Robert L. Thunhorst

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

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.

INTEGRATIVE ROLE OF THE LAMINA TERMINALIS IN THE REGULATION OF CARDIOVASCULAR AND BODY FLUID HOMEOSTASIS

1. Cardiovascular and body fluid homeostasis depends upon the activation and co‐ordination of reflexes and behavioural responses. In order to accomplish this, the brain receives and processes both neural and chemical input. Once in the brain, information from sources signalling the status of the cardiovascular system and body fluid balance travels, and is integrated, throughout a widely distributed neural network. Recent studies using neuroanatomical and functional techniques have identified several key areas within this neural network. One major processing node is comprised of structures located along the lamina terminalis.

The subfornical organ and the integration of multiple factors in thirst

Rats with lesions centered on the ventral stalk of the subfornical organ (SFO) were used to characterize the participation of this structure in the control of drinking. It is concluded that the SFO does indeed play some minor role in the mediation of drinking following intraventricular injections of angiotensin. Further, it is shown that lesions of the SFO, but not lesions of the adjacent septal-hippocampal tissue, attenuate osmotic thirst elicited by two doses of hypertonic saline. Diminished drinking responses following water deprivation, and normal feeding responses following food deprivation, underscore the importance of the SFO for drinking behavior in general, and an expanded role for the SFO in fluid regulation is suggested. However, some incidental observations suggest that the SFO is less than an equal partner with structures in the AV3V region in the overall control of water balance.

Afferent Signaling and Forebrain Mechanisms in the Behavioral Control of Extracellular Fluid Volumea

The body defends against reduced extracellular fluid volume both by activation of autonomic and endocrine reflexes and by mobilization of behavioral mechanisms. The behaviors that are required to correct an extracellular fluid deficit involve the ingestion of both water and sodium. It is reasonable to hypothesize that afferent neural input from both arterial and cardiopulmonary high pressure and volume receptors, and afferent humoral input in the form of ANG II, are important systemically-generated signals acting as afferent mediators of extracellular depletion-induced thirst and sodium appetite. Neural information from these signals has been shown to converge on forebrain structures located along the lamina terminalis where processing and integration of this input is likely to take place. This paper describes an analysis of the mechanisms of afferent signaling that accompanies a form of rapidly induced sodium appetite. Because volume and pressure-related input in concert with elevated activity of the renin-angiotensin system is likely to be important for generating this form of induced hypertonic sodium chloride and water intake, we have focused on the structures of the lamina terminalis, specifically the SFO, MnPO, and OVLT. Investigations that employ immunocytochemical methods for the detection of the early oncogene, c-fos, indicate that neurons in the lamina terminalis, as well as the SON and PVN, are activated by the composite of systemically derived signals necessary for producing thirst and sodium appetite. So far, there is no thorough understanding of how these visceral signals activate the neural substrates for these motivated behaviors. However, these studies, combining both functional and neuroanatomical approaches, provide a strategy for investigating the neurobiological basis of the behavioral and physiological control systems that maintain fluid balance and cardiovascular homeostasis. This paper describes an analysis of the mechanisms of afferent signaling that accompanies a form of rapidly induced sodium appetite. Because volume and pressure-related input, in concert with elevated activity of the renin-angiotensin system, is likely to be important for generating this form of induced hypertonic sodium chloride and water intake, we have focused on the structures of the lamina terminalis, specifically the SFO, MnPO, and OVLT. Investigations that employ immunocytochemical methods for the detection of the early oncogene, c-fos, indicate that neurons in the lamina terminalis, as well as the SON and PVN, are activated by the composite of systemically derived signals necessary for producing thirst and sodium appetite. So far, there is no thorough understanding of how these visceral sensory-related signals activate the neural substrates for these motivated behaviors.(ABSTRACT TRUNCATED AT 400 WORDS)

Salt Appetite: Interaction of Forebrain Angiotensinergic and Hindbrain Serotonergic Mechanisms

Methysergide injected bilaterally into the lateral parabrachial nucleus (LPBN) increases NaCl intake in several models of renin-dependent salt appetite. The present study investigated the role of angiotensin Type 1 (AT1) receptors in the subfornical organ (SFO) on this effect. The intake of 0.3 M NaCl and water was induced by combined administration of the diuretic, furosemide (FURO), and the angiotensin-converting enzyme inhibitor, captopril (CAP). Pretreatment of the SFO with an AT1 receptor antagonist, losartan (1 microgram/200 nl), reduced water intake but not 0.3 M NaCl intake induced by subcutaneous FURO+CAP. Methysergide (4 microgram/200 nl) injected bilaterally into the LPBN increased 0.3 M NaCl intake after FURO+CAP. Losartan injected into the SFO prevented the additional 0. 3 M NaCl intake caused by LPBN methysergide injections. These results indicate that AT1 receptors located in the SFO may have a role in mediating an enhanced sodium intake produced by methysergide treatment.

Effects of a non-peptide angiotensin receptor antagonist on drinking and blood pressure responses to centrally administered angiotensins in the rat

Both angiotensin II (ANG II) and angiotensin III (ANG III) administered centrally produce drinking and increases in blood pressure. The recent characterization of two subtypes for the ANG II receptor, the AT1 and AT2, raises the questions of whether drinking and pressor responses to ANG II can be separated pharmacologically and whether ANG III acts via the same receptor subtype. Therefore, the current study examined drinking and blood pressure responses to ANG II and ANG III administered centrally in adult male Sprague-Dawley rats in the presence or absence of a selective AT1 receptor antagonist. Blockade of the AT1 receptor abolished both drinking and pressor responses to ANG II and ANG III. However, drinking to the cholinergic agonist, carbachol, was unaffected. These results demonstrate that centrally administered ANG II and ANG III increase both water intake and blood pressure via the AT1 receptor subtype.

Effects of subfornical organ lesions on acutely induced thirst and salt appetite

We examined the role of the subfornical organ (SFO) in stimulating thirst and salt appetite using two procedures that initiate water and sodium ingestion within 1-2 h of extracellular fluid depletion. The first procedure used injections of a diuretic (furosemide, 10 mg/kg sc) and a vasodilator (minoxidil, 1-3 mg/kg ia) to produce hypotension concurrently with hypovolemia. The resulting water and sodium intakes were inhibited by intravenous administration of ANG II receptor antagonist (sarthran, 8 μg ⋅ kg-1 ⋅ min-1) or angiotensin-converting enzyme inhibitor (captopril, 2.5 mg/h). The second procedure used injections of furosemide (10 mg/kg sc) and a low dose of captopril (5 mg/kg sc) to initiate water and sodium ingestion upon formation of ANG II in the brain. Electrolytic lesions of the SFO greatly reduced the water intakes, and nearly abolished the sodium intakes, produced by these relatively acute treatments. These results contrast with earlier findings showing little effect of SFO lesions on sodium ingestion after longer-term extracellular fluid depletion.

Angiotensin-Converting Enzyme in Subfornical Organ Mediates Captopril-Induced Drinking

These experiments tested whether angiotensin-converting enzyme (ACE) located within the subfornical organ (SFO) participates in the generation of water intake during peripheral ACE blockade with captopril (CAP). Lesions of the SFO virtually abolished drinking in response to intraperitoneal CAP injection. Intracranially injected CAP suppressed drinking induced by intraperitoneal CAP more completely with direct SFO injection compared with intraventricular or control tissue injections. This central captopril treatment did not alter the drinking response to subcutaneous hypertonic saline. Intraventricular injections of the angiotensin II (ANG II) receptor blocker sarile reduced drinking during oral captopril treatment in rats rehydrating from water deprivation. The results indicate that (a) the SFO mediates drinking caused by peripheral ACE inhibition; (b) the ACE located within the SFO may locally convert ANG I to ANG II, which then stimulates thirst; and (c) central ANG II receptors mediate thirst caused by peripheral ACE inhibition.

Fos Expression in Rat Brain During Depletion-Induced Thirst and Salt Appetite

The expression of Fos protein (Fos immunoreactivity, Fos-ir) was mapped in the brain of rats subjected to an angiotensin-dependent model of thirst and salt appetite. The physiological state associated with water and sodium ingestion was produced by the concurrent subcutaneous administration of the diuretic furosemide (10 mg/kg) and a low dose of the angiotensin-converting enzyme (ACE) inhibitor captopril (5 mg/kg; Furo/Cap treatment). The animals were killed 2 h posttreatment, and the brains were processed for Fos-ir to assess neural activation. Furo/Cap treatment significantly increased Fos-ir density above baseline levels both in structures of the lamina terminalis and hypothalamus known to mediate the actions of ANG II and in hindbrain regions associated with blood volume and pressure regulation. Furo/Cap treatment also typically increased Fos-ir density in these structures above levels observed after administration of furosemide or captopril separately. Fos-ir was reduced to a greater extent in forebrain than in hindbrain areas by a dose of captopril (100 mg/kg sc) known to block the actions of ACE in the brain. The present work provides further evidence that areas of lamina terminalis subserve angiotensin-dependent thirst and salt appetite.

Leptin Mediates High-Fat Diet Sensitization of Angiotensin II–Elicited Hypertension by Upregulating the Brain Renin–Angiotensin System and Inflammation

Obesity is characterized by increased circulating levels of the adipocyte-derived hormone leptin, which can increase sympathetic nerve activity and raise blood pressure. A previous study revealed that rats fed a high-fat diet (HFD) have an enhanced hypertensive response to subsequent angiotensin II administration that is mediated at least, in part, by increased activity of brain renin–angiotensin system and proinflammatory cytokines. This study tested whether leptin mediates this HFD-induced sensitization of angiotensin II–elicited hypertension by interacting with brain renin–angiotensin system and proinflammatory cytokine mechanisms. Rats fed an HFD for 3 weeks had significant increases in white adipose tissue mass, plasma leptin levels, and mRNA expression of leptin and its receptors in the lamina terminalis and hypothalamic paraventricular nucleus. Central infusion of a leptin receptor antagonist during HFD feeding abolished HFD sensitization of angiotensin II–elicited hypertension. Furthermore, central infusion of leptin mimicked the sensitizing action of HFD. Concomitant central infusions of the angiotensin II type 1 receptor antagonist irbesartan, the tumor necrosis factor-&agr; synthesis inhibitor pentoxifylline, or the inhibitor of microglial activation minocycline prevented the sensitization produced by central infusion of leptin. RT-PCR analysis indicated that either HFD or leptin administration upregulated mRNA expression of several components of the renin–angiotensin system and proinflammatory cytokines in the lamina terminalis and paraventricular nucleus. The leptin antagonist and the inhibitors of angiotensin II type 1 receptor, tumor necrosis factor-&agr; synthesis, and microglial activation all reversed the expression of these genes. The results suggest that HFD-induced sensitization of angiotensin II–elicited hypertension is mediated by leptin through upregulation of central renin–angiotensin system and proinflammatory cytokines.