Chapter 9 Neurochemical Circuits Subserving Fluid Balance ...rci.rutgers.edu/~advis/pdfs/05_Neurochemical Circuits Subserving... · Every time there is a disturbance in extracellular

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

De Luca LA Jr, Menani JV, Johnson AK, editors. Neurobiology of Body Fluid Homeostasis: Transductionand Integration. Boca Raton (FL): CRC Press; 2014.

Chapter 9 Neurochemical Circuits Subserving Fluid Balance andBaroreflexA Role for Serotonin, Oxytocin, and Gonadal Steroids

Laura Vivas, Andrea Godino, Carolina Dalmasso, Ximena E Caeiro, Ana F Macchione, and Maria JCambiasso.

9.1. INTRODUCTION

Changes in body water/sodium balance are tightly controlled by the central nervous system(CNS) to avoid abnormal cardiovascular function and the development of pathological states.Every time there is a disturbance in extracellular sodium concentration or body sodium content,there is also a change in extracellular fluid volume and, depending on its magnitude, this can beassociated with an adjustment in arterial blood pressure (BP). The process of sensory integrationtakes place in different nuclei, with diverse phenotypes and at different levels of the CNS. Tocontrol those several changes, the CNS receives continuous input about the status of extracellularfluid osmolarity, sodium concentration, sense of taste, fluid volume, and BP (Figure 9.1). Signalsdetected by taste receptors, peripheral osmo-sodium, volume receptors, andarterial/cardiopulmonary baroreceptors reach the nucleus of the solitary tract (NTS) by the VIIth,IXth, and Xth cranial nerves. The other main brain entry of the information related to fluid andcardiovascular balance are the lamina terminalis (LT) and one of the sensory circumventricularorgans (CVOs), the area postrema (AP). The LT, consisting of the median preoptic nucleus(MnPO) and the other two sensory CVOs—i.e., subfornical organ (SFO) and organumvasculosum of the lamina terminalis (OVLT) —is recognized as a site in the brain that is crucialfor the physiological regulation of hydroelectrolyte balance. The SFO and OVLT lack a blood–brain barrier and contain cells that are sensitive to humoral signals, such as changes in plasmaand cerebrospinal fluid sodium concentration (Vivas et al. 1990), osmolality (Sladek and Johnson1983), and angiotensin II (ANG II) levels (Ferguson and Bains 1997; Simpson et al. 1978). Suchunique features make the SFO and OVLT key brain regions for sensing the status of the bodyfluids and electrolytes. Humoral and neural signals that arrive to the two main brain entries—thatis, the CVOs of the LT and within the hindbrain the AP-NTS—activate a central circuit thatincludes integrative areas such as the MnPO, the paraventricular (PVN), the supraoptic (SON),lateral parabrachial nucleus (LPBN), dorsal raphe nucleus (DRN), and neurochemical systemssuch as the angiotensinergic, vasopressinergic, oxytocinergic (OT), and serotonergic (5-HT)systems (Figures 9.1 and 9.2). Once these signals act on the above-mentioned neurochemicalnetworks, they trigger appropriate sympathetic, endocrine, and behavioral responses. Therefore,after a body fluid deficit, water and sodium intake and excretion need to be controlled tominimize disturbances of hydromineral homeostasis. In this context, hypovolemia andhyponatremia induced by body fluid depletion stimulate central and peripheral osmo–sodiumreceptors, taste receptors, volume and arterial/cardiopulmonary baroreceptors, and the renin–angiotensin system (RAS). This latter system, for example, acts mainly through the sensoryCVOs and/or the AP to activate brain neural pathways that elevate BP, release vasopressin andaldosterone (ALDO), increase renal sympathetic nerve activity, and increase the ingestion of

water and sodium. Among these responses, sodium appetite constitutes an important homeostaticbehavior involved in seeking out and acquiring sodium from the environment. Under normalcircumstances, the average daily intake of sodium in animals exceeds what is actually needed;however, when they are challenged by environmental (e.g., increased ambient temperature),physiological (e.g., exercise, pregnancy and lactation), or pathophysiological (e.g., emesis,diarrhea, adrenal, or kidney insufficiency) conditions, endocrine and autonomic mechanismsprimarily target the kidney, to influence the rate of water and sodium loss, and the vasculature, tomaintain arterial BP. Afterward, a behavioral mechanism such as sodium appetite is the means bywhich sodium loss to the environment is ultimately restored (Geerling and Loewy 2008). It isimportant to note that in humans, salt appetite is permanently enhanced after perinatal sodiumloss (Crystal and Berstein 1995, 1998; Leshem 2009), but putative sodium loss in adults due to,for example, hemorrhage, dehydration, or breastfeeding, does not increase salt appetitesignificantly; thus, the existence of sodium appetite as a result of sodium loss in adult humansremains controversial (Bertino et al. 1982; Beauchamp et al. 1983, 1987; Leshem 2009).

FIGURE 9.1

Neurochemical circuits involved in fluid balance regulation.

FIGURE 9.2

Schematic representation of brain angiotensinergic andserotonergic circuit interactions that may regulate thirst andsalt appetite.

This review will focus on evidence from our laboratory for neurophysiological mechanisms thatregulate sodium balance. Specifically, it tries to answer how the brain elicits sodium appetite inresponse to hyponatremia/hypovolemia associated with sodium depletion, which areas areactivated after sodium depletion, how the brain controls the inhibition of this behavior once thedeficit is compensated (satiety phase), and what role brain neurochemical groups have forendocrine responses. We close the chapter by analyzing the effects of gonadal hormones and sexchromosome complement (SCC) on sodium appetite and cardiovascular function, respectively.

9.2. MAPPING BRAIN NUCLEI INVOLVED IN APPETITIVE AND SATIETY PHASESOF SODIUM APPETITE

Previous studies from our laboratory have shown that acute sodium depletion by peritonealdialysis (PD) produces a rapid and significant drop in sodium concentration in serum and CSFwithin 1–4 h after PD, rising gradually until 20–24 h later when the animals not only recovernormal extracellular sodium values (possibly by body sodium reservoirs) but sodium appetitealso becomes evident (Ferreyra and Chiaraviglio 1977). In addition, the dialyzed animals haveshown a significant decrease in blood volume immediately after PD, returning to control values12 h later (Ferreyra and Chiaraviglio 1977).

As with any motivated behavior, sodium appetite has two phases: the appetitive phase is theflexible or adaptable behavior that an animal or person adopts, before the motivational goal isfound, whereas the satiety or consummatory phase that follows is elicited only by the goalstimulus, and thus consummates the appetitive phase (Berridge 2004). We have investigated the

brain areas and neurochemical systems involved in both the appetitive (24 h after PD and beforethe intake test) and satiety (after induced sodium intake) phases of sodium appetite (Franchiniand Vivas 1999; Franchini et al. 2002; Godino et al. 2007; Johnson et al. 1999; Vivas et al.1995). In the above-mentioned studies, we have distinguished the spatial brain pattern of c-fosexpression during the arousal or the satiation of sodium appetite stimulated by PD. Thisapproach was selected because Fos, the nuclear protein product of the immediately early gene c-fos, has been used as a marker of neural activation in response to a wide variety of stimuli. Theanalysis of the pattern of c-fos expression in the CNS, preceding and after depletion-inducedsodium ingestion, potentially identifies the individual cellular components of functional neuralnetworks accompanying the presence of sodium appetite and then its satiety. During sodiumdepletion or the appetitive phase of sodium appetite, the number of Fos-ir neurons increased inthe SFO, OVLT, and central and medial extended amygdala (ExA), whereas it decreased withinthe 5-HT neurons of the DRN, suggesting their participation in the genesis of sodium appetite.Moreover, after hypertonic sodium consumption induced by PD, Fos activity increased in thedifferent cell groups of the NTS, LPBN, AP, and MnPO; OT cells of the SON and PVN; and 5-HT neurons of the DRN, indicating their involvement in the inhibition of sodium appetite.However, during this satiety phase, some areas activated after sodium depletion, such as the LTand ExA, also showed increased activity. This evidence can be interpreted as remainingdepletion-induced elevation of Fos, or the Fos activity is the result of stimulation caused by theentry to the body of a hypertonic sodium solution during sodium access, that activates thirst sincethe animals did not ingest water during the intake test.

9.2.1. LAMINA TERMINALIS

Sodium-sensitive channels are expressed in glial cells (ependimary cells and astrocytes) of theSFO and OVLT as a response to physiological increase in extracellular sodium concentration(Noda 2007; Noda and Hiyama 2005; Watanabe 2000). Moreover, the presence of atrialnatriuretic peptide (ANP) and ANG II receptors has been described in neurons of both nuclei(Allen et al. 2000; Brown and Czarnecki 1990; Lenkei et al. 1998). In our first studies, weobserved that Fos immunoreactive neurons (Fos-ir), detected by immunohistochemistry, firstappeared in these nuclei 60 min after PD, increased gradually in the next 4 h, and remained highfor 27 h after PD. Fos-ir cells were distributed throughout the SFO body, with the core of theposterior sections being preferentially activated, whereas Fos-ir neurons occurred around theperiphery of OVLT (annular disposition) (Franchini and Vivas 1999; Vivas et al. 1995). Thepresent evidence supports previous results showing increased production of Fos within the OVLTand SFO after intravenous infusion of ANG II (McKinley et al. 1995), and shows that the spatialdistribution of Fos-ir cells in this condition is similar to that observed in sodium-depletedanimals by PD (Franchini and Vivas 1999). It is also important to note that this spatial pattern ofFos-ir cells is different from those observed in the SFO and OVLT after acute intravenousinfusion of hypertonic NaCl or sucrose (Oldfield et al. 1991). In these latter cases, Fos isdetected, for example, in many neurons in the dorsal cap of the OVLT with only a few neurons inthe perimeter of the SFO.

In a more recent study, we observed that c-fos expression at OVLT level is dependent on thetonicity of the solution consumed after PD, because depleted animals with isotonic solutionaccess had very low activation, the same neuronal activation as sham-dialyzed animals, whereassodium-depleted rats that consumed hypertonic NaCl had the highest level of activation,

probably because of the stimulation of sodium-sensitive cells (Godino et al. 2007). Consistentwith these data, the OVLT lesion attenuated the oxytocin plasma increase observed after intra-atrial infusion of hypertonic solution (Negoro et al. 1988), and the electrical activity of the SONincreased after hyperosmotic OVLT stimulation, but not after isosmotic stimulation (Richard andBourque 1992), suggesting that the OVLT plays a functional role in the osmoregulation ofneurohypophyseal hormone release after hypertonic drinking. Furthermore, angiotensinintracerebroventricular (icv) infusion experiments have also suggested that the SFO and OVLTdo not play the same roles. Infusions of ANG into the SFO produced water drinking withoutsaline intake, but infusions in the OVLT and the ventral part of the MnPO produced both waterand saline drinking. It is concluded that ANG acting in the OVLT, and the most ventral part ofthe median preoptic nucleus, is important for ANG-induced salt appetite (Fitts and Masson1990).

As previously shown (Franchini and Vivas 1999; Godino et al. 2007; Vivas et al. 1995), thesodium-depletion enhancement of Fos expression observed in SFO cells remains until sodiumaccess and does not change after hypertonic or isotonic sodium consumption. A possibleexplanation of this delayed deactivation process after sodium repletion may be associated withthe gradual decrease in the circulating ANG II levels until they reach the baseline values (Houptet al. 1998; Johnson 1985; Tordoff et al. 1991; Vivas et al. 1995). A well-characterized functionof the SFO is its role as a CNS target site for circulating ANG II; this octapeptide activates 70%of all SFO neurons with very few inhibitory neural responses (Ferguson and Bains 1996). The LTis also formed by another structure, the MnPO; however, the activation of Fos in the MnPO has adifferent pattern because in our previous studies MnPO only increased its neuronal activityduring the satiety phase of sodium appetite (Franchini and Vivas 1999). Previous lesion studiesdemonstrated that animals with ventral MnPO damage exhibit a chronic and robust hyperdipsiaand spontaneous sodium appetite, which occurs only at night (Gardiner and Stricker 1985;Gardiner et al. 1986). The brain-damaged rats had normal sodium concentrations, reninactivities, and ALDO levels in plasma during basal maintenance conditions, and they conservedsodium in urine when maintained on a sodium-deficient diet. However, in another study lesion(Fitts et al. 1990) including the most ventral part of the median preoptic nucleus and the OVLT, itwas observed to reduce saline intake induced by treatment with chronic oral captopril or sodiumdepletion without affecting water intake stimulated by different treatments. Taken together, theseresults suggest that the MnPO or local fibers of passage may play an important role in the tonicand phasic control of water and sodium intake.

9.2.2. EXTENDED AMYGDALA

A critical region integrating and modulating the hormone and neural information related to thecontrol of sodium appetite is the ExA complex. The ExA is formed by what appears to be acontinuum of structures, including mainly the central and medial amygdaloid nuclei (Ce and Me,respectively) and their extensions in the lateral and medial divisions of the bed nucleus of thestria terminalis (BSTL and BSTM, respectively) (Alheid et al. 1995; De Olmos et al. 1985;Johnson et al. 1999). The concept of the ExA was initially proposed by Johnston (1923), whopostulated that the amygdala and bed nucleus of the stria terminalis were once a single structurethat becomes separated in mammals by development of the internal capsule.Cytochemoarchitectural, tract tracing, immunocytochemical, and functional studies indicate thatthe BSTL-Ce and the region of the BSTM-Me have structural, hodological neurochemical, and

functional similarities (Aldheid et al. 1995; De Olmos et al. 1985; Johnston 1923; Price et al.1987). The lateral portions of the BNST and the CeA are reciprocally connected with severalnuclei involved in cardiovascular control and fluid balance (Holstege et al. 1985; Moga et al.1989; Sofroniew 1983). In addition, the amygdala and bed nucleus of the stria terminalis alsoreceive afferent input from the structures of the LT, as well as visceral and somatic inputs via theLPBN (Alden et al. 1994; Veinante and Freund-Mercier 1998). Most studies on the role of thisregion in sodium ingestion have focused on the CeA and MeA. Previous work from thislaboratory showed that amygdala damage or transection of ventral amygdalofugal pathwaydecreased sodium intake stimulated by PD-sodium depletion (Chiaraviglio 1971). Later on,different studies found that lesions of the CeA greatly impair the salt appetite responses todeoxycorticosterone acetate (DOCA), sodium depletion, subcutaneous (sc) administration ofyohimbine, and to icv ANG II (Galaverna et al. 1992, 1993; Reilly et al. 1994; Zardetto-Smith etal. 1994). Similar to CeA lesions, ablation of the BST also inhibited sodium appetite stimulatedby different treatments (Reilly et al. 1993, 1994; Zardetto-Smith et al. 1994). On the other hand,damage to the MeA by electrolytic lesions impairs or abolishes mineralocorticoid-inducedsodium appetite while not affecting intake induced by adrenalectomy or by acute sodiumdepletion. These latter types of salt appetite are dependent on a central action of ANG II(Nitabach et al. 1989; Schulkin et al. 1989). There is also evidence indicating that cells withinthe MeA are essential for this steroid-induced salt appetite, because cell body damage producedby ibotenic acid in this nucleus impairs ALDO-induced salt intake without interfering withsodium depletion-induced or angiotensin-dependent salt appetites (Zhang et al. 1993). Moreoveradrenal steroid implants (ALDO or DOCA) in the MeA produced a rapid arousal of specificsodium intake, and central administration of mineralocorticoid antagonist (RU28318) ormineralocorticoid receptor antisense inhibited salt appetite stimulated by systemic ALDO andDOCA, but not by adrenalectomy (Reilly et al. 1993; Sakai et al. 1996).

We have investigated the role of the ExA in sodium appetite control by using Fosimmunohistochemistry, giving thus the first evidence at cellular resolution and withoutimplicating invasive maneuvers about the involvement of specific confined groups along theExA components (central and medial division) in PD-induced sodium appetite (Johnson et al.1999). Body sodium depletion induced by PD produced a pattern of highly localized and intenseFos immunoreactive (Fos-ir) cells within specific sectors of the central and medial division of theExA. Compared with the control groups, the largest increase in c-fos activation was found in thecentral ExA division, specifically in the central subdivision of the lateral part of the centralamygdaloid nucleus and its continuation in the dorsal part of the lateral bed nucleus of the striaterminalis. Along the medial division of the ExA complex, we also found the activatedcorrespondent sectors of the medial amygdala and the medial bed nucleus, precisely theanterodorsal and caudal–ventral parts of the anterior medial amygdaloid nucleus and theintermediate subdivision of the posterior part of the medial bed nucleus. We have also analyzedthe participation of the ExA complex during the satiety phase of sodium appetite induced by PD,and the results showed that there was a major increase in c-fos expression in depleted animalswith access to hypertonic NaCl solutions compared with the isotonic NaCl access group (Godinoet al. 2007).

In summary, the medial ExA is one of the regions of the brain with the highest uptake ofaldosterone (De Nicola et al. 1992; McEwen et al. 1986), thus a likely site where ALDO exertsits action on sodium intake regulation (Nitabach et al. 1989; Sakai et al. 1996; Schulkin et al.

1989; Reilly et al. 1993; Zhang et al. 1993). Otherwise, ANG II immunoreactivity is found in thecentral ExA (Lind and Ganten 1990), and the CeA contains angiotensinergic as well asmineralocorticoid receptors, being postulated as a possible site of interaction between ANG IIand ALDO to synergistically induce sodium appetite in particular conditions of body sodiumdeficit (Fluharty and Epstein 1983; Thornton and Nicolaidis 1994).

In conclusion, these results demonstrate that an acute body sodium loss induces a specificstimulation of ExA complex, verifying the major role of these particular components in afunctional neural network that receive, and integrate inputs derived from electrolyte–fluidsensory systems.

9.2.3. HINDBRAIN

It was previously described by Houpt et al. (1998) and then confirmed by our studies (Franchiniand Vivas 1999) that different levels of the NTS show increased activity after hypertonic sodiumaccess induced by sodium depletion (satiety phase of salt appetite), but this nucleus shows noactivation during the appetitive phase. Together, these studies suggest this nucleus can integrateperipheral taste and visceral sensory signals during sodium depletion. This sodium-related inputoriginates primarily from the anterior portion of the tongue and is carried to the brain through thechorda tympani branch of VII cranial nerve. These fibers probably play a strong role in theinduction of sodium appetite through the suppression of the aversive aspects of sodium taste.Specifically, dietary sodium deprivation leads to decreases in the responses of chorda tympanifibers to sodium, but not to sucrose, hydrochloride acid, or quinine hydrochloride, thus allowingsodium consumption (Contreras 1978; Contreras and Frank 1979). Our study also indicated thata restricted population of neurons in the AP, the medial level of the NTS (mNTS and NTSadjacent to AP), and the LPBN (external subdivision) express c-fos after induced hypertonicsodium consumption (Franchini and Vivas 1999; Godino et al. 2007). These data are consistentwith previous lesion studies showing that ablation of the AP and immediately adjacent medialNTS markedly enhanced the ad libitum intake of saline solutions (need-free sodium appetite) andincrease stimulated sodium appetite (Contreras and Stetson 1981; Edwards et al. 1993). Inaddition, pretreatment with bilateral injections of serotonergic receptor antagonist into the LPBNsignificantly increases salt intake induced by either icv ANG II or sodium depletion (Menani etal. 1996). Collectively, these results have led to the hypothesis that the NTS, the AP, and theLPBN are components of a hindbrain inhibitory circuit modulating sodium and fluid ingestion.Of the many hindbrain areas that potentially mediate the inhibition of sodium appetite behavior,it is likely that the NTS plays a central role. As the major relay site for taste, the NTS may exertcontrol over both food and fluid ingestion through its neural projections to hindbrain somatic andautonomic motor nuclei, including the ventrolateral medulla, the vagal complex, and the LPBN(Van Giersbergen et al. 1992). Thus, induced expression of c-fos in the medial NTS afterstimulated sodium ingestion could be correlated with the inhibition of sodium intake. The NTSreceives viscerosensory inputs from volume receptors in the atriovenous junction, the stomach,and other abdominal viscera, from baroreceptors via the carotid sinus, and from hepaticosmoreceptors via the hepatic branch of the vagus (Carlson et al. 1997; Morita et al. 1997; VanGiersbergen et al. 1992). Hence, it is plausible that, in our model, gastric mechanoreceptoractivation, hepatic osmosodium receptor stimulation, and/or cholecystokinin release contribute tothe satiety signal and mirror c-fos expression seen in these hindbrain structures.

The data are consistent also with previous studies in which gastric distension increased the Fos-

positive neurons and the electrical activity of the NTS/AP and LPBN cells (Baird et al. 2001;Sabbatini et al. 2004; Suemori et al. 1994). For example, hypertonic saline ingestion by DOCA-treated rats may be inhibited by two presystemic signals, that is, gastrointestinal distension andosmolality increase, whereas during DOCA-induced isotonic NaCl ingestion in thegastrointestinal distension may provide the only signal that inhibits further intake (Stricker et al.2007). Our results could be explained as an additive effect of gastric stretch and hyperosmoticstimulation in the PD-hypertonic group, above all taking into account that vagal and splanchnicafferent nerves carry information sensed by hepatic osmo–sodium receptors, which is projectedto the NTS/AP and the LPBN in the brainstem (Kharilas and Rogers 1984; Kobashi et al. 1993;Tordoff et al. 1986). Accordingly, vagotomized and NTS/AP-lesioned rats drank larger volumesof concentrated saline solutions compared with control animals. NTS/AP-lesioned rats also havean attenuated increase of vasopressin and oxytocin release in response to intravenous hypertonicsaline infusion (Curtis et al. 1999; Huang et al. 2000; Stricker et al. 2001; Tordoff et al. 1986).Moreover, the c-fos expression in the NTS/AP and LPBN increased after intragastric hypertonicsodium infusion in nondeprived animals (Carlson et al. 1997). Together, these results suggest thatthis brainstem neural pathway mediates peripheral satiety and osmoregulatory signals thatmodulate fluid intake and neurohypophyseal hormone secretion.

9.3. SEROTONIN AND OXYTOCIN: NEUROCHEMICAL PROCESSING OFHYPERTONICITY AND SODIUM APPETITE

Early studies from Dr. Chiaraviglio’s laboratory (Munaro and Chiaraviglio 1981) showed that abody sodium overload increases the hypothalamic levels of serotonin (5-HT). Later, systemicinjections of 5-HT antagonists (e.g., dexfenfluramine) were shown to increase need-free andneed-induced sodium intake (Neill and Cooper 1989; Rouah-Rosilio et al. 1994). Finally, studiescombining focused lesions and 5-HT agonists and antagonists conclusively demonstrated thatbrain 5-HT circuits involving the DRN (a brain source of serotonin) and LPBN (which receivesneuronal projections from DRN and other sources) exert an inhibitory control on sodium appetite(Menani and Johnson 1995; Menani et al. 1996; Reis 2007; Olivares et al. 2003).Immunohistochemical work from our laboratory supported the notion of a DRN–LPBNinhibitory control of sodium intake by showing that neuronal activity in these nuclei is associatedwith sodium balance and sodium appetite. Fos-ir in many of the DRN subdivision cells wasdecreased by PD and increased when the animals were either at near sodium balance or in theprocess of restoring it by ingesting a 2% solution of NaCl (Franchini et al. 2002).

As previously noted, inhibitory mechanisms of sodium appetite also involve the oxytocinergicsystem. Thus, saline ingestion occurs when circulating levels of OT are suppressed, whereas it isinhibited when OT release is stimulated (Stricker and Verbalis 1986). Moreover, systemic OTadministration produces renal sodium excretion; however, it does not inhibit salt appetite insodium-deficient rats. In contrast, central OT administration inhibits angiotensinergic and PEG-induced sodium appetite (Stricker and Verbalis 1987, 1996), and centrally injected OT receptorantagonists increase sodium appetite stimulated by ANG II (Blackburn et al. 1992). Morerecently, it has been demonstrated that OT knockout mice show a significant increase inspontaneous and induced sodium consumption compared with wild type controls (Amico et al.2001; Puryear et al. 2001).

Our immunohistochemical studies are also consistent with an inhibitory role for oxytocin inresponse to hypertonicity because hypertonic NaCl ingestion induced by PD increased the

activity of oxytocinergic SON and PVN cells, similar to what it does for DRN cells (Franchiniand Vivas 1999). However, in contrast to DRN (Franchini et al. 2002), PD per se induced nochange in Fos-ir of oxytocinergic SON and PVN cells.

Because of the differences observed in the neural activity of 5-HT and OT cells in the PD model,and to find out whether this activity is a consequence of the sodium satiation process or thestimulation caused by the entry of a hypertonic sodium solution into the body during sodiumaccess, we analyzed the number of Fos-5-HT- and Fos-OT-immunoreactive neurons in the DRNand the PVN and SON, respectively, after isotonic vs. hypertonic NaCl intake induced by PD(Godino et al. 2007). As expected, body sodium status was equally restored by ingesting iso- orhypertonic sodium chloride solution during the satiety phase of sodium appetite, and the 5-HTneurons of DRN were activated after induced sodium ingestion, independently of their tonicity(iso- or hyper NaCl), whereas the hypothalamic OT neural activity and the oxytocin plasmaconcentration were only stimulated after hypertonic sodium ingestion (Godino et al. 2007).

Therefore, we may postulate the 5-HT system as a sodium satiety marker whose neurons wereactivated after body sodium status was reestablished, suggesting that this system is activatedunder conditions of satiety. Otherwise, the OT system maybe a marker of hypertonic stimulation,because the activity of the OT PVN and SON nuclei neurons and plasma OT release weredirectly correlated with the ingestion of hypertonic sodium solution during induced consumption,independently of the satiety condition, suggesting that this system is involved in the processingof hyperosmotic signals.

In summary, in light of the anatomic and functional evidence, it is reasonable to postulate thepresence of 5-HT pathways with cell bodies in the DRN that project to the LPBN as well as PVN(e.g., OT neurons) and other forebrain structures (ExA, CVOs), and that they act to exert bothtonic and phasic inhibitory tone in the control of sodium intake; to be precise, under conditionsof satiety, the raphe 5-HT cells act tonically to inhibit sodium intake (Reis 2007), and they arealso activated in the process of sodium ingestion to phasically increase inhibitory control andthereby limit excess sodium intake (Figure 9.2).

9.4. NEURAL PATHWAYS INTERACTIONS BETWEEN APPETITIVE AND SATIETYSYSTEMS

The cerebral structures involved in controlling the excitatory appetitive and inhibitory or satietyphases of sodium intake are likely to be interconnected with one another, constituting a neuralnetwork that integrates associated information (Fitzsimons 1998; Johnson and Thunhorst 2007).Our previous evidence indicates that modulation of salt appetite involves interactions betweenthe CVO receptive areas and inhibitory hindbrain serotonergic circuits (Figures 9.1 and 9.2)(Badauê-Passos et al. 2007; Godino et al. 2007, 2010). That is, for normal sodium appetitesensation, and consequently for appropriate salt drinking after sodium depletion, thehyponatremia and the released ANG II should act centrally both to activate brain osmo–sodiumand angiotensinergic receptors that stimulate salt appetite, and also to inhibit inhibitory brain 5-HT mechanisms, thus removing a “braking” mechanism. The central 5-HT circuits underlyingthis interaction mainly include bidirectional connections between the CVOs, 5-HT neurons of theDRN, and 5-HT terminals within the LPBN (Figure 9.2; Andrade-Franzé et al. 2010; Castro et al.2003; Cavalcante-Lima et al. 2005a,b; Colombari et al. 1996; Menani and Johnson 1995; Menaniet al. 1996, 1998 a,b, 2000; Olivares et al. 2003; Lima et al. 2004; Tanaka et al. 1998, 2001,

2004, 2003b).

Lind (1986) has anatomically demonstrated a neural angiotensin connection originating in theSFO and projecting to the DRN. ANG II injected via the carotid artery, or into the SFO,enhances the electrical activity of SFO neurons that project to the DRN (Tanaka et al. 1998,2003b). A microdialysis study (Tanaka et al. 2003) indicates that ANG II activation of SFOneurons projecting to the DRN results in inhibition of DRN neurons and reduced local 5-HTrelease in the SFO. This suggests that neurons in the SFO monitor the circulating levels of ANGII and send this information to the DRN. A comparable projection from the MnPO to the DRNmay play a similar role (Zardetto-Smith et al. 1995).

Our recent connectional studies using retrograde tracers in sodium-depleted rats ingesting saltsuggest that structures of the LT inform the DRN and LPBN of sodium status or sodiumconsumption, and/or of volume expansion by a descending neural pathway. In this way, cellswithin the LT may contribute to inhibitory mechanisms involving 5-HT neurons in the DRN andthe release of 5-HT within the LPBN, which limit the intake of sodium and prevent excessexpansion of extracellular volume (Badauê-Passos et al. 2007; Godino et al. 2010; Margatho etal. 2008). In these morphofunctional studies using the retrograde tracer, fluorogold (FG), withFos we found significantly increased numbers of Fos–FG double-immunolabeled neurons in theLT and several other brain areas previously involved in the control of water and saline drinkingand excretion after fluid depletion (Badaue-Passos et al. 2007; Godino et al. 2010). In thesestudies, the retrograde tracer was injected into the DRN or the LPBN approximately 10 daysbefore sodium depletion experiments. Subsequently, the rats were sodium depleted and wereallowed to rehydrate by drinking water and 2% NaCl. Increased numbers of double-labeledneurons were found in the OVLT, SFO, and the MnPO of the LT after the rats drank water andsaline in the case of FG injection into the DRN (Badauê-Passos et al. 2007). These resultssuggest that during the reestablishment of water and sodium balance, neurons of the LT that aremonosynaptically connected with the DRN become significantly stimulated by fluid ingestion.These neurons then send information to the DRN, resulting in modulation of the behavioralresponse and inhibiting further sodium intake. The number of double-labeled Fos–FG neurons inthe LT increased after sodium consumption following sodium depletion. In other experimentsusing a similar approach, FG was injected into the LPBN (Godino et al. 2010). We observed thatspecific groups of neurons along the LT, PVN, ExA, insular cortex, NTS and 5-HT cells of theDRN are both directly connected to the LPBN, and are significantly activated in response towater and sodium ingestion after PD. During the appetitive phase of sodium appetite, theorganism needs to acquire sodium salt from the environment to recover lost sodium andultimately restore natremia, plasma osmolality, and plasma volume. Additionally, with the onsetof sodium intake, an inhibitory signal is gradually required to avoid overingestion of sodium.This inhibitory signal represents the drive to achieve sodium satiety and is characterized byinterruption of the previously motivated salt intake. Control of sodium appetite is attributed inpart to serotonergic pathways of the DRN and the LPBN.

In these latter studies, we have also analyzed the associated endocrine response, specificallyoxytocin and ANP plasma release, because both hormones have been implicated in the regulatoryresponse to fluid reestablishment. In this regard, our data clearly demonstrated that inducedsodium ingestion in PD rats produced a significant increase in plasma OT and ANPconcentrations compared with control (sham) dialyzed animals with access to 2% NaCl. We have

previously mentioned the involvement of the oxytocinergic system in sodium appetite control,and these data once more confirm our hypothesis about the role of the oxytocinergic system inbody fluid regulation, signaling the entry to the body of a hypertonic sodium solution duringsodium intake (Godino et al. 2007). The oxytocin released would then act at cardiac level tostimulate ANP release (Haanwinckel et al. 1995) with both hormones acting at the kidney level,inducing renal diuresis/natriuresis and also antagonizing the central and peripheral ANG IIsystem, thus preventing sodium overload. With regard to involvement of the ANPergic system,peripheral and central ANPs are also seen to be modulated by the RAS antagonism (Zavala et al.2004) and, although plasma ANP concentration tended to decrease after sodium depletion, thisreduction did not reach a significant level.

9.5. ESTROGEN-DEPENDENT INHIBITION OF SODIUM APPETITE: A ROLE FORSEROTONIN

As discussed in Chapter 3, estradiol inhibits sodium appetite by opposing facilitatory ANG IImechanisms (Mecawi et al. 2008). Moreover, estradiol may also reduce sodium intake byaltering the gustatory processing of sodium taste because the electrophysiological responses ofthe chorda tympani nerve to oral NaCl were blunted by estrogen treatment in ovariectomizedfemale rats. This suggests that females are less sensitive to concentrated NaCl solutions duringhigh estrogen conditions (Curtis and Contreras 2006). We checked if estrogen could also interactwith the serotonergic inhibitory system in normally cycling and ovariectomized female rats.

Estrogenic modulation of serotonergic system activity may be involved in both tonic and phasicinhibition of sodium appetite, as several studies have shown that estrogen modulates tryptophan–hydroxylase enzyme activity and expression (Donner and Handa 2009; Hiroi et al. 2006;Sanchez et al. 2005). Our recently published results suggest an interaction between facilitatoryneurons of the OVLT and inhibitory serotonergic cells of the DRN (Dalmasso et al. 2011),because estradiol induced Fos activation in serotonergic cells of the DRN and reduced it inOVLT neurons (Figure 9.3). In other words, hormonal status during the estrous cycle andestradiol replacement after ovariectomy changes the neural activity induced by sodium depletionin cells of the OVLT and serotonergic cells of the DRN. In particular, there is an interestingcorrelation between a ~50% reduction in sodium appetite and the neural activity found in the(possibly facilitatory) neurons of the OVLT and the inhibitory serotonergic neurons of the DRN.Thus, taking into account our previous observations in males, our results in females show thatthe expected sodium depletion–induced activity of the OVLT is absent in ovariectomized ratstreated with estradiol, whereas the usual inhibitory tonic activity of serotonergic neurons of theDRN increases or remains unchanged, rather than decreases, after sodium depletion.

FIGURE 9.3

Estrogen, sodium appetite, and neural markers: (a) Sodiumintake (mL/100 g bw; 2 h) of diestrus (D), estrus (E),ovariectomized (OVX) and ovariectomized + estradiolreplacement (OVX + E2) groups, “treated with saline/normalsodium diet (S/NSD; (more...)

Taking into account these results and that: (1) serotonin and the DRN have been implicated in theinhibitory control of salt intake in males (Badauê-Passos et al. 2007; Cavalcante-Lima et al.

2005a,b; Franchini et al. 2002; Godino et al. 2007, 2010), (2) estrogen has an inhibitory effect onsodium consumption in females (Dalmasso et al. 2011), (3) signals arriving from the LT evokedby fluid depletion-induced sodium ingestion interact with this inhibitory serotonergic system(Badauê-Passos et al. 2007), and (4) estrogen modulates 5-HT synthesis and release (Robichaudand Debonnel 2005; Rubinow et al. 1998; Sanchez et al. 2005), it is possible to postulateserotonergic system involvement in the inhibitory action of estrogen on sodium appetite infemale rats. Another possibility, also considered in the schematic representation shown in Figure9.3d, is that changes in estrogen levels may modulate ANG-sensitive DRN-projecting neurons inthe OVLT, to suppress their response to circulating ANG II and consequently inhibit sodiumintake. Our results also demonstrate that estradiol influences vasopressinergic neural activity andthe associated diuresis after fluid depletion, before drinking. The increased vasopressinergicactivity observed in the hypothalamic cells of animals in E and OVX+E2 rats is consistent withprevious studies showing an increase in plasma AVP concentration as well as AVP-mRNA infemale rats in estrus and in OVX rats after estradiol replacement (Crofton et al. 1985; Crowley etal. 1978; Peysner and Forsling 1990). As shown in the schematic representation, estrogen may beacting directly on vasopressinergic neurons, modulating estrogen receptor beta density expressedin these neurons (Sladek and Somponpun 2008; Somponpun and Sladek 2003; Tanaka et al.2002). Likewise, estrogen may be modulating its alpha receptor density localized in the SFO andOVLT and—by means of these projections—be acting on vasopressinergic neurons (Grassi et al.2010; Kensicki et al. 2002; Menani et al. 1998a; Somponpun and Sladek 2004; Tanaka et al.2001, 2003a). On the other hand, taking into account our data regarding vasopressin neuralactivity and the inhibitory action of estrogen on induced sodium intake, it is possible to speculatethat central vasopressin, or vasopressin-mediated fluid retention during high estrogen states maybe another physiological mechanism limiting sodium ingestion (Sato et al. 1997).

In summary, the main finding of these results is a serotonergic system involvement, as a possiblemechanism in the inhibitory action of estrogen on induced sodium appetite, which may involvean interaction between excitatory neurons of the OVLT and inhibitory serotonin cells of the DRNkey brain cells underlying the responses to hyponatremia and hypovolemia.

9.6. SEX CHROMOSOME COMPLEMENT: ANG II AND GENDER-RELATEDDIFFERENCES IN BAROREFLEX

The arterial baroreceptor reflex is a major negative feedback mechanism involved in stabilizationof perfusion pressure, and changes in baroreflex control of heart rate (HR) have been describedin physiological and pathophysiological states. Clinical and basic findings indicate a sexuallydimorphic baroreflex control of HR. The acute administration of ANG II in normotensive maleand female patients induces increases in BP of similar magnitude; however, in men, bradycardicbaroreflex response is blunted relative to that observed in women (Gandhi et al. 1998). Likewise,in intact male mice, the slope of ANG II–induced baroreflex bradycardia is significantly less thanthat evoked by phenylephrine (PE), whereas no differences are observed in the response to bothpressor agents in gonadectomized female mice (Pamidimukkala et al. 2003). Although previousstudies have shown a facilitatory role of estrogen and testosterone on the baroreflex control ofHR (El-Mas et al. 2001; Pamidimukkala et al. 2003), classical hormonal manipulations havefailed to cause sex reversal of the ANG II–bradycardic baroreflex response.

A growing body of evidence indicates that some sexually dimorphic traits cannot be entirelyexplained solely as a result of gonadal steroid action, but may also be ascribed to differences in

SCC. Males and females carry a different complement of sex chromosome genes and areinfluenced throughout life by different genomes. Genetic and/or hormone pathways may thus actindependently or interact (synergistically/antagonistically) in modulating sexual dimorphicdevelopment (Arnold and Chen 2009; Arnold et al. 2004; Cambiasso et al. 1995; De Vries et al.2002).

In this context, we have investigated whether SCC modulates bradycardic baroreflex responseand contributes to the ANG II–bradycardic baroreflex sex differences (Caeiro et al. 2011). Tothis end, we used the four core genotype (FCG) mouse model, in which the effect of gonadal sexand SCC is dissociated (Figure 9.4), allowing comparisons of sexually dimorphic traits amongXX and XY females as well as in XX and XY males.

FIGURE 9.4

Schematic representation of four core genotype mousemodels, in which effect of gonadal sex and sex chromosomecomplement is dissociated. (Reprinted with permission fromCaeiro, X.E. et al., Hypertension, 58, 505–511, 2011.)

In conscious gonadectomized (GDX) free moving mice, we evaluated baroreflex regulation ofHR in response to changes in BP evoked by PE (1.0 mg/mL), and ANG II (100 µg/mL). Ourfindings revealed that the ANG II–bradycardic baroreflex sexual dimorphism response may beascribed to differences in sex chromosomes, indicating an XX-SCC facilitatory bradycardicbaroreflex control of HR. Moreover, the results showed that the PE-baroreflex bradycardicresponse depends on the complex interaction between SCC and gonadal steroids during criticalperiods of development in fetal and neonatal life (Caeiro et al. 2011). ANG II infusion in GDX-XY male mice induced a blunted bradycardic response when compared to PE administration,whereas GDX-XX female, GDX-XX male, and GDX-XY female mice showed the samebradycardic baroreflex response to both PE and ANG II. Mice with XX-SCC but with differentgonadal sex (GDX-XX male and GDX-XX female mice) showed the same bradycardicbaroreflex response. Moreover, the comparison of female mice with different SCC (GDX-XXfemale vs. GDX-XY female) showed an attenuated baroreflex response to both pressor agents inGDX-XY female mice, indicating an XX-SCC facilitatory bradycardic baroreflex effect (Figure9.5).

FIGURE 9.5

Comparative reflex bradycardic baroreflex responses tophenylephrine (PE) and angiotensin II (ANG II) infusion inMF1 gonadectomized (GDX) mice of the four core genotype(FCG). Graphs show mean relationship lines relating peakchanges in heart rate (HR; (more...)

Previous studies conducted in patients and spontaneously hypertensive rats have demonstrated anassociation of the Y chromosome with high BP (Ellis et al. 2000; Ely and Turner 1990). Morerecently, Ji et al. (2010) using the FCG mouse model, have shown that, after 2 weeks of ANG IIinfusion, mean arterial pressure is greater in GDX-XX than in GDX-XY mice. In the currentstudy, using the same mouse model, we found that acute ANG II infusion induces a blunted

bradycardic response in GDX-XY compared with GDX-XX mice, indicating that the acuteadministration of ANG II produced, regardless of the gonadal phenotype, a different baroreflexresponse depending on the genetic sex.

Although these results described in the previous paragraph appear to be contradictory, it isimportant to note that chronic infusion of ANG II triggers regulatory responses associated withneuroendocrine compensatory mechanisms. In particular, changes in ANG II receptor expressionattributed to increases in ANG II levels have been reported. In vitro and in vivo studies haveshown an upregulation of central AT1R expression in response to physiological increases inplasma ANG II levels induced by water deprivation and sodium depletion (Barth and Gerstberger1999; Chen et al. 2003; Sanvitto et al. 1997). Studies carried out by Wei et al. (2009) have alsodemonstrated that the sc infusion of a low dose of ANG II for 4 weeks induces an increase inAT1R mRNA expression in the SFO, and PVN, although no significant effect on BP is observed.Moreover, increases in AT1R expression have been reported in pathophysiological states, such ashypertension (Saavedra et al. 1986). Thus, changes in AT1R expressions in central brain areasattributed to chronic ANG II infusion may differentially influence the activity andresponsiveness of the RAS system.

It is important to point out that the AT2R gene (Agtr2) is located in the X chromosome (DeGasparo et al. 2000; Koike et al. 1994), whereas the AT1R gene (Agtr1) is localized in anautosome chromosome (Arnold et al. 2004; Szpirer et al. 1993). Thus, it is tempting to speculatethat genes residing on the sex chromosomes (which are asymmetrically inherited between malesand females) could well be influential in eliciting and maintaining sex-bias phenotypes (Daviesand Wilkinson 2006). If this is the case, differential transcription or expression of theAT1R/AT2R might be responsible for ANG II sex-biased differences.

9.7. CONCLUDING COMMENTS

In summary, we can postulate that mechanisms controlling fluid and cardiovascular balance relyon many different neurochemical systems acting on similar neural pathways in parallel andsimultaneously or in different moments, in relation to the changing physiological bodyconditions. Besides these mechanisms, there is the influence of gonadal hormones and a directmodulation by sex chromosomes, the latter an important subject for future research. Elucidatingthe foundational sources of sexually dimorphic traits may offer important insights into designingimproved oriented sex-tailored therapeutic treatments for cardiovascular and renal diseases.

ACKNOWLEDGMENTS

This work was, in part, supported by grants from the CONICET, ANPCyT, MinCyT Roemmers,FUCIBICO, and SECyT Universidad Nacional de Córdoba. Carolina Dalmasso and Ana FabiolaMacchione were recipients of CONICET fellowships.

REFERENCES

Alden M, Besson J. M, Bernard J. F. Organization of the efferent projections from thepontine parabrachial area to the bed nucleus of the stria terminalis and neighboringregions: A PHA-L study in the rat. J Comp Neurol. 1994;341:289–14. [PubMed:7515078]

Alheid G. F, de Olmos J, Beltramino C. A. Amygdala and extended amygdala. In: Paxinos

G, editor. In The Rat Nervous System. 2nd. San Diego: Academic Press; 1995. pp. 495–578.

Allen A. M, Zhuo J, Mendelsohn F. A. Localization and function of angiotensin AT1receptors. Am J Hypertens. 2000;13:31S–8S. [PubMed: 10678286]

Amico J. A, Morris M, Vollmer R. R. Mice deficient in oxytocin manifest increased salineconsumption following overnight fluid deprivation. Am J Physiol Regul Integr CompPhysiol. 2001;281:R1368–73. [PubMed: 11641104]

Andrade-Franzé G. M, Andrade C. A, De Luca L. A Jr, De Paula P. M, Menani J. V. Lateralparabrachial nucleus and central amygdala in the control of sodium intake.Neuroscience. 2010;165:633–41. [PubMed: 19909794]

Arnold A. P, Chen X. What does the “four core genotypes” mouse model tell us about sexdifferences in the brain and other tissues? Front Neuroendocrinol. 2009;30:1–9. [PMCfree article: PMC3282561] [PubMed: 19028515]

Arnold A. P, Xu J, Grisham W, Chen X, Kim Y. H, Itoh Y. Minireview: Sex chromosomesand brain sexual differentiation. Endocrinology. 2004;145:1057–62. [PubMed:14670983]

Badauê-Passos D Jr, Godino A, Johnson A. K, Vivas L, Antunes-Rodrigues J. Dorsal raphénuclei integrate allostatic information evoked by depletion-induced sodium ingestion.Exp Neurol. 2007;206:86–94. [PubMed: 17544397]

Baird J. P, Travers J. B, Travers S. P. Parametric analysis of gastric distension responses inthe parabrachial nucleus. Am J Physiol Regul Integr Comp Physiol. 2001;281:R1568–80. [PubMed: 11641130]

Barth S. W, Gerstberger R. Differential regulation of angiotensinogen and AT1A receptormRNA within the rat subfornical organ during dehydration. Brain Res. 1999;64:151–64.[PubMed: 9931478]

Berridge K. C. Motivation concepts in behavioral neuroscience. Physiol Behav.2004;81:179–209. [PubMed: 15159167]

Beauchamp G. K, Bertino M, Engelman K. Modification of salt taste. Ann Intern Med.1983;98:763–9. [PubMed: 6847015]

Beauchamp G. K, Bertino M, Engelman K. Failure to compensate decreased dietary sodiumwith increased table salt usage. JAMA. 1987;258:3275–8. [PubMed: 3682116]

Bertino M, Beauchamp G. K, Engelman K. Long-term reduction in dietary sodium altersthe taste of salt. Am J Clin Nutr. 1982;36:1134–44. [PubMed: 7148734]

Blackburn R. E, Demko A. D, Hoffman G. E, Stricker E. M, Verbalis J. G. Central oxytocininhibition of angiotensin-induced salt appetite in rats. Am J Physiol Regul Integr CompPhysiol. 1992;263:R1347–53. [PubMed: 1336319]

Brown J, Czarnecki A. Autoradiographic localization of atrial and brain natriuretic peptidereceptors in rat brain. Am J Physiol Regul Integr Comp Physiol. 1990;258:R57–63.[PubMed: 2154136]

Caeiro X. E, Mir F. R, Vivas L. M, Carrer H. F, Cambiasso M. J. Sex chromosomecomplement contributes to sex differences in bradycardic baroreflex response.Hypertension. 2011;58:505–11. [PubMed: 21810650]

Cambiasso M. J, Díaz H, Cáceres A, Carrer H. F. Neuritogenic effect of estradiol on ratventromedial hypothalamic neurons co-cultured with homotopic or heterotopic glia. JNeurosci Res. 1995;42:700–9. [PubMed: 8600303]

Carlson S. H, Beitz A, Osborn J. W. Intragastric hypertonic saline increases vasopressin and

central Fos immunoreactivity in conscious rats. Am J Physiol Regul Integr CompPhysiol. 1997;272:R750–8. [PubMed: 9087636]

Castro L, Athanazio R, Barbetta M. et al. Central 5- HT2B/2C and 5-HT3 receptorstimulation decreases salt intake in sodium depleted rats. Brain Res. 2003;981:151–9.[PubMed: 12885436]

Cavalcante-Lima H. R, Badaue-Passos D Jr, de-Lucca W Jr. et al. Chronic excitotoxic lesionof the dorsal raphe nucleus induces sodium appetite. Braz. J. Med. Biol. Res.2005a;38:1669–75. [PubMed: 16258637]

Cavalcante-Lima H. R, Lima H. R, Costa-e-Sousa R. H. et al. Dipsogenic stimulation inibotenic DRN-lesioned rats induces concomitant sodium appetite. Neurosci Lett.2005b374:5–10. [PubMed: 15631886]

Chiaraviglio E. Amygdaloid modulation of sodium chloride and water intake in the rat. JComp Physiol Psychol. 1971;76:401–7. [PubMed: 4331436]

Chen Y, da Rocha M. J, Morris M. Osmotic regulation of angiotensin AT1 receptor subtypesin mouse brain. Brain Res. 2003;965:35–44. [PubMed: 12591117]

Colombari D. S. A, Menani J. V, Johnson A. K. Forebrain angiotensin type 1 receptors andparabrachial serotonin in the control of NaCl and water intake. Am J Physiol RegulatoryIntegrative Comp Physiol. 1996;271:R1470–6. [PubMed: 8997341]

Contreras R. J. Salt taste and disease. Am J Clin Nutr. 1978;31:1088–97. [PubMed: 352128]Contreras R. J, Frank M. Sodium deprivation alters neural responses to gustatory stimuli. J

Gen Physiol. 1979;73:569–94. [PMC free article: PMC2215192] [PubMed: 458420]Contreras R, Stetson P. Changes in salt intake after lesions of the area postrema and the

nucleus of the solitary tract in rats. Brain Res. 1981;211:355–66. [PubMed: 7237128]Crystal S. R, Bernstein I. L. Morning sickness: Impact on offspring salt preference.

Appetite. 1995;25:231–40. [PubMed: 8746963]Crystal S. R, Bernstein I. L. Infant salt preference and mother’s morning sickness. Appetite.

1998;30:297–307. [PubMed: 9632460]Crofton J, Baer P, Share L, Brooks D. Vasopressin release in male and female rats: Effects

of gonadectomy and treatment with gonadal steroid hormones. Endocrinology.1985;117:1195–200. [PubMed: 4017961]

Crowley W. R, O’Donohue T. L, George J. M, Jacobowitz D. M. Changes in pituitaryoxytocin and vasopressin during the estrous cycle and after ovarian hormones, evidencefor mediation by norepinephrine. Life Sciences. 1978;23:2579–86. [PubMed: 570235]

Curtis K. S, Contreras R. J. Sex differences in electrophysiological and behavioralresponses to NaCl taste. Behav Neurosci. 2006;120:917–24. [PubMed: 16893297]

Curtis K. S, Huang W, Sved A. F, Verbalis J. G, Stricker E. M. Impaired osmoregulatoryresponses in rats with area postrema lesion. Am J Physiol Regul Integr Comp Physiol.1999;277:R209–19. [PubMed: 10409275]

Dalmasso C, Amigone J. L, Vivas L. Serotonergic system involvement in the inhibitoryaction of estrogen on induced sodium appetite in female rats. Physiol and Behav.2011;104:398–407. [PubMed: 21554894]

Davies W, Wilkinson L. S. It is not all hormones: Alternative explanations for sexualdifferentiation of the brain. Brain Res. 2006;1126:36–45. [PubMed: 17101121]

De Gasparo M, Catt K. J, Inagami T, Wright J. W, Unger T. International union ofpharmacology: XXII. The angiotensin II receptors. Pharmacol Rev. 2000;52:415–72.[PubMed: 10977869]

De Nicola A. F, Grillo C, Gonzalez S. Physiological, Biochemical and Molecularmechanisms of salt appetite control by mineralocorticoid action in brain. Braz J MedBiol Res. 1992;25:1153–62. [PubMed: 1341910]

De Olmos J, Aldheid G. F, Beltramino C. Amygdala. In: Paxinos G, editor. In The RatNervous System. Vol. 1. Orlando, FL: Academic Press; 1985. pp. 223–234. Forebrainand Midbrai.

De Vries G. J, Rissman E. F, Simerly R. B. et al. A model system for study of sexchromosome effects on sexually dimorphic neural and behavioral traits. J Neurosci.2002;22:9005–14. [PubMed: 12388607]

Donner N, Handa R. J. Estrogen receptor beta regulates the expression of tryptophan-hydroxylase 2 mRNA within serotonergic neurons of the rat dorsal raphe nuclei.Neuroscience. 2009;163:705–18. [PMC free article: PMC2740745] [PubMed:19559077]

Edwards G. L, Beltz T. G, Power J. D, Johnson A. K. Rapid-onset “need-free” sodiumappetite after lesions of the dorsomedial medulla. Am J Physiol Regul Integr CompPhysiol. 1993;264:R1242–7. [PubMed: 8322980]

Ellis J. A, Stebbing M, Harrap S. B. Association of the human Y chromosome with highblood pressure in the general population. Hypertension. 2000;36:731–3. [PubMed:11082135]

El-Mas M. M, Afify E. A, El-Din M. M. M, Omar-Din A. G, Sharabi F. M. Testosteronefacilitates the baroreceptor control of reflex bradycardia: Role of cardiac sympatheticand parasympathetic components. J Cardiovasc Pharmacol. 2001;38:754–63. [PubMed:11602822]

Ely D. L, Turner M. E. Hypertension in the spontaneously hypertensive rat is linked to theY chromosome. Hypertension. 1990;16:277–81. [PubMed: 2394486]

Ferguson A. V, Bains J. S. Electrophysiology of the circumventricular organs. FrontNeuroendocrinol. 1996;17:440–75. [PubMed: 8905349]

Ferreyra M. D, Chiaraviglio E. Changes in volemia and natremia and onset of sodiumappetite in sodium depleted rats. Physiol Behav. 1977;19:197–201. [PubMed: 607231]

Fitts D. A, Masson D. B. Preoptic angiotensin and salt appetite. Behav Neurosci.1990;104:643–50. [PubMed: 2206434]

Fitts D. A, Tjepkes D. S, Bright R. O. Salt appetite and lesions of the ventral part of theventral median preoptic nucleus. Behav Neurosci. 1990;104:818–27. [PubMed:2244988]

Fitzsimons J. T. Angiotensin, thirst, and sodium appetite. Physiol Rev. 1998;78:583–686.[PubMed: 9674690]

Fluharty S. J, Epstein A. N. Sodium appetite elicited by intracerebroventricular infusion ofangiotensin II in the rat: II. Synergistic interaction with systemic mineralocorticoids.Behav Neurosci. 1993;97:746–58. [PubMed: 6639747]

Franchini L, Vivas L. Fos induction in rat brain neurons after sodium consumption inducedby acute body sodium depletion. Am J Physiol Regul Integr Comp Physiol.1999;276:R1180–7. [PubMed: 10198401]

Franchini L, Johnson A. K, de Olmos J, Vivas L. Sodium appetite and Fos activation inserotonergic neurons. Am J Physiol Regul Integr Comp Physiol. 2002;282:R235–43.[PubMed: 11742843]

Galaverna O. G, De Luca L. A Jr, Shulkin J, Yao S, Epstein A. N. Deficits in NaCl ingestion

after damage to the central nucleus of the amygdala in the rat. Brain Res Bull.1992;28:89–98. [PubMed: 1540849]

Galaverna O. G, Seeley R. J, Berridge K. C, Grill H. J, Epstein A. N, Schulkin J. Lesions ofthe central nucleus of the amygdale: Effects on taste reactivity, taste aversion learningand sodium appetite. Behav Brain Res. 1993;59:11–7. [PubMed: 8155277]

Gandhi S. K, Gainer J, King D, Brown N. J. Gender affects renal vasoconstrictor responseto ANG I and ANG II. Hypertension. 1998;31:90–6. [PubMed: 9449397]

Gardiner T. W, Stricker E. M. Hyperdipsia in rats after electrolytic lesions of nucleusmedianus. Am J Physiol Regul Integr Comp Physiol. 1985;248:R214–23. [PubMed:3970236]

Gardiner T. W, Jolley J. R, Vagnucci A. H, Stricker E. M. Enhanced sodium appetite in ratswith lesions centered on nucleus medianus. Behav Neurosci. 1986;100:531–5.[PubMed: 3527192]

Geerling J. C, Loewy A. D. Central regulation of sodium appetite. Exp Physiol.2008;93:177–209. [PubMed: 17981930]

Godino A, Margatho L. O, Caeiro X. E, Antunes-Rodrigues J, Vivas L. Activation of lateralparabrachial afferent pathways and endocrine responses during sodium appetiteregulation. Exp Neurol. 2010;221:275–84. [PubMed: 19913016]

Godino A, De Luca L. A Jr, Antunes-Rodrigues J, Vivas L. Oxytocinergic and serotonergicsystems involvement in sodium intake regulation: Satiety or hypertonicity markers? AmJ Physiol Regul Integr Comp Physiol. 2007;293:R1027–36. [PubMed: 17567719]

Grassi D, Amorim M. A, Garcia-Segura L. M, Panzica G. Estrogen receptor alpha isinvolved in the estrogenic regulation of arginine vasopressin immunoreactivity in thesupraoptic and paraventricular nuclei of ovariectomized rats. Neurosci Lett.2010;474:135–9. [PubMed: 20298751]

Haanwinckel M. A, Elias L. K, Favaretto A. L, Gutkowska J, McCann S. M, Antunes-Rodrigues J. Oxytocin mediates atrial natriuretic peptide release and natriuresis aftervolume expansion in the rat. Proc Natl Acad Sci USA. 1995;92:7902–6. [PMC freearticle: PMC41254] [PubMed: 7644511]

Hiroi R, McDevitt R. A, Neumaier J. F. Estrogen selectively increases tryptophanhydroxylase-2 mRNA expression in distinct subregions of rat midbrain raphe nucleus:Association between gene expression and anxiety behavior in the open field. BiolPsychiatry. 2006;60:288–95. [PubMed: 16458260]

Holstege G, Meiners L, Tan K. Projections of the bed nucleus of the stria terminalis to themesencephalon, pons, and medulla oblongata in the cat. Exp Brain Res. 1985;58:379–91. [PubMed: 3996501]

Houpt T. A, Smith G. P, Joh T. H, Frankmann S. P. C-fos like immunoreactivity in thesubfornical organ and nucleus of the solitary tract following salt intake by sodiumdepleted rats. Physiol Behav. 1998;63:505–10. [PubMed: 9523891]

Huang W, Sved A. F, Stricker E. M. Vasopressin and oxytocin release evoked by NaCl loadsare selectively blunted by area postrema lesions. Am J Physiol Regul Integr CompPhysiol. 2000;278:R732–40. [PubMed: 10712295]

Ji H, Zheng W, Wu X. et al. Sex chromosome effects unmasked in angiotensin II-inducedhypertension. Hypertension. 2010;55:1275–82. [PMC free article: PMC2905778][PubMed: 20231528]

Johnson A. K, De Olmos J, Pastuskovas C. V, Zardetto-Smith A. M, Vivas L. The extended

amygdala and salt appetite. Ann N Y Acad Sci. 1999;877:258–80. [PubMed: 10415654]Johnson A. K. The periventricular anteroventral third ventricle (AV3V): Its relationship

with the subfornical organ and neural system involved in the maintaining body fluidhomeostasis. Brain Res Bull. 1985;15:595–601. [PubMed: 3910170]

Johnston A. K, Thunhorst R. L. The neuroendocrinology, neurochemistry and molecularbiology of thirst and salt appetit. In: Lajtha A, Blaustein J. D, editors. In Handbook ofNeurochemistry and Molecular Neurobiology. 3rd. Berlin: Springer-Verlag; 2007. pp.641–687.

Johnston J. B. Further contributions to the study of the evolution of the forebrain. J CompNeurol. 1923;35:337–481.

Kensicki E, Dunphy G, Ely D. Estradiol increases salt intake in female normotensive andhypertensive rats. J Appl Physiol. 2002;93:479–83. [PubMed: 12133853]

Kharilas P. J, Rogers R. C. Rat brainstem neurons responsive to changes in portal bloodsodium concentration. Am J Physiol Regul Integr Comp Physiol. 1984;247:R792–9.[PubMed: 6093603]

Kobashi M, Ichikawa H, Sugimoto T, Adachi A. Response of neurons in the solitary tractnucleus, area postrema and lateral parabrachial nucleus to gastric load of hypertonicsaline. Neurosci Lett. 1993;158:47–50. [PubMed: 8233072]

Koike G, Horiuchi M, Yamada T, Szpirer C, Jacob H. J, Dzau V. J. Human type 2angiotensin II receptor gene: Cloned, mapped to the X chromosome, and its mRNA isexpressed in the human lung. Biochem Biophys Res Commun. 1994;30:1842–50.[PubMed: 7945336]

Lenkei Z, Palkovits M, Corvol P, Llorens-Cortes C. Distribution of angiotensin type-1receptor messenger RNA expression in the adult rat brain. Neuroscience. 1998;82:827–41. [PubMed: 9483539]

Leshem M. Biobehavior of the human love of salt. Neurosci Biobehav Rev. 2009;33:1–17.[PubMed: 18708089]

Lima H. R, Cavalcante-Lima H. R, Cedraz-Mercez P. L. et al. Brain serotonin depletionenhances the sodium appetite induced by sodium depletion or beta-adrenergicstimulation. An Acad Bras Cienc. 2004;76:85–92. [PubMed: 15048197]

Lind R. W. Bi-directional, chemically specified neural connections between the subfornicalorgan and the midbrain raphe system. Brain Res. 1986;384:250–61. [PubMed: 3779379]

Lind W, Ganten D. Angiotensi. In: Bjorklund A, Hokfelt T, Kuhar M. J, editors. InHandbook of Chemical Neuroanatomy, Vol.9: Neuropeptides in the CNS. Part II.Amsterdam: Elsevier; 1990.

Margatho L. O, Godino A, Oliveira F. R, Vivas L, Antunes-Rodrigues J. Lateralparabrachial afferent areas and serotonin mechanisms activated by volume expansion. JNeurosci Res. 2008;86:3613–21. [PubMed: 18683241]

McEwen B. S, Lambdin L, Rainbow T. C, De Nicola A. F. Aldosterone effects on saltappetite in adrenalectomized rats. Neuroendocrinology. 1986;43:38–43. [PubMed:3713988]

McKinley M. J, Badoer E, Vivas L, Oldfield B. J. Comparison of c-fos expression in theforebrain of conscious rats after intravenous or intracerebroventricular angiotensin.Brain Res Bull. 1995;37:131–7. [PubMed: 7606488]

Mecawi A. S, Lepletier A, Araujo I. G, Fonseca F. V, Reis L. C. Oestrogenic influence onbrain AT1 receptor signalling on the thirst and sodium appetite in osmotically stimulated

and sodium-depleted female rats. Exp Physiol. 2008;93:1002–10. [PubMed: 18441334]Menani J. V, Colombari D. S. A, Beltz T. G, Thunhorst R. L, Johnson A. K. Salt appetite:

Interaction of forebrain angiotensinergic and hindbrain serotonergic mechanisms. BrainRes. 1998a;801:29–35. [PubMed: 9729254]

Menani J. V, De Luca L. A Jr, Johnson A. K. Lateral parabrachial nucleus serotonergicmechanisms and salt appetite induced by sodium depletion. Am J Physiol RegulatoryIntegrative Comp Physiol. 1998b;274:R555–60. [PubMed: 9486317]

Menani J. V, De Luca L. A Jr, Thunhorst R. L, Johnson A. K. Hindbrain serotonin and therapid induction of sodium appetite. Am J Physiol Regulatory Integrative Comp Physiol.2000;279:R126–131. [PubMed: 10896873]

Menani J. V, Johnson A. K. Lateral parabrachial serotonergic mechanisms: Angiotensin-induced pressor and drinking responses. Am J Physiol Regulatory Integrative CompPhysiol. 1995;269:R1044–9. [PubMed: 7503290]

Menani J. V, Thunhorst R. L, Johnson A. K. Lateral parabrachial nucleus and serotonergicmechanisms in the control of salt appetite in rats. Am J Physiol Regulatory IntegrativeComp Physiol. 1996;270:R162–8. [PubMed: 8769798]

Moga M. M, Saper C. B, Gray T. S. Bed nucleus of the stria terminalis: Cytoarchitecture,immunohistochemistry, and projection to the parabrachial nucleus in the rat. J CompNeurol. 1989;283:315–32. [PubMed: 2568370]

Morita H, Yamashita Y, Nishimida Y, Tokuda M, Hatase O, Hosomi H. Fos induction in ratbrain neurons after stimulation of the hepatoportal Na-sensitive mechanism. Am JPhysiol Regulatory Integrative Comp Physiol. 1997;272:R913–23. [PubMed: 9087655]

Munaro N, Chiaraviglio E. Hypothalamic levels and utilization of noradrenaline and 5-hydroxytryptamine in the sodium depleted rat. Pharmacol Biochem Behav. 1981;15:1–5.[PubMed: 6170073]

Negoro H, Higuchi T, Tadokoro Y, Honda K. Osmoreceptor mechanisms for oxytocinrelease in the rat. Jpn J Physiol. 1988;38:19–31. [PubMed: 3386052]

Neill J. C, Cooper S. J. Selective reduction by serotonergic agents of hypertonic salineconsumption in rats: Evidence for possible 5-HT1C receptor mediation.Psychopharmacology. 1989;99:196–201. [PubMed: 2508154]

Nitabach M, Schulkin J, Epstein A. N. The medial amygdala is a part of amineralocorticoid-sensitive circuit controlling NaCl intake in the rat. Behav Brain Res.1989;35:127–34. [PubMed: 2818832]

Noda M. Hydromineral neuroendocrinology: Mechanism of sensing sodium levels in themammalian brain. Exp Physiol. 2007;92:513–522. [PubMed: 17350991]

Noda M, Hiyama T. Y. Sodium-level-sensitive sodium channel and salt-intake behavior.Chem Senses. 2005;30 Suppl 1:i44–5. [PubMed: 15738187]

Oldfield B. J, Bicknell R. J, McAllen R. M, Weisinger R. S, McKinley M. J. Intravenoushypertonic saline induces Fos immunoreactivity in neurons throughout the laminaterminalis. Brain Res. 1991;561:151–6. [PubMed: 1797341]

Olivares E. L, Costa-E-Sousa R. H, Cavalcante-Lima H. R, Lima H. R, Cedraz-Mercez P. L,Reis L. C. Effect of electrolytic lesion of the dorsal raphe nucleus on water intake andsodium appetite. Braz J Med Biol. 2003;36:1709–16. Res. [PubMed: 14666256]

Pamidimukkala J, Taylor J. A, Welshons W. V, Lubahn D. B, Hay M. Estrogen modulationof baroreflex function in conscious mice. Am J Physiol Regul Integr Comp Physiol.2003;284:R983–9. [PubMed: 12521927]

Peysner K, Forsling M. L. Effect of ovariectomy and treatmentwith ovarian steroids onvasopressin release and fluid balance in the rat. J Endocrinol. 1990;124:277–84.[PubMed: 2313218]

Puryear R, Rigatto K. V, Amico J. A, Morris M. Enhanced salt intake in oxytocin deficientmice. Exp Neurol. 2001;171:323–8. [PubMed: 11573985]

Reilly J. J, Mamani D. B, Schulkin J, McEwen B. S, Sakai R. R. Effect of amygdala adrenalsteroid implants in rat brain on sodium intake (Abstract) Appetite. 1993;21:201.

Reilly J. J, Maki R, Nardozzi J, Schulkin J. The effects of lesions of the bed nucleus of thestria terminalis on sodium appetite. Acta Neurobiol Exper. 1994;54:253–7. [PubMed:7817841]

Reis L. C. Role of the serotoninergic system in the sodium appetite control. An Acad BrasCienc. 2007;79:261–83. [PubMed: 17625681]

Richard D, Bourque C. W. Synaptic activation of rat supraoptic neurons by osmoticstimulation of the organum vasculosum of the lamina terminalis. Neuroendocrinology.1992;55:609–11. [PubMed: 1584342]

Robichaud M, Debonnel G. Oestrogen and testosterone modulate the firing activity ofdorsal raphe nucleus serotonergic neurones in both male and female rats. JNeuroendocrinol. 2005;17:179–85. [PubMed: 15796770]

Rouah-Rosilio M, Orosco M, Nicolaidis S. Serotoninergic modulation of sodium appetite inthe rat. Physiol Behav. 1994;55:811–6. [PubMed: 8022898]

Rubinow D. R, Schmidt P. J, Roca C. A. Estrogen–serotonin interactions: Implications foraffective regulation. Biol Psychiatry. 1998;44:839–50. [PubMed: 9807639]

Saavedra J. M, Correa F. M, Kurihara M, Shigematsu K. Increased number of angiotensin IIreceptors in the subfornical organ of spontaneously hypertensive rats. J Hypertension.1986;4:S27–S30. [PubMed: 3471907]

Sabbatini M, Molinari E, Grossini C, Mary D. A, Vacca G, Cannas M. The pattern of c-Fosimmunoreactivity in the hindbrain of the rat following stomach distension. Exp BrainRes. 2004;157:315–23. [PubMed: 15252702]

Sakai R. R, Ma L. Y, Zhang D. M, McEwen B. S, Fluharty S. J. Intracerebral administrationof mineralocorticoid receptor antisense oligonucleotides attenuate adrenal steroid-induced salt appetite in rats. Neuroendocrinology. 1996;64:426–9. [PubMed: 8990075]

Sanchez R. L, Reddy A. P, Centeno M. L, Henderson J. A, Bethea C. L. A secondtryptophan hydroxylase isoform, TPH-2 mRNA, is increased by ovarian steroids in theraphe region of macaques. Brain Res Mol Brain Res. 2005;135:194–203. [PubMed:15857682]

Sanvitto G. L, Johren O, Hauser W, Saavedra J. M. Water regulation upregulates ANG IIAT1 binding and mRNA in rat subfornical organ and anterior pituitary. Am J PhysiolEndocrinol Metab. 1997;273:E156–63. [PubMed: 9252492]

Sato M. A, Sugawara A. M, Menani J. V, De Luca L. A Jr. Idazoxan and the effect ofintracerebroventricular oxytocin or vasopressin on sodium intake of sodium-depletedrats. Regul Pept. 1997;69:137–42. [PubMed: 9226397]

Schulkin J, Marini J, Epstein A. N. A role for the medial region of the amygdala inmineralocorticoid-induced salt hunger. Behav Neurosci. 1989;103:178–85. [PubMed:2923671]

Simpson J. B, Epstein A. N, Camargo J. S Jr. Localization of receptors for the dipsogenicaction of angiotensin II in the subfornical organ of rat. J Comp Physiol Psychol.

1978;92:581–601. [PubMed: 211148]Sladek C. D, Johnson A. K. Effect of anteroventral third ventricle lesions on vasopressin

release by organ-cultured hypothalamo-neurohypophyseal explants.Neuroendocrinology. 1983;37:78–84. [PubMed: 6888661]

Sladek C. D, Somponpun S. J. Estrogen receptors: Their roles in regulation of vasopressinrelease for maintenance of fluid and electrolyte homeostasis. Front Neuroendocrinol.2008;29:114–27. [PMC free article: PMC2274006] [PubMed: 18022678]

Sofroniew M. V. Direct reciprocal connections between the bed nucleus of the striaterminalis and dorsomedial medulla oblongata: Evidence from immunohistochemicaldetection of tracer proteins. J Comp Neurol. 1983;213:399–405. [PubMed: 6833532]

Somponpun S. J, Sladek C. D. Osmotic regulation of estrogen receptor-β in rat vasopressinand oxytocin neurons. J Neuroscience. 2003;23:4261–9. [PubMed: 12764114]

Somponpun S. J, Sladek C. D. Depletion of oestrogen receptor-β expression inmagnocellular arginine vasopressin neurones by hypovolaemia and dehydration. JNeuroendocrinol. 2004;16:544–9. [PubMed: 15189329]

Stricker E. M, Verbalis J. G. Interaction of osmotic and volume stimuli in regulation ofneurohypophyseal secretion in rats. Am J Physiol Regul Integr Comp Physiol.1986;250:R267–75. [PubMed: 3946641]

Stricker E. M, Verbalis J. G. Central inhibitory control of sodium appetite in rats:Correlation with pituitary oxytocin secretion. Behav Neurosci. 1987;101:560–7.[PubMed: 2820437]

Stricker E. M, Verbalis J. G. Central inhibition of salt appetite by Oxytocin in rats. RegulPept. 1996;66:83–85. [PubMed: 8899898]

Stricker E. M, Bushey M. A, Hoffmann M. L, McGhee M, Cason A. M, Smith J. C.Inhibition of NaCl appetite when DOCA-treated rats drink saline. Am J Physiol RegulIntegr Comp Physiol. 2007;292:R652–62. [PubMed: 16990496]

Stricker E. M, Craver C. F, Curtis K. S, Peacock-Kinzing K. A, Sved A. F, Smith J. C.Osmoregulation in water-deprived rats drinking hypertonic saline: Effects of areapostrema lesions. Am J Physiol Regul Integr Comp Physiol. 2001;280:R831–42.[PubMed: 11171664]

Suemori K, Kobashi M, Adachi A. Effects of gastric distension and electrical stimulation ofdorsomedial medulla on neurons in parabrachial nucleus of rats. J Auton Nerv Syst.1994;48:221–9. [PubMed: 7963257]

Szpirer C, Riviere M, Szpirer J. et al. Chromosomal assignment of human and rathypertension candidate genes: Type 1 angiotensin II receptor genes and the SA gene. JHypertens. 1993;11:919–25. [PubMed: 8254174]

Tanaka J, Kariya K, Miyakubo H, Sakamaki K, Nomura M. Attenuated drinking responseinduced by angiotensinergic activation of subfornical organ projections to theparaventricular nucleus in estrogen-treated rats. Neurosci Lett. 2002;324:242–6.[PubMed: 12009532]

Tanaka J, Okumura T, Sakamaki K, Miyakubo H. Activation of serotonergic pathways fromthe midbrain raphe system to the subfornical organ by hemorrhage in the rat. ExpNeurol. 2001;169:156–62. [PubMed: 11312568]

Tanaka J, Hayashi Y, Yamato K, Miyakubo H, Nomura M. Involvement of serotonergicsystems in the lateral parabrachial nucleus in sodium and water intake: A microdialysisstudy in the rat. Neurosci Lett. 2004;357:41–44. [PubMed: 15036609]

Tanaka J, Miyakubo H, Fujisawa S, Nomura M. Reduced dipsogenic response induced byangiotensin II activation of subfornical organ projections to the median preoptic nucleusin estrogen-treated rats. Exp Neurology. 2003a;197:83–9. [PubMed: 12504870]

Tanaka J, Kariya K, Nomura M. Angiotensin II reduces serotonin release in the ratsubfornical organ area. Peptides. 2003b;24:881–7. [PubMed: 12948840]

Tanaka J, Ushigome A, Hori K, Nomura M. Responses of raphe nucleus projectingsubfornical organ neurons to angiotensin II in rats. Brain Res Bull. 1998;45:315–8.[PubMed: 9510425]

Thornton S. N, Nicolaidis S. Long term mineralocorticoid-induced changes in rat neuronproperties plus interaction of aldosterone and AII. Am J Physiol Regul Integr CompPhysiol. 1994;266:R564–71. [PubMed: 8141416]

Tordoff M. G, Fluharty S. J, Schulkin J. Physiological consequences of NaCl ingestion byNa depleted rats. Am J Physiol Regul Integr Comp Physiol. 1991;261:R289–95.[PubMed: 1877687]

Tordoff M. G, Schulkin J, Friedman M. I. Hepatic contribution to satiation of salt appetitein rats. Am J Physiol Regul Integr Comp Physiol. 1986;251:R1095–1102. [PubMed:3789195]

Van Giersbergen P. L. M, Palkovits M, De Jong W. Involvement of neurotransmitters in thenucleus tractus solitarii in cardiovascular regulation. Physiol Rev. 1992;72:789–824.[PubMed: 1352638]

Veinante P, Freund-Mercier M. J. Intrinsic and extrinsic connections of the rat centralextended amygdala: An in vivo electrophysiological study of the central amygdaloidnucleus. Brain Res. 1998;794:188–98. [PubMed: 9622626]

Vivas L, Chiaraviglio E, Carrer H. F. Rat organum vasculosum laminae terminalis in vitro:Responses to changes in sodium concentration. Brain Res. 1990;519:294–300.[PubMed: 2397412]

Vivas L, Pastuskovas C. V, Tonelli L. Sodium depletion induces Fos immunoreactivity incircumventricular organs of the lamina terminalis. Brain Res. 1995;679:34–41.[PubMed: 7648263]

Watanabe E, Fujikawa A, Matsunaga H. et al. Nax2/NaG channel is involved in control ofsalt intake behavior in the central nervous system. J Neurosci. 2000;20:7743–51.[PubMed: 11027237]

Wei S. G, Yu Y, Zhang Z. H, Felder R. B. Angiotensin II upregulates hypothalamic AT1receptor expression in rats via the mitogen-activated protein kinase pathway. Am JPhysiol Heart Circ Physiol. 2009;296:H1425–33. [PMC free article: PMC2685358][PubMed: 19286949]

Zardetto-Smith A. M, Beltz T. G, Johnson A. K. Role of the central nucleus of the amygdalaand bed nucleus of the stria terminalis in the experimentally-induced salt appetite. BrainRes. 1994;645:123–34. [PubMed: 8062074]

Zavala L, Barbella Y, Y , Israel A. J. Neurohumoral mechanism in the natriuretic action ofintracerebroventricular administration of renin. J Renin Angiotensin Aldosterone Syst.2004;5:39–44. [PubMed: 15136973]

Zhang D. M, Epstein A. N, Shulkin J. Medial region of the amygdala: Involvement inadrenal-steroid-induced salt appetite. Brain Res. 1993;600:20–6. [PubMed: 8422586]

© 2014 by Taylor & Francis Group, LLC.

+

Bookshelf ID: NBK200961 PMID: 24829993