referred to as involuntary dehydration (131). Stricker and colleagues (292, 302) have modeled this inhibition of drinking in the hypovolemic rat and have demonstrated that the attenuated water intake can be resolved by the ingestion of sodium (300, 302). Typically when given the choice, hypovolemic rats consume water (i.e., display thirst) in preference to concentrated saline solutions for the first several hours after extracellular fluid loss. Only later will such animals begin to consume concentrated saline solutions. Over the long term, hypovolemic animals ingest water

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and concentrated NaCl solutions in a ratio that produces the equivalent of isotonic saline, which is, of course, the ideal concentration to restore a normovolemic state. The experimental production of salt appetite dates to Richter’s pioneering work demonstrating that adrenalectomy produces ingestion of sodium solutions in the rat (259). Adrenalectomy removes the principal source of the mineralocorticoid hormone, aldosterone, resulting in loss of sodium in the urine, saliva, and feces. Thus, the absence of salt-retaining mineralocorticoid hormones results in compensatory salt-ingesting behaviors. However, pharmacological doses of mineralocorticoids also stimulate a powerful salt appetite (260). This appears paradoxical in the light of the marked retention of sodium that is initiated by aldosterone administration. Thus, either the absence or the excess of mineralocorticoid hormones causes sodium intake (119). Salt appetite is also produced by the same hypovolemic treatments that stimulate thirst. Administration of diuretics (148), hyperoncotic colloids given ip or sc (307), and glucose dialysis (88) reliably stimulate salt appetite in rats. In sheep, saliva can be diverted from a parotid gland to create a considerable loss of sodium and, in turn, impressive intakes (65).

SYSTEMIC STIMULI, RECEPTOR SYSTEMS AND AFFERENT SIGNALING PATHWAYS Osmoreceptors and Sodium Receptors

Gilman (127) concluded that any hypertonic solute that was excluded from cells was a potent stimulus for thirst. The classic studies by Verney (345) bolstered the concept of effective osmolality (i.e., increased extracellular osmolality produced by solutes that do not cross the cell membrane) by demonstrating that intracarotid injections of highly concentrated (i.e., supraphysiological) sodium chloride, dextrose, or sodium sulfate, but not urea, caused antidiuresis. A more precise demonstration of the importance of effective osmoles in producing antidiuresis was also accomplished by administering very low concentrations of NaCl and sucrose by the same intraarterial route. At osmolar concentrations that could be considered physiological, both substances produced antidiuresis. Observing this effect, Verney introduced the term osmoreceptors to describe the cells controlling VP release that shrink in response to hyperosmotic agents (345). A new understanding of the nature of the blood–brain barrier and the rate of exchange of water and hypertonic substances across it prompted Andersson (6) to suggest that the Verney osmoreceptor was really a sodium receptor. Andersson pointed out that systemically administered hypertonic solutions, irrespective of the nature of their molecular characteristics, increase the sodium concentration of brain extracellular fluid because of the movement of water out of the CNS. In support of this idea, Andersson and colleagues (7, 244) demonstrated that intracerebroventricular (icv) infusions of hypertonic glucose and

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hypertonic sucrose, in contrast to hypertonic saline, were ineffective osmotic agents for stimulating thirst and antidiuresis. However, McKinley and colleagues (208) subsequently pointed out that administering solutions composed of only hyperosmolar glucose and sucrose dilutes extracellular sodium, possibly disrupting neural function nonspecifically. McKinley et al. (208, 210) supported this idea in experiments using icv infusions of hypertonic solutions made by adding sucrose to artificial cerebrospinal fluid (ACSF). The result was that the hypertonic sucrose solution made with ACSF was a potent osmotic stimulus in contrast to the hypertonic sucrose solution made with water. However, it is notable that hypertonic solutions composed of sucrose or fructose in ACSF were still less effective stimuli than equiosmolar hypertonic solutions made with NaCl added to ACSF. Therefore, these investigators (210) argued that both osmo- and sodium receptors may be present in brain. The remarkable discovery by Andersson (5) that injection of hypertonic saline into the brain of goat elicited drinking, coupled with the work of Verney (345), focused early research on identifying osmo- and Na1 receptors in the brain. However, recent work has emphasized the importance of osmo- and Na1 receptors located in the periphery, particularly in the splanchnic-hepatoportal circulation (see 33 for review). Studies by Haberich and his colleagues (135) drew attention to the importance of hepatic osmo- and Na1 receptors for the maintenance of body fluid balance. Haberich (135) demonstrated that water produced diuresis more effectively when administered into the portal vein than systemically via the vena cava. Furthermore, portal injection of hypertonic saline was more effective than systemic delivery in evoking antidiuresis. Vagal afferent nerve activity is altered by hyper- and hypoosmotic injections into the portal vein (2, 8, 236, 265). Baertschi and Vallet (12) recorded increased firing rates from fibers in the hypothalamo-neurohypophyseal tract in response to hyperosmotic solutions administered into the portal vein, and similar treatment elevates plasma levels of VP (12, 49). In rats, VP is released in response to intragastric administration of hypertonic saline solutions in quantities that increase osmolality in the splanchnic vein and hepatoportal regions, but not systemically. Infusions of hypertonic NaCl into the portal vein cause an hepatorenal reflex in several species as shown by increased natriuresis and a fall in renal nerve activity (62, 230, 246). It has been argued that such reflex responses are due to sodium receptors in the hepatoportal region because administration of hypertonic sucrose into the portal vein has no effect on renal nerve activity (230). Taken together such results indicate the presence of receptors in the liver, portal vein, and/or the mesenteric veins that drain the upper small intestine (48). There is a role for peripheral osmo- and Na1 receptors in the control of thirst and salt appetite. Blake and Lin (28) observed that the quantity of isotonic saline consumed by rats following 24 h of water deprivation was reduced by hepatic portal vein infusions of hypertonic saline, and this reduction was abolished by right vagotomy. Tordoff and colleagues (333, 334) have also shown that salt appetite in sodium deficient rats was reduced by saline infusions into the portal vein at concentrations as low as isotonic (0.15 M). Recently, Kraly

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and co-workers (182) demonstrated that water intake is elicited by intragastric administration of hypertonic saline at concentrations that do not increase systemic osmolality. Total subdiaphragmatic vagotomy nearly abolishes drinking after such dipsogenic intragastric infusions (182). There are important functional implications of the presence of osmoreceptors located in the splanchnic region. As Haberich (135) has pointed out, the portal circulation provides an ‘‘advanced post in a dangerous front line between the enteral and parenteral spaces of the body.’’ It is clearly advantageous to have these early warning mechanisms that activate reflex and behavioral responses to buffer large changes in both systemic and brain osmolality due to ingested solute. However, these mechanisms would not be of notable advantage when osmolality is increased throughout the body as a result of renal or evaporative water loss.

Baroreceptors

Hypovolemia activates autonomic and endocrine reflexes that mitigate the negative effects of disrupted body fluid homeostasis. In the face of progressively declining cardiac output that accompanies even modest depletions, sympathetic reflexes maintain arterial pressure (134) by increasing heart rate and causing vasoconstriction. Sympathetic responses to mild hypovolemia also increase proximal tubular reabsorption of sodium mediated by the action of norepinephrine (NE) on a1-noradrenergic receptors (67). Hemorrhage activates several endocrine mechanisms including the release of renin, VP, oxytocin (OXY), aldosterone, epinephrine, NE, adrenocorticotropic hormone, and glucocorticoids. These renal, adrenal, and pituitary hormones work with the autonomic nervous system to decrease water and sodium loss, adjust the distribution of water between intra- and extracellular fluid compartments, and modify regional hemodynamics to optimize available resources. Reflex and the behavioral responses that defend against hypovolemia are activated by reduced activity of vascular baroreceptor afferents and increased circulating ANG II. Systemic vascular receptors are located on both the venous and the arterial sides of the circulation. The vascular baroreceptors located in the heart, great veins, and pulmonary circulation are referred to as cardiopulmonary receptors. The application of the single descriptor, cardiopulmonary receptors, to define these sensory elements is misleading because they comprise several types of receptors in various locations that have both myelinated and unmyelinated afferent fibers. The most thoroughly investigated cardiopulmonary receptors are those located in the great veins and atria that detect changes in blood volume. Another set of important cardiopulmonary receptors is located in the cardiac ventricles. The rate and magnitude of extracellular fluid loss determine whether hypovolemia is accompanied by hypotension. At the onset of hypovolemia, sympathetically mediated vasoconstriction maintains blood pressure in the face of falling cardiac output. However, there appears to be a threshold at which extracellular

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fluid loss (and/or hypotension) produces an abrupt withdrawal of sympathetic tone to the vasculature and an accompanying marked bradycardia (277). This seemingly paradoxical sympatholytic response has been attributed by Thoren (314) to activation of cardiac ventricular receptors as the heart contracts around an empty ventricular chamber. It is thought that the same ventricular receptors are stimulated by agents such as serotonin (5-HT) acting on 5-HT3 receptors, nicotine and bradykinin (343, also see 369 for review). The shift from sympathetic activation to sympathetic inhibition which accompanies the progression from compensated to uncompensated hypovolemia appears to have a behavioral counterpart. As will be discussed later in this review, modest reductions (i.e., 20–40 mm Hg) of blood pressure below normal resting levels increase salt appetite. In contrast, experimental manipulations which produce severe hypotension inhibit salt appetite (see 170 for review of this issue). Additional sets of baroreceptors located in the aortic arch and carotid sinus (i.e., sinoaortic baroreceptors) respond to changes in arterial pressure. The role of these arterial baroreceptors has been well characterized in the reflex control of sympathetic activity and hormone (e.g., VP and renin) release, but a role for these afferent mechanisms in the behavioral control of fluid balance is just beginning to be explored (170, 254, 306). Reductions in venous return to the heart that result in so-called unloading of cardiac baroreceptors stimulate drinking in dogs. Reductions in venous return can be produced experimentally by constriction of a cuff placed around the vena cava (254, 319) or by inflation of a balloon surgically implanted inside the vena cava (109). In either case, blood flow through the vena cava is impeded, producing a fall in venous return and often a reduction in arterial blood pressure. Drinking in response to constriction of the vena cava appears to be mediated by baroreceptor afferents because this drinking is reduced in dogs that have undergone surgical transection of the nerves supplying either the cardiopulmonary or the sinoaortic baroreceptors (254) and is abolished by combined denervation of both sets of baroreceptors. In the absence of input from cardiopulmonary and sinoaortic baroreceptors, constriction of the vena cava does not cause drinking even though angiotensin levels are substantially elevated (254). Zimmerman et al. (368) demonstrated that crushing the left atrial appendage with its associated cardiac receptors reduced water drinking of hypovolemic sheep. These findings are consistent with a stimulatory role of these neural afferents for drinking in response to extracellular fluid loss. Loading of cardiac baroreceptors can be mimicked by inflation of an intravascular balloon placed at the junction of the left pulmonary vein and the left atrium. The mechanical stimulation of these receptors reduces spontaneous water intake in dogs and also reduces water intake in response to isoproterenol treatment, iv infusions of hypertonic saline, and water deprivation (228). Similar results for extracellular dehydration-related drinking have been obtained in rats after inflation of a balloon placed at the junction of the superior vena cava and right atrium (175). These results suggest that cardiopulmonary receptors provide signals that inhibit water intake when body fluids are

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expanded. In dog, temporary reductions of cardiopulmonary activity by vagal blockade increase water intake in response to reduced venous return (109). An understanding of the role of systemic baroreceptor mechanisms in thirst and sodium appetite is very limited compared to current knowledge about autonomic and endocrine reflexes controlling fluid balance. Furthermore, the relatively slow progress in elucidating baroreceptor mechanisms in the control of thirst and salt appetite can be contrasted with more rapid advances in the understanding of hormonal signals of thirst and salt appetite. Particularly relevant is the discovery of the potent dipsogenic (103) and natriorexigenic (36, 37) actions of ANG II.

The Peripheral (i.e., Endocrine) Renin–Angiotensin System (RAS) and Thirst and Salt Appetite

The steady stream of evidence implicating circulating ANG II as a major afferent signal for initiating thirst and salt appetite has largely been the result of the seminal work of Fitzsimons (103) and his colleagues. In early experiments attempting to identify the vascular receptors for hypovolemic thirst, Fitzsimons (103) discovered a renal thirst mechanism. Normovolemic rats drink substantial quantities of water when cardiac return is reduced by ligating the inferior vena cava or when renal blood flow is compromised by coarctation of the descending aorta above the renal arteries. These dipsogenic responses are markedly diminished by nephrectomy (103). As further evidence for a role of the kidney in thirst, Fitzsimons demonstrated that renal extracts contained a thirst factor which he determined by bioassay to be identical to renin (103). It was subsequently shown that systemically administered renin (103) and ANG II (110) are dipsogenic. Hypotension, hypovolemia, and various pharmacological (e.g., isoproterenol, phentolamine) treatments which activate the RAS induce drinking (see 104, 107 for review). Fitzsimons and Simons (110) initially infused high doses of ANG II iv (0.05 to 3.0 nmol/kg/min for periods of 30 to 310 min) to generate drinking. Using refined behavioral methods, Hsiao et al. (144) demonstrated that drinking could be induced reliably in rats with an iv dose of approximately 25 pmol/kg/ min. While this dose is still large and probably in the high physiological range, it is markedly lower than the initial quantities used to induce thirst. Mann et al. (198) infused ANG II iv at the rates used by Hsiao et al. (144) and found that resting plasma levels of ANG II increased from approximately 100 to roughly 200 pmol/ml during the infusion. In the time since ANG II was first implicated as a dipsogen, there have been several challenges to the idea that the octapeptide has a physiological role in drinking (1, 10, 247, 293, 295, 341). Concerns raised by various investigators have included (i) the need to administer large systemic doses of renin or ANG II to induce drinking; (ii) reports by some investigators that only small increases in intake are obtained with renin or ANG II; and (iii) the alternative possibility that circulating ANG II in certain thirst-inducing paradigms (e.g., isoproter-

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enol) is not directly dipsogenic but plays a permissive role by maintaining blood pressure at levels compatible with drinking behavior. In this light, it is instructive to consider how the plasma levels of ANG II generated by various thirst-inducing manipulations or during physiological states in which drinking is stimulated compare with those generated by Hsiao and associates (144; see Fig. 1). For example, circulating levels of ANG II reach roughly 350, 400, 400, and 875 pmol/ml plasma by 8 h after sc treatment with 5 ml of 20% polyethylene glycol, 48 h of water deprivation, 30 min after isoproterenol treatment (30 µg/kg, sc), and 1 h after caval ligation, respectively (166, 198). These data indicate that at the time that animals would normally initiate drinking in response to these dipsogenic treatments, plasma levels of angiotensin surpass the empirically established dipsogenic threshold for iv infused ANG II. Therefore, it is logically consistent that circulating ANG II makes a contribution to the drinking response after these dipsogenic treatments (168, 199). In

FIG. 1. Summary indicating plasma levels of angiotensin II (ANG II) obtained following various challenges to activate the endogenous renin–angiotensin system. These are presented on the regression line of the relationship between infused ANG II dose (abscissa) and circulating level of octapeptide (ordinate). Intact-25 pmol/kg/min and Intact-100 pmol/kg/min indicate levels of circulating ANG II after 60-min infusions of the indicated dose into unanesthetized rats. Lower crosshatched areas represent the range of control values of plasma ANG II. Upper crosshatched area represents approximate ANG II plasma level at dipsogenic threshold. The threshold at which ANG II induces drinking with iv infusion was established by Hsaio et al. (144). Abbreviations: DI, diabetes insipidus; RH, renal hypertension; PEG, polyethylene glycol; ISOP, isoproterenol. From Johnson and Thunhorst (170) with permission of the publisher.

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addition as will be considered in a later section, it is also important to note that arterial pressure is a critical factor that influences the dipsogenic potency of ANG II (82, 170). The role of the endocrine RAS in salt appetite has also been controversial (107). Surgical procedures that alter the activity of the RAS such as nephrectomy, adrenalectomy, renal artery constriction, or ureteric ligation have marked effects on sodium intake. However, it is not clear if the effects of these surgical procedures on sodium intake can be attributed to changes in renin secretion and the production of ANG II. Thus, the effectiveness of nephrectomy in completely abolishing salt appetite induced by hypovolemia may be due to the loss of the source of renin, to anuria, or to general debilitation (111, 304). The robust salt appetite following excision of the adrenal glands with the consequent loss of mineralocorticoid may be directly related to increased renin secretion and formation of ANG II, indirectly related to a massive loss of sodium in the urine, to changes in salivary sodium content (118), or to reduced sodium concentration at sodium receptors in the brain (352). Clipping the renal arteries produces salt appetite preceded by increased renin secretion (226). However, clipping of the renal arteries also produces hypertension, so the salt appetite produced in these circumstances may be a pathophysiological response. Ligation of the ureters suppresses salt appetite, despite markedly increasing renin secretion, but it is not known if the attenuation of salt appetite is due primarily to alterations of renal function or to the release of unidentified inhibitory factors (111, 220). Drug treatments that target the endocrine RAS produce ambiguous effects on salt appetite. For example, salt appetite of sodium-depleted rats has not been shown to be prevented by pharmacological blockade of the renal RAS with ANG II receptor antagonist (272). Doses of systemically administered angiotensin converting enzyme (ACE) inhibitor that reduce the salt appetite of sodium deficient rats are typically so high that their suppressive actions have been attributed to inhibition of the brain RAS rather than the peripheral RAS (224, 272). Intravenous infusions of ANG II do not reliably stimulate salt appetite in sodium-replete rats (95, 112, 272) or rabbits (312), although they may in sheep (353). In any case, the sodium ingestion produced by iv ANG II has been attributed to indirect effects including angiotensin-induced pressure natriuresis and slowly developing negative sodium balance (312, 353, 362). The early evidence supported the assertion that the central, or brain, RAS is more important than the endocrine RAS in producing salt appetite. Centrally administered ANG II readily stimulates salt appetite without prior natriuresis and negative sodium balance (11, 36, 37, 46, 113, 114). Furthermore, centrally administered ACE inhibitors and ANG II receptor antagonists easily inhibit depletion-induced salt appetite (43, 224, 274, 354). Circulating ANG II was ascribed a minor role in the production of salt appetite. For example, Epstein and colleagues (80, 272, 362) proposed in the synergy hypothesis of salt appetite that the role of renally derived ANG II is in essence only to stimulate the secretion of aldosterone following sodium depletion and that brain-derived

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ANG II synergized with aldosterone to produce salt appetite through their combined actions within the CNS. The first convincing demonstrations that systemically administered ANG II produces salt appetite not attributable to its indirect effects were provided by Weisinger and colleagues in sodium deficient cow (27), sheep (351), rabbit (313), and mouse (348). The sodium-deficient animals were treated with doses of ACE inhibitors sufficient to prevent the endogenous formation of ANG II both peripherally and centrally. In all cases, blockade of the endogenous RAS reduced or abolished salt appetite. Subsequently, systemic administration of ANG II to these ACE-blocked, sodium-deficient animals either partially or fully restored salt appetite without producing additional sodium loss. These results were taken as evidence that during times of sodium deficiency increased levels of circulating ANG II could stimulate salt appetite, probably by acting on brain areas that lie outside of the blood–brain barrier, namely, the circumventricular organs (CVOs). Recent work has extended the findings of Weisinger and co-workers to the sodium-deficient rat. In this demonstration, rats were depleted of sodium by diuretics and then infused iv either with captopril (CAP; 2.5 mg/h) or the vehicle (5% dextrose in water [D5W]; 322). Upon presentation of 0.3 M NaCl, rats infused with D5W showed a robust salt appetite (Fig. 2) while rats infused with CAP had no salt appetite at all. Importantly, both groups of rats showed normal water intakes and pressor responses to icv injections of angiotensin I (ANG I) after the salt appetite tests. This confirmed that the brain RAS remained unblocked in CAP-treated rats and indicated that selective blockade of the endocrine RAS is sufficient to abolish depletion-induced salt appetite. Subsequent work showed that the salt appetite response of sodium-depleted, CAP-blocked rats is reestablished within minutes by iv infusion of ANG II (99). Together, these findings indicate that salt appetite after sodium depletion in rats is dependent on the presence of circulating ANG II. Therefore, rather than being of minimal importance, the endocrine RAS may be a critical factor for stimulating salt appetite after periods of sodium depletion in rats as well as in other species. To suggest that the endocrine RAS has an essential role in depletion-induced salt appetite does not minimize the importance of a brain RAS in this behavior. If the peripheral and central RASs function in series, as has been proposed for thirst and other endocrine and autonomic responses (152, 188), then both may be required for the expression of salt appetite (320, 322).

Arterial Blood Pressure and Blood Volume Control of Thirst and Salt Appetite

New experimental strategies have made it possible to begin to establish the relative roles of hormonal and baroreceptor signals in the mediation of fluid ingestion. Furthermore, increased attention is being paid to interactions be-

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FIG. 2. Cumulative intake of 0.3 M NaCl solution beginning 18 h after furosemide-induced sodium depletion in groups of naive rats receiving continuous intravenous infusions of 5% dextrose in water (D5W) vehicle or 2.5 mg/h captopril (CAP) during the entire period of depletion and testing. Values are means 6 SE. Captopril infusion completely suppressed sodium depletioninduced salt appetite. From Thunhorst and Fitts (322) with permission of the publisher.

tween these two classes of afferent signals in the control of body fluid regulation (82, 170, 299, 326, 328). ANG II has been regarded as a dipsogenic hormone since the demonstration by Fitzsimons and Simons (110) that its iv administration produces drinking in rats. Although the dipsogenic response to iv infusions of ANG II has been confirmed in several species by many investigators (54, 106, 285, 337), the often weak nature of the dipsogenic response has been considered evidence against a physiological role of the renal RAS in the control of drinking behavior (293, 295, 341). For example, Van Eekelen and Phillips (341) note that the doses of iv ANG II that are required to produce even modest dipsogenic responses result in plasma levels of the hormone that are in the high physiological range. However, evidence (82, 87, 263) now indicates that the dipsogenic potency of iv ANG II has been underestimated due to the confounding influences of acute hypertension on drinking behavior. In fluid-replete animals in normal hydromineral balance, exogenous ANG II often produces nonphysiological increases of arterial pressure (82). Under natural conditions involving hypovolemia, the reflex increase in circulating levels of endogenous ANG II serves to maintain arterial

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pressure at approximately normotensive levels. A greater experimental drinking response to iv infusion of ANG II is unmasked if arterial pressure is normalized by the coadministration of hypotensive agents (87, 263; see Fig. 3). The pressure-induced inhibition of water drinking in response to ANG II appears to be mediated by cardiopulmonary or arterial baroreceptors, as the combined surgical removal of both sets of these neural sensors in dogs permits a greater drinking response to iv ANG II (178). In rats, removal of only the arterial baroreceptors does not affect the drinking response to systemically administered angiotensin (173, 257). Therefore, the data suggest that cardiopulmonary baroreceptors or some combination of cardiopulmonary and arterial baroreceptor signals act as inhibitory modulators of drinking behavior when arterial pressure is elevated.

FIG. 3. Effects of minoxidil on mean arterial pressure (MAP) and water intake of rats infused intravenously with a combination of ANG II and captopril for 90 min. Captopril prevented the endogenous formation of ANG II during testing. Vertical arrow indicates time of injection of minoxidil or isotonic saline control. Rats drank significantly more water during infusion with ANG II when MAP was reduced by minoxidil. Values are mean 6 SE. *Significantly greater than that of saline control, p , 0.05. The number of rats is in parentheses. From Robinson and Evered (263) with permission of the publisher.

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Elevation of arterial pressure also inhibits drinking in response to centrally administered ANG II. Ganglionic blockade simultaneously augments pressor responses and decreases drinking responses to central injections of ANG II in dogs (183). Rats of the Brattleboro strain drink more in response to central injections of ANG II compared to Long–Evans rats (136), possibly reflecting their genetic lack of VP and consequent diminished pressor responses to central injections of ANG II (136, 167). Moderate reductions in arterial pressure below normal resting levels increase drinking in response to centrally administered ANG II (326). In these studies, rats received central infusions of relatively low doses of ANG II (4 or 16 ng/h) with arterial pressure at resting levels or reduced by iv infusion of minoxidil (25 µg/kg/min). With a high dose of ACE inhibitor (CAP, 0.33 mg/min) included in both infusions to prevent the endogenous formation of ANG II during testing, centrally administered ANG II produced dose-related increases in water intake at resting levels of arterial pressure (Fig. 4), and notably the dipsogenic response to centrally administered ANG II doubled under hypotensive conditions. If the level of arterial pressure modulates angiotensin-induced drinking, it is reasonable to hypothesize that carotid sinus and aortic arch baroreceptors are

FIG. 4. Effects of iv captopril and minoxidil on water intakes in response to icv ANG II. Rats received iv infusions of captopril (CAPTOPRIL) or minoxidil in combination with captopril (MINOXCAP) beginning at t0. Separate groups received icv infusions of ANG II at 4 (A) or 16 (B) ng/h starting at t60 (broken lines). Each dose of icv ANG II produced water intakes that were greater during MINOXCAP treatment, when arterial pressure was reduced below normal resting levels, than during captopril treatment, when pressure was normal. Water intakes to icv ANG II were significantly dose-related. From Thunhorst and Johnson (326) with permission of the publisher.

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involved. However, deafferenting the arterial baroreceptors did not disrupt the ability of arterial pressure to modulate drinking in response to ICV ANG II (330; Fig. 5). The potential contribution of other systemic baroreceptors (e.g., cardiopulmonary baroreceptors, renal baroreceptors; 290) in mediating the influences of arterial pressure on fluid ingestion remains to be investigated. Little is known about potential interactions between hormonal and baroreceptor signals controlling salt appetite. Substantial evidence suggests that ANG II and aldosterone stimulate salt appetite but that neither hormone is strictly essential for the response (118, 296), so that other mechanisms must regulate salt appetite, including cerebral sodium sensors (352) and possibly baroreceptors. Evidence for a role of baroreceptors in salt appetite is largely circumstantial. Almost without exception, such evidence relies on producing hypovolemic/ hypotensive conditions known to alter baroreceptor activity, but few experiments have asked whether animals lacking baroreceptors show salt appetite in response to hypovolemic/hypotensive conditions. Similarly, the finding that distention of the right atrium in the rat inhibits salt appetite has been interpreted as evidence for inhibitory neural signals arising from atrial barore-

FIG. 5. Effects of iv captopril, minoxidil, and phenylephrine on water intake in response to icv infusions of ANG II (16 ng/h) in sham and sinoaortic denervated (SAD) rats. Water intake was significantly increased when mean arterial pressure (MAP) was reduced below normal resting levels during iv minoxidil plus captopril treatment and was significantly decreased when MAP was elevated during phenylephrine plus captopril treatment, compared with water intake during vehicle infusions of captopril. Sinoaortic denervation did not affect water intake in response to icv infusion of ANG II. From Thunhorst et al. (330) with permission of the publisher.

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ceptors under conditions of volume expansion; alternatively, this may reflect release of inhibitory hormones from the atrium itself (335). To help resolve this issue, it must be determined whether distention of the atrium inhibits salt appetite in animals with deafferented atrial baroreceptors. One difficulty in accepting a role for baroreceptors in the initiation of salt appetite has been the temporal dissociation of hypovolemia and salt appetite (107, 299). Hypovolemic treatments often produce water drinking with delays of only 30–60 min, but sodium ingestion typically commences hours after treatment and only after water intake has occurred. This temporal delay between the hypovolemic stimulus and salt appetite may be an experimental artifact. Stricker (296, 297) suggests that rats maintained on standard laboratory diet with its high sodium content have a reserve of body sodium that acts as a buffer against the extracellular-depleting effects of hypovolemia. When rats are maintained on a sodium-deficient diet for 2–4 days before study, they may show salt appetite with the onset of hypovolemia. The question remains as to how the reserve of body sodium delays the expression of salt appetite when hypovolemia readily produces the ingestion of water. Compared with rats on standard diets, those on sodium-deficient diets have reduced plasma volume and plasma sodium concentrations (296, 301) and increased levels of plasma renin activity and aldosterone (304). When challenged by hypovolemia, sodium-deficient rats have greater reductions in plasma volume, larger increases in plasma renin activity and aldosterone, and more difficulty maintaining arterial pressure in the face of the accruing deficits than rats maintained on standard diet (301, 304). The increased activity of the renin–angiotensin–aldosterone axis in rats on sodium-deficient diets supports the synergy hypothesis for the generation of salt appetite. Furthermore, the difficulty these rats have maintaining arterial pressure, combined with the greater reductions in plasma volume in response to hypovolemia, is consistent with the idea that baroreceptors may contribute facilitatory signals or remove inhibitory inputs under these conditions. Rats maintained on sodium-deficient diets also have blunted secretion of OXY in response to hypovolemia (303), which may reflect reduced activity of central mechanisms inhibiting sodium ingestion. Animals develop salt appetite more rapidly in response to hypovolemia if they are simultaneously made moderately hypotensive. Stricker (297) demonstrated that rats treated with polyethylene glycol showed immediate salt appetite when injected with a low dose of ACE inhibitor. A rapidly developing salt appetite is also produced by administering CAP to rats made hypovolemic by injection of the diuretic furosemide (FURO; 97, 204, 327). These are two examples of ‘‘paradoxically enhanced’’ salt appetite (to be discussed in a later section), and the sodium ingestion in these circumstances is likely due to increased formation of ANG II within brain CVOs (97, 204, 297, 327). It is noteworthy that in both situations peripheral ACE blockade causes a reduction in arterial pressure (123, 327) which may be essential for the rapid induction of salt appetite (327). When infusions of phenylephrine are used to maintain arterial pressure at basal levels during combined treatment with FURO and

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CAP, the salt appetite response is selectively blunted, although water drinking is quite normal (327). It is currently unclear if hypotension facilitates the appearance of salt appetite by changing neural input to critical CNS sites or by further increasing renin secretion to augment formation of ANG II. There are hints in the literature that acute increases in arterial pressure may inhibit salt appetite, as they do thirst, but this possibility has not been adequately explored. For example, iv infusions of ANG II that elevate arterial pressure approximately 40 mm Hg above baseline slightly reduced the salt appetite of sodium-deficient sheep (32). In hypotensive sodium-deficient rats, saline drinking was stimulated soon after the start of ANG II infusion but abated as arterial pressure rose above normal basal levels (99). A pressuremediated inhibition of salt appetite could partly explain why it takes such prolonged iv infusions of ANG II to stimulate salt appetite in fluid-replete rats. There is one report that denervation of the arterial baroreceptors reduces salt appetite in sodium-deplete rats by half (331). It is not known if this reduction in salt appetite following denervation is due directly to the absence of baroreceptor signals, indirectly to altered hormonal responses (e.g., reduced renin secretion), or both.

INTEGRATIVE ACTIONS OF THE CNS Brain Neural Networks and the Reflex and Behavioral Controls of Body Fluid Homeostasis

Mechanisms of Afferent Signaling: Neural and Humoral Inputs Information reflecting the status of body fluids is imparted to the CNS by both afferent nerves and circulating factors. The nucleus of the tractus solitarius (NTS) serves as the major port of access to the brain for most of the systemically derived input carried in the IXth and Xth cranial nerves (239). Small molecules or highly lipophilic substances (e.g., aldosterone) generated in the periphery communicate directly with the brain, and other substances that are excluded from the CNS by the blood–brain barrier (e.g., insulin) may use special transport mechanisms to enter the brain. However, some of the most important systemic signals generated in response to changes in body fluid status, such as the peptides ANG II and atrial natriuretic peptide (ANP), are excluded by the blood–brain barrier and must act via CVOs. In vertebrates, there are several small periventricular structures which lack a blood–brain barrier (see 211, 347 for review of CVOs). Early investigations implicated many of the CVOs (e.g., median eminence, posterior pituitary, pineal) as sites of brain neuroendocrine release into vascular portal systems or the systemic circulation. Additionally, there is substantial evidence that three CVOs, the subfornical organ (SFO), the organum vasculosum of the lamina terminalis (OVLT), and the area postrema (AP), function as receptors of blood-borne information. Much of the insight into the sensory role of these

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structures was acquired in the course of studying the function of the CNS in body fluid and cardiovascular homeostasis. The SFO, OVLT and AP can be appropriately referred to as sensory CVOs (154, 164).

The Nature of Neural Processing in Motivated States Such as Thirst and Salt Appetite Fundamental concepts underlying the processing of sensory information by the central nervous system have changed markedly in the past 20 years. There has also been considerable progress in defining the organization and chemical characteristics of many CNS pathways. Neuroanatomical tract tracing techniques and functional mapping methods, such as ablation, electrical stimulation, metabolic activation (e.g., 2-deoxy glucose method), and expression of immediate early genes (e.g., c-fos) have implicated numerous brain structures in the processing of systemically derived information related to intra- and extracellular volume and arterial blood pressure. Most notable among these regions are the (i) AP, (ii) NTS, (iii) caudal and rostral ventrolateral medulla, (iv) parabrachial nuclei, (v) SFO, (vi) periventricular tissue of the anteroventral third ventricle (AV3V) [i.e., ventral median preoptic nucleus (vMePO), OVLT, periventricular preoptic nuclei], (vii) both the magnocellular and the parvocellular components of the hypothalamic paraventricular nuclei, (viii) supraoptic nuclei, (ix) amygdala (particularly central nucleus and medial nucleus), (x) bed nucleus of the stria terminalis (BNST), (xi) lateral hypothalamus/perifornical region, (xii) the zona incerta, (xiii) dorsomedial and ventromedial hypothalamus, (xiv) locus coeruleus, (xv) dorsal motor complex of the vagus, and (xvi) intermediolateral cell column of the spinal cord. This work has established a collection of structures and their connections that constitute a body fluid-related neural network that carries and integrates information pertinent to the control of fluid balance. Although every structure and pathway in the brain can, in principle, influence information processing in this neural network, some regions are relatively more important for handling visceral input related to hydromineral balance. Neural networks have several features that are well suited for the control of homeostatic behaviors and physiological mechanisms controlling body fluid balance. The organization of the body fluid-related neural network, in principle, allows visceral information reflecting fluid balance to be broadly distributed from the several relatively small loci that act as neural and endocrine ports of access into the brain. Also, the property of parallel distributed processing of information typical of neural networks provides redundancy so that damage to a portion of the system may not be catastrophic. It is likely that this system is inherently modifiable, exhibiting plasticity associated with recovery of function, and capable of storing information. The central resetting of baroreceptor reflexes is a classic example of plasticity in control of the cardiovascular system, and this capacity for modification is probably a consequence of func-

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tional properties of the neural network maintaining arterial blood pressure. Similar plasticity is likely to exist in the circuitry subserving thirst and salt appetite. For example, chronically enhanced sodium preference and salt appetite may result from a single episode of an acute sodium deficiency (89, 273). Several neurotransmitters/neuromodulators associated with the body fluidrelated neural network have been identified. These include (i) glutamate, (ii) g-aminobutyric acid (GABA), (iii) acetylcholine, (iv) NE, (v) 5-HT, (vi) ANG II, (vii) VP, (viii) OXY, and (ix) corticotrophin releasing hormone. The brain renin–angiotensin and noradrenergic systems are broadly distributed in the CNS (21, 187). Together, these two neurochemical systems innervate most of the structures implicated in the body fluid-related neural network. One can conceive of many of the aforementioned neurotransmitters/neuromodulators inputting into nodes of this network as components of local circuits associated with specific processing of facilitory or inhibitory information. There is an emerging body of data indicating a regional localization of function (processing modules) in the neural network subserving thirst and salt appetite. In particular, forebrain structures including those located along the lamina terminalis appear to play a facilitory role in the generation of thirst and sodium appetite. A second set of findings implicates a hindbrain system, particularly the AP, the NTS, and the parabrachial nucleus (56, 283) as part of the neural substrate providing inhibitory modulation of these behavioral responses under conditions of expanded extracellular fluid volume. These excitatory and inhibitory systems undoubtedly converge and interact at many nodes within the body fluid-related neural network, although for heuristic purposes the following discussion is organized to describe these facilitory and inhibitory circuits independently.

Facilitory Neural Circuits and Neurochemical Systems

Role of Structures Along the Lamina Terminalis in Body Fluid Regulation Early in embryonic development, the rostral end of the neural tube is closed by a layer of ependymal cells. Technically this band of cells comprises the lamina terminalis and in mature vertebrates constitutes the anterior wall of the third cerebral ventricle. Adjacent to the lamina terminalis are three midline nuclei—the SFO, the MePO, and the OVLT—and the anterior commissure. Morphological studies of the SFO by Dietrickx (68) and Palkovitz (245) led them to the prescient speculation that this CVO might be involved in sodium and water homeostasis. Substantial support for this idea was provided by the work of Simpson and Routtenberg (286), who demonstrated that stimulation of the SFO with ANG II produces reliable drinking with extremely low doses of the peptide. However, there is evidence that the SFO is not the only site of dipsogenic action for ANG II in the brain. For example, rats will drink in

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response to icv ANG II after SFO lesions provided that cerebrospinal fluidborne peptide reaches the rostral portion of the ventral third ventricle (i.e., the preoptic recess) (38). Ablation studies demonstrated that lesions destroying rostral nuclei surrounding the ventral third ventricle abolish drinking to both systemically and centrally injected ANG II (41, 42, 157, 158). Such lesions also have several other major effects on the regulation of body fluid and cardiovascular homeostasis (40–42, 158). The specific periventricular tissue destroyed by this ablation, which has been defined as an AV3V lesion, encompasses the OVLT, the vMePO, the periventricular preoptic nuclei, and the periventricular nuclei at the rostral level of the anterior hypothalamus. The name AV3V was chosen to describe the lesion because its constellation of functionally defined effects is not localizable to a single anatomical structure. Both the acute and the chronic effects of AV3V lesions on body fluid and cardiovascular regulation have been studied extensively and various aspects have been summarized in several reviews (34, 57, 149, 151–153, 157, 160–163, 366). Only a few of the most salient features will be discussed here. Some prominent effects of AV3V lesions are summarized in Table 1. Immediately after placement of AV3V lesions, animals show an acute period of adipsia and do not release VP in the face of severe hypovolemia and hypertonicity. Animals with AV3V lesions will die of dehydration typically within 5–7 days unless they are hydrated. Although rats with AV3V lesions do not consume TABLE 1 Prominent Effects of AV3V Lesions Acute effects Adipsia Impaired secretion of vasopressin Severe weight loss and if untreated, debilitation and death due to dehydration Chronic effects Reductions in body weight Recovery of ad libitum drinking Impaired drinking responses to experimental challenges Attenuated water deprivation-induced drinking Abolished cellular dehydration-induced drinking Extracellular thirst Abolished angiotensin II-induced drinking Attenuated isoproterenol-induced drinking Attenuated caval ligation-induced drinking Attenuated polyethylene glycol treatment-induced drinking Altered ad libitum sodium intake Impaired sodium depletion-induced salt appetite Impaired vasopressin secretion to hypertonic saline and ANG II Impaired natriuresis Impaired pressor responses to hypertonic saline and ANG II Protection against most forms of experimentally-induced hypertension Hypernatremia

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water acutely, they continue to eat and will readily drink palatable fluids (i.e., sucrose, saccharin, and liquid diets) in sufficient quantities to survive. Gradually, over the course of 7 to 10 days, the initially adipsic rats can be ‘‘weaned’’ back to water. Nearly all animals maintained through the acute postlesion period recover ad libitum water intake and sustain themselves in the benign laboratory environment. On average, the mean daily water intake of a group of ‘‘recovered’’ animals with AV3V lesions is comparable to that of animals with sham lesions. However, on a day to day basis, the consumption of individual animals during the chronic phase varies widely (190). For the rest of their lives, animals with AV3V lesions show severe impairments in thirst, VP release, and pressor responses to several cardiovascular and fluid regulatory challenges. Especially affected are reflex and behavioral responses to humoral factors (i.e., ANG II and increased plasma osmolality). Although animals with AV3V lesions respond to sustained hypovolemic challenges as long as there is a significant contribution from vascular baroreceptors (41), drinking is still impaired (190), presumably due to the loss of response to ANG II which contributes to hypovolemic thirst (166). As in intact rats, recovered animals with AV3V lesions have a high probability of drinking in association with food intake (i.e., meal-associated thirst). However, unlike control animals, ‘‘recovered’’ AV3V animals do not demonstrate a strong positive correlation between meal size and the amount of water consumed (16). Rats with AV3V lesions appear to lack the fine control of water intake under ad libitum conditions which may reflect impaired responsiveness to the humoral (i.e., osmolality and ANG II) signals of hydrational status.

Osmoreceptors and the AV3V Based on functional studies showing that rats with AV3V lesions have impaired drinking, antidiuretic responses, and pressor responses in the face of plasma hyperosmolality or to hypertonic stimuli, it was proposed that the AV3V region houses osmoreceptive cells (41, 158, 165). One classic qualification for establishing a region as a site housing osmoreceptors is that electrolytic lesions of the region should impair drinking and/or antidiuretic responses to hyperosmotic stimulation. Although this criterion is important, it is not sufficient to define the location of osmoreceptors. Electrolytic lesions do not distinguish between destruction of cell soma (i.e., in this case, osmoreceptors) and fibers of passage. However, the hypothesis of the AV3V as a site containing osmoreceptors received further support from additional functional studies which compared the sensitivity of the lateral preoptic area, a region implicated earlier as osmosensitive (29, 248), with the effects of injections into the AV3V. Injections into the optic recess of the third ventricle were markedly more effective in inducing drinking than lateral preoptic administrations (39). Experiments by Thrasher and colleagues in dog and McKinley and coworkers in sheep that employed both systemic and icv administration of

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osmo-active solutions led these investigators to conclude that cephalic osmoreceptors probably reside within one or more of the CVOs (210, 317). As noted above, the OVLT is the CVO consistently destroyed by AV3V lesions, and AV3V lesions are effective in markedly attenuating or abolishing both osmotically evoked antidiuretic responses mediated by VP release (151, 165) and cellular dehydration-induced drinking (39, 41). Consequently, the OVLT emerged as a logical choice for a structure housing osmoreceptors mediating antidiuretic hormone release and thirst. Given its small size and location, it is difficult to ablate the entire OVLT in the rat without encroaching on adjacent structures. Consequently, investigators have resorted to in vitro methods to study the OVLT in rats or have employed larger animals. One early study used hypothalmo-neurohypophyseal explants from rats with AV3V lesions. The explants were cut in the horizontal plane at the dorsal edge of the OVLT thereby eliminating input from more dorsal structures. In contrast to control explants with intact AV3V regions, the hypothalmo-neurohypophyseal tissue from rats with AV3V lesions (i.e., with nothing dorsal to the OVLT) did not release VP in response to osmotic stimulation with hypertonic ACSF (287). This provided further evidence of involvement of the OVLT, rather than dorsal (i.e., MePO and SFO), lamina terminalis structures as a site for osmoreceptors. Recently, Bourque and co-investigators (see 33 for review) studied rat OVLT neurons in hypothalamic explants under Ca21-free conditions and individual cells after acute dissociation. The application of hypertonic solutions to both of these in vitro preparations depolarizes cells of the OVLT, providing further evidence of the osmosensitivity of OVLT neurons. The depolarization of OVLT neurons results from activation of nonselective cationic channels (33). In vivo studies in sheep and dog support the in vitro rat studies implicating the OVLT as osmosensitive. Ablations restricted to the OVLT markedly raise the threshold and reduce the magnitude of responses for drinking and VP release to hyperosmotic stimulation (209, 318). However, it is necessary to ablate additional AV3V tissue surrounding the OVLT to completely abolish cellular dehydration-induced drinking and VP release (209, 318; see 150, 153 for review and discussion). There is evidence indicating that there are osmosensitive cells in other CVOs (143, 192, 284) as well as in structures located within the blood–brain barrier (33, 202). For example, Bourque et al. (33) presented electrophysiological evidence similar to that described above for osmosensitive units in both the SFO and the MePO. Mangiapane and colleagues (197) have shown that ablation of the MePO of the rat produces deficits in osmotically stimulated drinking and VP release. King and Baertschi (177) using electrolytic lesions argue that input from splanchnic/hepatic osmo- or sodium receptors which ascends the neuraxis via the NTS and ventrolateral medulla projects to the MePO before it proceeds to hypothalamic magnocellular vasopressinergic neurons. Taken together, current data implicate AV3V regions beyond the OVLT in osmoreception and/or the processing of osmotic information.

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Angiotensin Action in the Lamina Terminalis Because lesions of both SFO and AV3V attenuate angiotensin-induced pressor responses, drinking and VP release, the relationship between these two areas of the lamina terminalis has been investigated extensively. Tract tracing studies (187, 193, 222, 223) have been especially illuminating by establishing the major neural connections between these two regions. The most prominent pathway in this local circuitry is a large descending projection originating in the SFO that travels down the lamina terminalis into the vMePO and OVLT. In these more ventral regions, close appositions between apparent fiber terminals and cell bodies are frequently observed. This suggests that the MePO and OVLT receive direct input from the SFO. Such anatomical evidence, along with additional functional data, such as the sensitivity of the AV3V region to icv-injected ANG II (38) and the capacity of icv angiotensin receptor antagonists to block blood-borne ANG II-induced drinking (169), has led to a model in which ANG II may act in two different modes along the lamina terminalis (188). First, ANG II acts at the SFO as a hormone with the blood-borne peptide acting on receptors to activate a descending angiotensinergic pathway with terminals ending in several forebrain structures including the vMePO. Second, ANG II is released from the terminals of these descending projections and acts as a neurotransmitter/neuromodulator. This model is also supported by functional studies showing that knife cuts of descending fibers from the SFO abolish drinking and attenuate pressor responses to blood-borne ANG II (78, 189, 191). Such transections have little effect on angiotensin-induced responses when the peptide is administered directly into the ventricles of the forebrain where it can gain access to the periventricular tissue of the AV3V (189). Since the time this model was initially proposed, additional data have been generated that are consistent with the hypothesis. These observations include: (i) the presence of high concentrations of angiotensin receptors located in a heavy band throughout the lamina terminalis (219, 252), (ii) in situ hybridization studies indicating the presence of high levels of angiotensinogen messenger RNA in the AV3V (196), and (iii) additional electrophysiological studies (235, 316, 336) supplementing earlier work (e.g., 90, 133, 180) indicating that there are ANG II sensitive cells located at sites all along the lamina terminalis. In light of an increased understanding of the relationship of the AV3V to other CNS regions that control hydromineral balance, it is possible to understand why AV3V lesions produce such profound, global effects on body fluid and cardiovascular regulation. Lesions of the AV3V are likely to destroy (i) sensory receptors (e.g., osmoreceptors), (ii) fibers of passage, and (iii) cells involved in integration of hydromineral-related sensory input from multiple brain and systemic receptor systems (Fig. 6). Neuroanatomical studies indicate that the OVLT, MePO, and SFO are richly interconnected with one another. Cell bodies in the SFO, MePO, and OVLT are the origins of descending pathways which project directly to several additional forebrain structures. Functional evidence associated with the structures of these terminal fields accounts for many

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FIG. 6. Sensory circumventricular organs (CVOs) associated with the lamina terminalis and descending projections to forebrain regions involved in autonomic, neuroendocrine, and behavioral control of body fluid and cardiovascular homeostasis. OVLT, organum vasculosum of the lamina terminalis. From Johnson (154) with permission of the publisher.

known actions of brain angiotensin in the control of thirst, sympathetic activation, and the secretion of VP, OXY, and adrenocorticotropic hormone.

Descending Angiotensinergic and Ascending Adrenergic Systems, and the Integrative Actions of Structures of the Ventral Lamina Terminalis Rats with brain lesions induced by icv injection of the neurotoxin 6-hydroxydopamine (6-OHDA) exhibit many of the same signs as rats with AV3V lesions. Specifically, both have (i) chronic reductions in body weight, (ii) transient postsurgical adipsia, (iii) permanent impairments to cellular and extracellular thirst challenges, (iv) pressor deficits and reduced VP release in response to ANG II and hypertonic saline administration, and (v) a failure to develop many forms of experimental hypertension. It is reasonable to consider whether electrolytic AV3V lesions and 6-OHDA ablations produce damage to similar brain structures and to determine which catecholaminergic substrate (dopamine vs. NE) is critical for producing these effects. Initial experiments focused on determining if the depletion of NE or dopamine is critical. Varying doses of

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6-OHDA were administered in conjunction with catecholamine uptake blockers to produce selective widespread depletions of dopamine, NE, or both catecholamines. These studies demonstrated that damage to brain noradrenergic systems was primarily responsible for impairments in angiotensin-induced drinking and pressor responses (17). Additional studies using local injections of 6-OHDA into tissue along the lamina terminalis (i.e., SFO, MePO, OVLT; 18, 19, 58) demonstrated that neurotoxin administration into the OVLT and vMePO impaired drinking and pressor responses evoked by ANG II. However, the presence of NE innervation of the ventral lamina terminalis was not critical for drinking and pressor responses produced by sc hypertonic saline or icv carbachol. ANG II-induced pressor and drinking responses have been restored in rats with 6-OHDA lesions of the ventral lamina terminalis by transplantation of NE cell bodies into the parenchyma of the catecholamine-depleted region (212, 213). Similarly, animals with thirst deficits after 6-OHDA lesions drink in response to icv ANG II when pretreated with icv NE (59). Taken together, the outcomes of catecholamine depletion and repletion studies indicate that NE must be present in the tissues of the ventral lamina terminalis in order to obtain drinking and pressor responses induced by exogenous ANG II. Noradrenergic innervation of the AV3V region arises from the A1, A2, and A 6 catecholamine cell groups located in the hindbrain (275). In turn, these brainstem aminergic cell groups receive reciprocal innervation from the ventral lamina terminalis (i.e., MePO; 364). There are several functional studies indicating that brainstem noradrenergic cell groups are activated by hypotension and hypovolemia (74, 227, 255), and it has been hypothesized (57, 152) that hypovolemia and hypotension activate ascending noradrenergic pathways to release NE into the ventral lamina terminalis region. Consistent with this is the observation that hypovolemia induced by sc polyethylene glycol treatment increases NE turnover in the MePO (355). NE has been demonstrated to modulate information processing in several CNS structures including nuclei in primary sensory pathways (e.g., vision, olfaction, 147, 264). At these sites, NE reduces the basal level of firing and thereby enhances the signal-to-noise ratio in response to a stimulus evoking activity in the primary sensory pathway (115, 147, 361). Therefore, NE may have a similar action to facilitate throughput in the angiotensinergic sensory pathway that connects the SFO via the MePO with the rest of the neural network that maintains body fluid and cardiovascular homeostasis.

Converting Enzyme Inhibitors and the Paradoxical Enhancement of Thirst and Salt Appetite: The Role of Local ANG II Generation

Lehr et al. (186) observed what they termed ‘‘paradoxical enhancement’’ of drinking while using the competitive ACE inhibitor teprotide (SQ 20, 881) to test the role of the RAS in so-called renin-dependent and renin-independent thirsts. They reasoned that teprotide would block renin-dependent thirst by preventing the formation of ANG II. Unexpectedly, sc injections of teprotide

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increased the drinking response to several purported renin-dependent dipsogens, including isoproterenol, polyethylene glycol, and caval ligation, and to water deprivation. The additional water drinking caused by the sc injection of teprotide was eliminated by concurrent central administration of the ACE inhibitor through icv cannulas. Lehr et al. concluded that water drinking during peripheral treatment with teprotide results from increased delivery of ANG I to the brain of the rat where it is converted to ANG II at some central site. In a footnote to the article, they referenced work by Simpson and Routtenberg (286) demonstrating that the SFO is extremely sensitive to the dipsogenic effect of ANG II and used this evidence to suggest that the SFO is one brain site where such central conversion could occur. Under physiological conditions, most circulating ANG I is converted to ANG II by ACE located in the microvasculature of several structures but most notably the lung (234). Therefore, only small amounts of ANG I are available as substrate for ACE located in peripheral tissues and brain. Systemically administered ACE inhibitors increase the survival of ANG I in the blood which may then act as substrate for ACE located in the brain (280). Obviously, in order for there to be central conversion of ANG I to ANG II to occur, some ACE in brain must remain unblocked during peripheral ACE inhibition. Autoradiographic studies provide some support for this possibility. Two ACE inhibitors (i.e., lisinopril and perindopril) have been studied and shown to spare some portion of ACE activity in the brain, including the CVOs, at doses that greatly reduce ACE activity in lung and abolish ACE activity in plasma (269–271). The phenomenon of paradoxical enhancement of water drinking has been confirmed by many investigators using many different thirst challenges and several different ACE inhibitors (70, 85, 139, 184, 266). Paradoxical enhancement of sodium ingestion (75, 84, 116, 267, 297) and VP secretion (179, 332) have also been observed with peripheral ACE blockade. The effects of ACE inhibitors on water drinking, sodium ingestion, and VP secretion are doserelated and biphasic. The range of doses that generates the biphasic response pattern varies greatly with experimental conditions. Generally, renin-dependent responses are augmented at ‘‘low’’ doses of ACE inhibitor and attenuated at ‘‘high’’ doses. For example, the ACE inhibitor CAP administered systemically in doses ranging from 0.1 to 15 mg/kg greatly increases water drinking to isoproterenol, caval ligation, and water deprivation while doses ranging from 25 to 100 mg/kg suppress drinking in response to these stimuli (13, 83, 108, 174). Similar biphasic effects of ACE inhibitors have been demonstrated for salt appetite (77, 224, 327, 350) and VP secretion (332). Most investigators interpret the biphasic dose effects of peripheral ACE inhibition in the manner of Lehr et al. (186). That is, low doses of ACE inhibitor block formation of systemic ANG II so that increased levels of circulating ANG I enter the brain where it is converted to ANG II. Higher systemic doses or the central administration of ACE inhibitors prevent the central formation of ANG II and thus prevent the exaggerated behavioral responses (69, 76, 85, 86, 108, 186, 224, 262, 279, 309).

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Two models can be derived from the mechanism initially proposed by Lehr et al. (186) to explain paradoxical enhancement of fluid ingestion. The first model will be referred to as the spillover hypothesis. This model argues that blockade of peripheral ACE causes plasma concentrations of ANG I to become so high that ANG I crosses, or spills over, the blood–brain barrier. ANG I that ‘‘leaks’’ into the brain is then converted to ANG II in brain regions located behind the blood–brain barrier to stimulate an exaggerated response. The main problem with the spillover hypothesis is that ANG I is a decapeptide and, like the smaller peptide ANG II (278), is not likely to cross the blood–brain barrier despite its elevated levels during peripheral ACE inhibition. Regardless, it remains to be experimentally demonstrated that there are increased levels of ANG I in brain areas located behind the blood–brain barrier during peripheral ACE inhibition. An alternative to the spillover hypothesis utilizes the presence and properties of CVOs to explain the mechanism of ACE inhibition-induced water intake. Substances in the blood readily penetrate the CVOs because these areas of the brain are highly vascularized and lack an effective blood–brain barrier. According to this model, ANG I achieves high levels in the blood during peripheral ACE inhibition and enters CVOs where it is converted to ANG II. In other words, circulating ANG I accesses the brain in the same manner that circulating ANG II does, across fenestrated capillaries in CVOs. This locally formed ANG II then causes drinking by acting at the same angiotensin receptors in the CVOs that respond to circulating ANG II. Figure 7 summarizes this model which will be referred to here as the CVO conversion hypothesis. This alternative to the spillover hypothesis eliminates the need to postulate that ANG I crosses the blood–brain barrier. Furthermore, the CVOs contain some of the highest levels of ACE activity in the brain (35, 45, 55, 251), making them appropriate brain sites for such conversion to occur. The CVOs possess ANG II receptors (45, 342) that mediate several CNS responses to circulating ANG II. Finally, CVOs have been experimentally implicated in the paradoxical enhancement of water drinking and sodium ingestion. For example, so-called paradoxically enhanced water drinking is suppressed to a greater degree by ACE inhibitor injected directly into the SFO than by injections into the lateral ventricles for access to brain parenchyma in general (324). Both lesions of the SFO (323) and knife-cut transections of the ventral efferent fibers of the SFO (204) abolish paradoxically enhanced water drinking. Infusions of ANG II receptor antagonist in the proximity of the SFO reduce the additional component of water intake following peripheral ACE inhibition (97). Similarly, the paradoxical increase in sodium intake observed in sodium-deficient rats given low doses of ACE inhibitors is suppressed by injections of ACE inhibitor into tissue near the OVLT (98). These findings indicate that paradoxically enhanced water drinking and sodium ingestion both rely on the functional integrity of CVOs and that the site for the central conversion of ANG I to ANG II is likely to be one or both of the forebrain CVOs.

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FIG. 7. Proposed model of the interface between the endocrine and the brain renin–angiotensin systems. The classic endocrine renin–angiotensin system forms blood-borne ANG I from hepatic derived angiotensinogen and renal-derived renin. ANG II, under physiological conditions, is formed from ANG I by angiotensin converting enzyme (ACE) in the lungs. Under pathophysiological or pharmacological conditions, residual amounts of ANG I survive passage through the lungs to arrive at tissue sites. Receptors in CVOs are stimulated either by blood-borne ANG II or by ANG II formed locally within the CVO from blood-borne ANG I. Angiotensinergic neurons then stimulate target areas of the visceral neuraxis.

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Evidence from Fos immunoreactivity (Fos-ir) studies supports a role for the lamina terminalis and associated CVOs in mediating paradoxically enhanced water and sodium intake. The early gene product Fos is used as a functional marker of neuronal activity (140). Rowland et al. (268) demonstrated that injection of low doses of ACE inhibitor increased isoproterenol-induced expression of Fos-ir in certain structures of the lamina terminalis. This effect paralleled the enhancement of water intake observed under the same conditions. Administration of higher doses of ACE inhibitor abolishes both water drinking and the expression of Fos-ir in the structures of the lamina terminalis in response to isoproterenol. In other studies, parallel changes in behavior and expression of Fos-ir along the lamina terminalis were obtained in sodiumdepleted animals given high and low doses of ACE inhibitors (366). In these studies, low doses of ACE inhibitor increased Fos-ir in the structures of the lamina terminalis, especially in the SFO and in the OVLT. The increased Fos-ir in the CVOs was abolished by giving higher doses of ACE inhibitor or the specific ANG II Type 1 receptor (AT1) antagonist losartan. These findings indicate that the increased Fos-ir in forebrain structures during peripheral ACE inhibition fits the pattern of the paradoxically enhanced responses caused by peripheral antagonism of ACE. The paradoxical enhancement of thirst and salt appetite may serve as an important model of the actions of a circulating prohormone delivered to a target tissue which contains the trigger enzyme to generate the active hormone. The conventional understanding has been that the central effects of angiotensin are mediated by circulating ANG II and not by ANG II formed within the CVOs from circulating ANG I. However under pathophysiological conditions, such systemic conversion may not be complete, so that residual unconverted ANG I may reach target tissues such as CVOs. Thus mechanisms of the paradoxical enhancement of thirst and salt appetite may be of more than theoretical interest and may have implications for understanding the etiology of hypertension. There is evidence that the central administration of ACE inhibitors reduces arterial blood pressure in many forms of hypertension (145), although the precise central location(s) of such an action has not been identified. Some investigators have recently argued that the critical actor in some forms of hypertension is not circulating ANG II but ANG II produced in specific tissue RASs (e.g., brain, heart, adrenal; 339, 344). Brain CVOs may use circulating ANG I as a precursor to generate local ANG II for immediate action on adjacent AT1 receptors.

Salt Appetite and the Lamina Terminalis The first demonstrations that ANG II produced salt appetite upon central administration utilized injections into the forebrain ventricles (11, 36, 37, 113). This was a fortunate choice of location as it was later determined that salt appetite is stimulated by acute infusions of ANG II only if the area of perfusion includes the forebrain, and not if delivery is limited to the hindbrain (97).

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Additionally, sodium depletion-induced salt appetite is suppressed by infusions of ANG II receptor antagonists into the lateral ventricles of the forebrain, but not by administration of the antagonists into the fourth ventricle of the hindbrain (97). Salt appetite after sodium depletion is abolished in the rat by disconnecting the forebrain from the hindbrain by supracollicular decerebration (132). As has been discussed with thirst, considerable work now points to an essential role of the lamina terminalis of the forebrain for the expression of renin-dependent forms of salt appetite, including salt appetite following sodium depletion. The evidence for an essential role of the endocrine RAS in the expression of sodium depletion-induced salt appetite underscores the importance of work directed at determining the role of forebrain CVOs in the genesis of salt appetite. One plausible mechanism by which circulating ANG II may activate salt appetite is by acting on receptors located in CVOs to stimulate central pathways governing sodium ingestion. The participation of the SFO of the lamina terminalis in salt appetite was examined in the light of its known role in mediating the effects of ANG II. Early attempts to establish a role for the SFO in salt appetite were unsuccessful. Knife-cuts of the major efferent pathways of the SFO did not affect salt appetite produced either by treatment with a combination of deoxycorticosterone acetate (DOCA; 5 mg/kg) and FURO (10 mg/kg) or by maintenance for 4 days on sodium-deficient diet (281). These results show that the SFO does not influence salt appetite via its terminal fields. However, two later reports showed that electrolytic lesions of the SFO diminished salt appetite of rats following sodium depletion (321, 349), indicating that the SFO has a role in renin-dependent salt intake. The divergent conclusions may partly be explained by the duration over which salt appetite was measured in the three studies. The first study (281) reported total saline consumed over 48 h. This considerable period may have permitted additional (i.e., compensatory) mechanisms to normalize saline intakes of animals with transection of SFO efferent fibers (321). The two later studies reported saline intakes in the first 2 h after saline solution was reintroduced to the depleted animals. Not all forms of renin-dependent salt intake are affected by SFO lesions. For example, lesions of the SFO do not eliminate the exaggerated salt intake caused by peripheral ACE inhibition (323). In fact, peripheral ACE inhibition appears to completely normalize the salt appetite response of sodium-deplete rats with SFO lesions (349). Therefore, the available lesion data suggest that the SFO plays a significant role in the salt appetite response to sodium depletion, but not in the exaggerated intake of sodium following ACE inhibition. It was logical to assess the role of the AV3V region in sodium intake because this unique area of the brain is critical for cardiovascular and hydromineral balance (41, 158). Effects of lesions within the AV3V on salt appetite are mixed and depend on the size of the lesion, including the subnuclei that are destroyed, and the means by which salt appetite is produced (e.g., sodium depletion, DOCA). Lesions that encompass the entire AV3V region do not affect ad libitum

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consumption of concentrated saline solution by rats maintained on standard laboratory diet (64), but reduce the relatively greater daily intakes of concentrated saline solutions by rats maintained on sodium deficient diet (15). AV3V lesions also retard the development of sodium depletion-induced salt appetite (64). On the other hand, rats with AV3V lesions show a normal increase in salt ingestion during acute formalin-induced hyponatremia (15). Smaller lesions of the AV3V region that are confined mainly to the OVLT reduce salt intake after sodium depletion by about half (47). Interestingly, lesions that encompass both the OVLT and the adjacent third of the vMePO reduce sodium ingestion in response to renin-dependent forms of salt appetite (i.e., sodium depletion-induced and ACE inhibitor-induced; 101) but increase sodium intake elicited by daily injections of DOCA (96, 101). The mechanism by which these lesions increase DOCA-induced salt appetite is unknown. Lesions of the vMePO that spare the OVLT greatly increase need-free sodium intake in some animals (124). It has thus been proposed that lesions of the MePO remove a mechanism related to OXY secretion that tonically inhibits salt appetite. MePO lesions impair the osmoregulatory stimulation of OXY secretion (125). However, identical lesions do not affect sodium intake after sc polyethylene glycol (124). Brain lesions may disrupt thirst and salt appetite by destroying neural substrates for these behaviors and by altering body fluid and plasma parameters that, in turn, reduce thirst and salt appetite. For example, AV3V lesions render animals chronically hypernatremic and hyperosmotic (41, 64) which could interfere with salt appetite by affecting cerebral sodium/osmoreceptors and endocrine responses to extracellular fluid depletion. Lesions of the SFO cause persistently elevated levels of circulating OXY (92) which may reflect increased activity of central mechanisms inhibitory to salt appetite. Brain stimulation studies circumvent some of the interpretational difficulties inherent in lesion studies. As previously discussed, discrete injections of low doses of ANG II into the SFO induce water drinking (285, 286). The OVLT is also reported to be sensitive to the dipsogenic effects of ANG II (250). In studies in which animals have access to both water and saline solution, Fitts and Masson (98) found that ANG II infused near the SFO stimulates only water drinking, while identical infusions into the OVLT and/or adjacent portion of the MePO nucleus stimulate saline ingestion as well as water drinking. Curiously, the best sodium intake was elicited by infusion of ANG II receptor antagonist into the SFO. Although this sodium intake was attributed to agonist properties of the receptor antagonist, ANG II itself did not stimulate salt intake upon administration into the SFO. It is possible that ANG II acts at the SFO to engage central mechanisms that are inhibitory to salt appetite including OXY secretion (14, 91–93, 301, 303, 306; this hypothesis is discussed in detail below). Discrete, local administration of ACE inhibitor or ANG II receptor antagonist directly into forebrain CVOs selectively reduces water or sodium ingestion depending on the model of salt appetite that is employed and the CVO that is targeted (52, 97, 98). Fluharty and Epstein (113) observed a greater salt appetite response to

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central administration of ANG II in rats treated with aldosterone than in untreated rats. Since levels of ANG II and aldosterone are high in sodiumdeficient animals, they argued that central administration of ANG II to aldosterone-treated rats more closely mimics natural conditions which produce salt appetite than does ANG II infused into sodium-replete rats with low levels of endogenous aldosterone. It would not be surprising if other signals related to sodium deficiency modulate the central actions of ANG II. Thunhorst and Johnson (325) have reported that central infusions of ANG II stimulated salt appetite more readily in hypotensive, sodium-deficient rats than in normotensive, sodium-replete rats. Furthermore, brain lesions of the ventromedial hypothalamic nucleus, which blunt the pressor responses to centrally administered ANG II (159), dramatically increase the salt appetite response to ANG II injected into the AV3V area (44). It is therefore possible that prior treatment with aldosterone, reductions in body/plasma sodium, or unloading of baroreceptors may remove inhibitory mechanisms allowing ANG II to more effectively stimulate salt appetite.

Salt Appetite and the Amygdala/Extended Amygdala It has been proposed that the function of the amygdala is to interpret the significance of internal and external stimuli and bias the animals toward the most appropriate adaptive behavior (128, 253). Salt appetite is a homeostatic behavior requiring central integration of both visceral sensory input (humoral and neural) related to sodium balance and somatic sensory input (e.g., taste) for activation of the appropriate behaviors. Most studies on the role of the amygdala in sodium ingestion have focused on the basolateral, central, and medial nuclei of the amygdala. Ablation of the basolateral amygdala reduces salt appetite induced by DOCA treatment (232). Lesions of the central nucleus of the amygdala (CeA) nearly abolish ad libitum sodium intake in rats and greatly impair the salt appetite response to DOCA, sodium depletion, sc administration of yohimbine, and icv ANG II (120, 363). The global impairment of salt intake in rats with lesions of the central nucleus does not appear to be the result of disordered gustatory function (121). Rats with such lesions discriminate between different tastes, and their differential responses to tastes are modified by their internal states, yet they fail to consume sodium (282). Lesions of the medial region of the amygdala impair mineralocorticoid-induced salt appetite, but not sodium depletion-induced salt appetite (237, 367). This selective impairment does not seem to result from disruption of connections to the ventral forebrain through the stria terminalis (22). The medial amygdala does not appear to be necessary for the generation of renin-dependent salt appetite, as evidenced by the failure of lesions of medial amygdala to prevent depletion-induced salt appetite. However, tachykinins ingested into medial amygdala inhibit renin-dependent forms of salt appetite (203). Recent reviews (4, 66, 253) have reaffirmed the concept initially proposed by

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Johnston (171) that the amygdala and the BNST were once a single structure which become separated in mammals by development of the internal capsule. Both tract tracing and immunocytochemical studies suggest that the lateral and ventral portions of the BNST are more similar to the CeA and that the medial region of the bed nucleus and medial amygdala are closely related. The ventral and lateral portions of the BNST and the CeA are each reciprocally connected with several nuclei involved in cardiovascular control and fluid balance (142, 225, 289, 365). Taken together, the structural, neurochemical, and functional similarities and interrelationships between the central nucleus and the related portions of the BNST support the idea that these two nuclei are likely to have similar functions. Electrolytic ablation of either the CeA or the BNST causes a significant reduction in sodium intake following systemic administration of the a2-adrenergic receptor antagonist, yohimbine, or 24 h after sodium depletion (363). Neither lesion affects water intake to sc ANG II or to sc hypertonic saline, indicating a specificity of the lesion for salt appetite. Since lesions of the lateral BNST and of the central nucleus each reduced sodium intake by approximately 50%, future studies will be necessary to determine if combined lesions of these structures will result in more complete abolition of the behavior. Inhibitory Neural Circuits and Neurochemical Systems

Early Investigations of the Role of the Hindbrain and the Reflex Controls of Body Fluid Balance The hindbrain is the gateway for neural input from the viscera and it has had a long history in the study of reflex control of the circulation and fluid balance. Claude Bernard in the mid-19th century noted that puncturing the floor of the 4th cerebral ventricle increased urinary excretion (see 61). More recent studies have described activation of hindbrain neurons by systemic infusions of hypertonic saline (51) and elevation of urinary sodium/potassium ratios in rats over the 24-h period following lesions in the region of the obex (288). In the dog, lesions of the AP, the hindbrain sensory CVO, do not seem to produce marked alterations in water and electrolyte balance (359), although electrical stimulation in and around the AP (358) increases excretion of both sodium and chloride and increases urine volume and creatinine clearance in this species. Although such studies clearly implicate the hindbrain in the control of hydromineral balance, the role of this region in the behaviors contributing to such homeostatic processes has only recently been investigated. The AP and Immediately Adjacent Nucleus of the Tractus Solitarius (mNTS) in Salt Appetite and Thirst The AP is a bilaterally symmetrical CVO lying in the caudal aspects of the rhomboid fossa of the 4th ventricle. Its role as a chemosensitive region detect-

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ing circulating toxins which trigger emesis was established in the 1950s by Borison and colleagues (see 221 for review). Thus, the AP was the first of the three sensory CVOs to have a demonstrated receptive function at the blood– brain interface. It was also the first CVO to be convincingly implicated as a central target for circulating ANG II (94, 172, 338). These seminal studies indicate that ANG II acts at the AP to reduce the gain of cardiovascular baroreceptor reflexes to thereby enhance the pressor actions of ANG II. It is extremely difficult to use chemical or electrical stimulation of the AP in unanesthetized animals to study its function because it is small and difficult to access. As a consequence, most of the functional research on the AP in behaving animals has involved ablation studies (53, 71, 73, 146, 242, 346). When discussing the functional effects of AP lesions, it is important to appreciate the fact that none of the results of the current studies in which the entire AP is ablated can be taken as indicative of effects that are attributable solely to the AP. In most if not all of the experiments effectively removing all of the AP, the lesions encroach on adjacent NTS tissue. Even in studies where there has been a scrupulous effort to limit destruction to the AP, there is degeneration of adjacent NTS neuropile reflecting the substantial neural interconnectivity between the AP and the NTS. Careful attention to histological characterization of the extent of NTS involvement in AP lesions is thus essential in correlating AP ablation with functional consequences. The first paper to report an effect of AP lesions on water and sodium ingestion was by Contreras and Stetson (53). These investigators described increased ad libitum consumption of NaCl solutions across a range of concentrations in two-bottle preference tests. Similar effects have been observed by others (53, 71, 146, 181, 346). Although Hyde and Miselis (146) provided evidence that increased sodium intake may be secondary to increased sodium excretion after AP ablation, others have found minimal effects of AP lesions on sodium excretion (53, 346). Contreras and Stetson (53) have emphasized the importance of reducing damage to the NTS in conjunction with AP lesions. In their studies, animals with lesions restricted mainly to the AP (i.e., minimal damage to the NTS) showed the greatest overconsumption of NaCl solutions. A recent study investigating the impact of AP lesions on NaCl intake examined control and ablated rats maintained on ad libitum water and standard laboratory diet exposed to 1, 2, and 3% NaCl solutions in short-term (3-h) intake tests (71). In this acute situation, rats with AP/mNTS lesions consumed significantly greater amounts of each concentration of hypertonic saline (Table 2) on an initial exposure to the solutions than control rats with intact APs. For example, AP/mNTS ablated rats consumed an average of approximately 3 mmol of sodium in the form of 3% NaCl solution. The remarkable nature of the 3-h intakes of NaCl by rats with AP lesions can be appreciated better when one considers that the extracellular fluid volume of a 350-g rat is roughly 90 ml and contains slightly more than 12 mmol of sodium. Therefore, during the 3-h intake period, AP/mNTS ablated rats consumed NaCl equivalent to 25% of their extracellular sodium. Occasionally, individual rats with AP/mNTS lesions have been observed to drink nearly 20 ml of 3% NaCl during such 3-h tests,

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TABLE 2 Three-Hour Intakes (ml) of 1, 2, and 3% Saline by Area Postrema / Medial Nucleus of the Tractus Solitarius (AP/mNTS) Lesion and Sham Lesion Rats Group Saline concentration (%)

Sham lesion

AP/mNTS

1

3.4 6 0.4 (n 5 10) 1.6 6 0.4 (n 5 10) 0.4 6 0.2 (n 5 14)

42.7 6 5.2* (n 5 10) 24.4 6 3.0* (n 5 10) 5.5 6 0.8* (n 5 14)

2 3

Note. Values are means 6 SEM; n 5 number of observations. * Significantly greater than sham lesion group; p , 0.01.

which is nearly sufficient to replace all readily exchangeable extracellular sodium. A further characterization of AP/mNTS lesioned rats indicates that the increased consumption of NaCl is not due to an enhanced renal loss of sodium or water during the test period. Specifically, rats with AP/mNTS lesions that have been bilaterally nephrectomized still show a significant increase in the intake of 3% saline compared to intact controls. It is also worth noting that in the face of such increases in NaCl intake during 3-h tests, it is possible for animals with AP/mNTS lesions to express an even greater intake when they are sodium depleted with FURO and switched to sodium-deficient diet 24 h prior to presentation of the 3% NaCl solution (Fig. 8). Edwards and Ritter (73) were the first to report enhanced water intake in response to dipsogenic challenges after AP lesions. These investigators found that animals with AP/mNTS lesions drank more than controls in response to systemically administered isoproterenol (73) and extracellular depletion with sc polyethylene glycol. Importantly, AP ablated rats with slight damage to the mNTS (i.e., AP/mNTS lesions) do not manifest exaggerated drinking responses to systemically injected hypertonic saline (73) or to centrally administered carbachol (242). As a result, it has been proposed (73, 242) that the AP functions to inhibit water intake in response to extracellular dehydration and that this mechanism may be more closely associated with the control of constant plasma and extracellular fluid volume than with the maintenance of intracellular volume.

The Lateral Parabrachial Nucleus (LPBN) in Thirst and Sodium Appetite Early anatomical tract tracing studies (194, 238, 258) demonstrated that the LPBN receives a substantial portion of the output of the NTS. Such observa-

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FIG. 8. Three-hour, depletion-induced intake of 3% saline by area postrema-medial portion of the nucleus of the tractus solitarius lesion (APX) (n 5 17) and sham lesion (SHAM) rats (n 5 18) before and after sodium depletion induced by furosemide treatment and low-sodium diet. APX rats increased their intake of 3% saline after depletion compared with their intake before depletion (*p , 0.02). Sodium depletion also significantly increased intake of 3% saline by the sham rats (*p , 0.01). From Edwards et al. (71) with permission of the publisher.

tions were responsible for studies exploring the proposition that in hypovolemic/ hypotensive states excitatory information derived from vascular baroreceptors ascends from the NTS to the forebrain via the parabrachial nucleus (241). It was suggested that depriving the forebrain of ascending arterial pressure/ vascular volume information by lesions of the LPBN would result in impaired drinking responses. Contrary to this prediction, lesions located in the lateral portion of the LPBN (i.e., LLPBN) have the opposite effect. Drinking responses to systemic isoproterenol (241) and both sc (241, 242) and icv (242) ANG II are significantly enhanced in animals with lesions in the LLPBN. The same lesion does not cause overdrinking in response to systemic hypertonic saline or icv carbachol (241, 242). The overdrinking responses observed after lesions of the LLPBN are not dependent on the method used to interrupt the flow of neural information. That is, both lidocaine injections into the LPBN (215) and excitotoxic chemical lesions (i.e., ibotenic acid) destroying LPBN cell bodies (72) significantly increase drinking in response to icv ANG II. The fact that destruction of LPBN soma without damage to fibers of passage produces overdrinking is evidence that this nucleus is a site of neural integration for the control of fluid intake (72). Lesions of the LLPBN produce effects on thirst nearly identical to those described for AP/mNTS lesions (73). Both types of lesion enhance drinking in response to extracellular thirst challenges but not to cellular dehydration. These observations have led to the hypothesis that the LLPBN and the

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AP/mNTS relate to one another as components of a hindbrain system which limits extracellular volume expansion (72, 241, 242). Anatomical studies (56, 283, 340) indicate that both the NTS and the AP send major projections to the LPBN. Lanc¸a and van der Kooy (185) emphasized the presence of an ascending serotonergic pathway from the AP to the parabrachial nucleus. Therefore, 5-HT release into the LPBN might inhibit drinking. Consistent with this hypothesis, bilateral administration of 5-HT or the more selective serotonergic 5-HT2A/2C receptor agonist [6]-2,5-dimethoxy-4-iodoamphetamine (DOI) significantly suppresses water intake in response to icv ANG II. Conversely the relatively nonselective 5-HT1/2 receptor antagonist methysergide injected bilaterally into the LPBN produces a marked enhancement in drinking in response to icv ANG II (216). Although there is a remarkable degree of similarity in the pattern of enhanced water intake in response to extracellular stimuli between rats with AP/mNTS lesions and those with LPBN lesions, the two types of lesions differ in their effects on salt appetite. Whereas, AP/mNTS lesions promote exaggerated ad libitum and experimentally induced NaCl intake (53, 71, 146, 181, 346), LPBN lesions do not increase sodium intake (L. E. Ohman and A. K. Johnson, unpublished observations; G. L. Edwards, personal communication). One reason why there may be a dissociation between salt and water intake for the two types of lesions is that the AP/mNTS and LPBN may each receive different amounts of excitatory vs inhibitory input derived from other sources. Perhaps AP/mNTS lesions destroy mainly inhibitory salt appetite-related substrates, but LPBN ablation removes not only inhibitory input but also a substantial facilitory component as well. On the basis of chemical neuroanatomy of 5-HT described just above, one strategy to dissociate and reveal the nature of inhibitory and excitatory components in the LPBN is to employ direct injections of receptor agonists and antagonists into the LPBN. Such experiments indicate that bilateral administration of methysergide into the LPBN remarkably enhances intakes of 0.3 M NaCl and water. In two-bottle drinking tests, methysergide injections into LPBN increased water and sodium ingestion in response to ANG II administered icv and into SFO and to combined systemic treatments with FURO/CAP (52, 218; see Fig. 9). Furthermore, administration of the 5-HT2A/2C receptor agonists significantly reduced 0.3 M saline intake to FURO/CAP treatment. Therefore, inhibitory serotonergic mechanisms associated with the LPBN appear to limit both of the behaviors that act to restore and expand extracellular fluid volume.

Functional Interpretation of AP/mNTS-LPBN Pathways in the Behavioral Control of Extracellular Volume The results of AP/mNTS and LPBN lesion and injection studies along with the current understanding of input from the periphery suggest that inhibitory signals originating from the vena cava and from atrial baroreceptors arrive at the AP/mNTS and then ascend to the LPBN. The hypothesis that the LPBN

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FIG. 9. (A) Cumulative 0.3 M NaCl intakes. (B) Individual 0.3 M NaCl intakes. (C) Cumulative water intakes. (D) Individual water intakes induced by subcutaneous furosemide (FURO; 10 mg/ kg) 1 captopril (CAP; 5 mg / kg) after previous injection of vehicle or methysergide (4 µg/200 nl) bilaterally into lateral parabrachial nuclei (LPBN). (A, C) Values are means 6 SE. *Significantly different from vehicle pretreatment tested by t tests ( p , 0.05). n 5 8 rats. From Menani et al. (218) with permission of the publisher.

may function to integrate information derived from systemic inhibitory input is supported by a recent study (243) which examined the effects of LPBN lesions on changes in behavior produced by stretch of the superior vena cava and right atrium. As discussed earlier, Kaufman (175) demonstrated that stretching the superior vena cava and right atrium by inflating a small intravascular balloon inhibits drinking in response to extracellular-related thirst challenges, specifically systemically administered isoproterenol and extracellular fluid depletion with sc polyethylene glycol. However, stretching the superior vena cava and right atrium does not inhibit drinking in response to systemic injections of hypertonic saline. The inhibitory effects of superior vena cava and right atrium stretch on drinking to isoproterenol are impaired in animals with LPBN lesions (243; Fig. 10). These observations are consistent with the idea that the LPBN receives and integrates information reflecting extracellular (blood) volume.

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FIG. 10. The effects of lateral parabrachial nucleus (LPBN) lesions on the inhibition of drinking by inflation of a balloon at the junction of the right atrium and superior vena cava. Drinking was induced by sc isoproterenol (30 µg / kg) in rats with bilateral lesions of the lateral portion of the LPBN (LLPBN) or sham lesions. As indicated by the significant interaction, at 1 h after treatment, enhanced water intake in rats with LLPBN lesions (X) was not reduced as it was in the case of sham lesion (W) animals.

The input disrupted by lesions of the LPBN may derive from atrial stretch receptors located in the superior vena cava and right atrium region. This input is carried to the CNS by the vagus or possibly by humoral signals generated by atrial stretch. Stretch of the superior vena cava and right atrium releases ANP (176, 214), and this peptide when administered either centrally (100) or systemically (9) inhibits water and sodium intake. Circulating ANP may act on the AP to activate the ascending AP/mNTS to LPBN pathway. Of course, it is also possible that neurally derived signals carried via the vagus and circulating ANP act in concert to prevent excessive fluid intake. The ascending projections from the AP or NTS to the LPBN may contain other neurotransmitters/neuromodulators in addition to 5-HT which modify fluid intake responses. For example, bilateral administration of cholecystokinin (CCK) into the LPBN suppresses sodium intake induced by icv ANG II, whereas the CCK receptor antagonist proglumide administered bilaterally enhances sodium intake (217). Neuroanatomical studies (138) indicate the presence of a CCK pathway projecting from the NTS to the parabrachial nucleus. This pathway may be one link in a series of CCK neurons projecting via the vagus from the periphery to NTS, NTS to LPBN, and LPBN to forebrain which may influence taste and viscerally related homeostatic functions (200). This CCK pathway or similar projections with other neurotransmitters/ neuromodulators could also be related to other visceral inputs, such as those derived from gastric distention which inhibits fluid intake (60). In particular afferent signals from the gastrointestinal tract (e.g., stomach; 60), splanchnic and hepatic circulation (182), and kidneys (329) may travel in this projection.

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The Midline Septal Area in Thirst and Salt Appetite Lesions of the midline septum/diagonal band of Broca produce effects similar to those observed after ablation of the LPBN and AP/mNTS. Harvey and Hunt (137) first reported large increases in ad libitum water intake after septal lesions, and in addition, electrical stimulation of the septal area suppresses drinking induced by water deprivation (129, 229, 360). Animals with septal lesions also overrespond to polyethylene glycol (30, 294, 298) and isoproterenol (31). However, similar to AP/mNTS and LPBN ablated animals, rats with septal lesions typically do not overdrink in response to cellular dehydration (30, 31). Septal lesions, therefore, produce effects on thirst that are quite comparable to those produced by AP/mNTS and LPBN lesions. Furthermore, septal lesions enhance the intake of sodium (130, 233). In a preliminary study, Sullivan and co-workers (308) examined the effects of ibotenic acid destruction of cell bodies in the vertical limb of the diagonal band of Broca, an area contiguous with the medial septum and with similar cell types and neurochemistry. Neurotoxic lesions of the vertical limb of the diagonal band of Broca significantly increase water intake in response to extracellular depletion with polyethylene glycol but do not increase drinking to cellular dehydration with systemic hypertonic saline. Thus, it seems that the midline septum and diagonal band of Broca may be a rostral representation of the AP/mNTS–LPBN inhibitory pathway. If this is true, it is unclear whether information projects directly from the hindbrain circuitry to the forebrain region or whether an ascending multisynaptic pathway is involved.

OXY Systems and Salt Appetite The fact that rats maintained on sodium deficient diet have blunted secretion of OXY during hypovolemia is of theoretical interest given the recently proposed role for a central oxytocinergic system as an inhibitory mechanism for the control of salt appetite (301, 303). Sodium ingestion can vary inversely with circulating levels of OXY; for example, salt appetite does not occur in animals with elevated levels of plasma OXY. Although it was predicted that OXY would suppress salt appetite, peripheral administration of synthetic OXY actually increased sodium intake to polyethylene glycol treatment (305). It was subsequently proposed that circulating levels of OXY simply mirror the activity of a central oxytocinergic system which is causally related to the control of sodium ingestion. For example, reduced levels of circulating OXY in rats maintained on a sodium-deficient diet indicate lower activity of central inhibitory mechanisms, so that, during hypovolemic conditions, there is a greater salt appetite response with shorter latency. A number of additional observations support this hypothesis. Treatments or conditions (e.g., naloxone, hyperosmolality, nausea) that stimulate OXY secretion are associated with reduced salt appetite in response to hypovolemia (25, 301, 305). Treatments which suppress OXY

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secretion (e.g., sodium deprivation, alcohol) increase salt appetite (26, 301). In addition, salt appetite in response to centrally administered ANG II is enhanced by central pretreatment with an OXY receptor blocker (23). Finally, salt appetite in response to hypovolemia and centrally administered ANG II is increased in animals after inactivation of central oxytocinergic systems by administration of a conjugate of oxytocin and the cytotoxin ricin (24).

Central a2-Adrenergic Receptors and Salt Appetite In two preliminary reports, it has been demonstrated that systemic and icv (195, 240) administration of the selective a2-adrenoceptor antagonist yohimbine significantly increases drinking when animals have access to water. More recently, administration of yohimbine has been shown to induce salt appetite with short latency (96, 155, 156, 363). When tested in both one- and two-bottle tests, sc yohimbine (1.0–9.0 mg/kg) produces significant increases in hypertonic NaCl intake. Other a2-adrenoceptor antagonists such as rauwolseine and idazoxan are also effective in inducing a rapid onset salt appetite. The yohimbine-induced salt appetite is inhibited by treatment with the a2-noradrenergic receptor agonist clonidine. Recently we have observed that infusion of low doses of yohimbine into the lateral ventricle significantly increases 2% NaCl intake, which suggests that the a2-adrenoceptor antagonist probably produces its natriorexigenic effect directly through a CNS action. A substantial literature indicates that systemic treatment with a2-receptor agonists, such as clonidine, produces a pattern of sympathetic and endocrine responses that would collectively reduce extracellular fluid volume and lower arterial blood pressure. Given the putative CNS action of clonidine and its use as an antihypertensive therapeutic agent, many studies have been performed to determine its mechanism and site of action. Although clonidine may exert some of its blood pressure lowering effects through actions on the imidazoline receptor (see 81 for review), it is still very likely that a substantial component of its antihypertensive effect derives from action on central a2-adrenoceptors. Microinjection studies implicate the NTS (63) and the ventrolateral medulla (126) as sites in the central neural circuitry where the a2-adrenoceptor agonist acts to decrease sympathetic and increase parasympathetic efferent nerve activity. Other antihypertensive/volume reducing actions of clonidine include reduced renin secretion (249) and lowered VP release (256). Taken together reports that a2-adrenoceptor antagonists increase the ingestion of water and hypertonic NaCl and that systemically administered clonidine inhibits experimental thirst (357) suggest that these a2-adrenoceptorrelated behaviors are consistent with other physiological mechanisms which limit or reduce blood volume and blood pressure. In light of their general actions on both extracellular- and intracellular-depletion-induced drinking responses, Fregly, Rowland and colleagues (117, 356) have hypothesized that a2-adrenoceptor mechanisms lie in a final common path mediating thirst. An

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alternative to this idea is that a2-adrenoreceptor agonists act at several locations on the sensory side of the central body fluid-related neural network to produce a modulatory action on thirst and sodium appetite.

SUMMARY AND CONCLUSIONS

Signals for the behavioral controls of body fluid homeostasis arise from both the intracellular and the extracellular fluid compartments. The intracellular compartment is monitored by putative osmoreceptors and/or sodium receptors located in the brain and periphery. The integrity of the AV3V is essential for normal behavioral, autonomic, and endocrine responses elicited by increased plasma osmolarity and /or sodium concentration. There are osmosensitive cells located within the AV3V, most notably in the OVLT and MePO. In addition, it is likely that information about extracellular osmolarity and sodium concentration derived from the periphery (e.g., the splanchnic/hepatoportal vasculature) and from other brain-related osmosensitive regions (e.g., SFO, AP) projects to and/or through the vMePO or other sites within the AV3V. Figure 11 summarizes many of the major points addressed in this review related to the afferent stimuli and central circuitry relevant to the behavioral controls of extracellular fluid volume. To the right and above the large box representing the brain are the neural and humoral inputs that communicate the status of body fluid and cardiovascular homeostasis to the CNS. Among these putative stimuli, circulating ANG II is a potent stimulus for thirst. In physiological states, circulating ANG II is a participant in the generation of thirst and its actions are complemented by additional visceral afferent inputs. ANG II addresses the CNS through brain CVOs. Because sensory CVOs such as the SFO have high concentrations of converting enzyme, it is possible that the so-called paradoxical enhancement of drinking and salt intake that occurs with low doses of converting enzyme inhibitor reflects local generation of ANG II within these areas of blood–brain interface. Hypovolemia and / or hypotension results in neural input from vascular baroreceptors to the CNS to enhance activity in central facilitory systems and conversely hypervolemia and / or hypertension activates inhibitory mechanisms. Other types of viscerally derived input from the gastrointestinal tract, splanchnic and hepatoportal circulation, and the kidneys may also contribute to this input. In the brain, angiotensin acting in the SFO has been proposed to result in the activation of several descending projections to key forebrain structures such as the MePO, perifornical area, CeA, supraoptic nucleus, and paraventricular nucleus. These pathways and their termination sites are probably associated with control of the behaviors and reflexes that maintain body fluid balance and cardiovascular homeostasis. Angiotensinergic neurons from the SFO and other lamina terminalis structures descend to innervate several of these forebrain sites (see Fig. 6). Ascending facilitory and inhibitory inputs project into many of

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FIG. 11. Diagram depicting the nature of neural and hormonal inputs into the brain and the central neural pathways that mediate sensory integration of signals for the generation of drinking (thirst) and sodium ingestion (salt appetite). Both inhibitory and excitatory inputs from the periphery derive from arterial and cardiopulmonary baroreceptors and probably other visceral receptors (e.g., gastric, hepatic/portal, renal). Information carried in afferent nerves projects mainly to the nucleus of the tractus solitarius (NTS). Angiotensin (ANG) acts in the form of ANG II on angiotensin type 1 (AT1) receptors in the subfornical organ (SFO). Information reflecting input to the SFO is carried in descending pathways, some of which are likely to use ANG in the mode of a neurotransmitter, to forebrain structures such as those in the anteroventral third ventricle (AV3V). Ascending information to the forebrain is carried in from noradrenergic cell groups (A) in the hindbrain which are activated by arterial and cardiopulmonary receptor input under conditions of hypotension and / or hypovolemia. ANG and noradrenergic (NE) inputs act synergistically in forebrain nuclei. A hindbrain inhibitory pathway originating in the area postrema (AP) and medial NTS ascends to the lateral parabrachial nucleus. This projection uses serotonin (5-HT) as a neurotransmitter and prevents against excessive sodium and water intake to limit excess expansion of blood volume. Inhibitory input is likely to ascend the neuraxis either directly or indirectly (perhaps to or through the midline septum) to interact with forebrain structure in the neural network regulating hydromineral balance.

these forebrain regions, such as those in the ventral lamina terminalis. Synaptic increases of ANG II and NE within key forebrain sites act to reinforce the actions of one another to activate corrective responses to hypotension and hypovolemia. The facilitory actions of ascending noradrenergic input at these forebrain sites are probably mediated through a1-adrenergic receptors. Several recent studies have described the role of inhibitory influences arising in the periphery and activating neural circuitry in the hindbrain. Central structures implicated in this inhibitory system are the AP/mNTS and the LPBN. The inhibitory actions of 5-HT and CCK on the LPBN have been

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associated with a hindbrain projection from the AP/mNTS to the LPBN that has been proposed to protect animals from overexpansion of the extracellular fluid compartment. The midline septum and ascending limb of the diagonal band of Broca may represent a rostral component of the hypothesized AP/mNTS– LPBN inhibitory circuitry. Central OXY and a2-adrenergic mechanisms have also been implicated as having inhibitory roles on the behavioral responses that lead to expanded extracellular volume. The specific structures and pathways associated with OXY and a2-adrenergic inhibition remain to be defined. Integration of information derived from facilitory and inhibitory visceral inputs occurs at many different nodes (nuclei) in a sensory network that regulates hydromineral balance. The outputs of this network control motor pattern generators responsible for the appetitive and consummatory behaviors associated with states that are commonly referred to as thirst and salt appetite.

ACKNOWLEDGMENTS This review is dedicated to James T. Fitzsimons on the occasion of his retirement from Cambridge University. Preparation of this review was supported in part by grants from the National Heart, Lung and Blood Institute HL 14388, HL 57472, HL 57472, HL 54292 from the National Aeronautics and Space Administration (NASA) NAGW-4358, and from the Office of Naval Research N00014-97-1-0145.

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