10.1. INTRODUCTION

Body fluid homeostasis is maintained by a steady-state interchange of water between extracellular fluid (ECF) and intracellular fluid compartments. The main source of body water in terrestrial vertebrates is from drinking and, once in the body, it is distributed between body fluid compartments. The mechanisms that keep the body fluid osmolarity within its narrow range (280–300 mOsm/L) depend on matching the water volume excreted by the kidneys and the fluid intake volume. Sodium is the main electrolyte in ECF and sodium loss or gain is usually accompanied by an increase or decrease in water in this compartment in order to maintain sodium concentration. Body sodium and fluid balance is achieved through mechanisms that control sodium intake and sodium urinary excretion. The relationship between water and sodium in ECF may change both the osmolarity and volume of this compartment. Whereas the osmolarity of ECF is regulated by water intake and renal water excretion, the volume is controlled by the sodium content in the ECF, which is determined by the amount of sodium intake and the amount of sodium excreted in the urine (Verbalis 2003).

Changes in the water and sodium content of ECF may result in severe consequences to the cardiovascular system. Furthermore, some pathological cardiovascular conditions may lead to changes in body fluid homeostasis. Increased sodium levels in ECF increase the effective circulating volume, leading to an enhancement in cardiac output and blood pressure (BP). On the other hand, heart failure may decrease water and sodium urinary excretion, promoting a fluid disorder in the body. Therefore, it is unsurprising to find overlapping mechanisms controlling cardiovascular function and body fluid homeostasis.

Multiple sensory signals that trigger thirst and sodium appetite in response to dehydration are basically produced by hyperosmolarity and/or hypovolemia of the ECF (Fitzsimons 1998; Johnson 2007; McKinley and Johnson 2004; Stricker and Sved 2000; Chapters 2, 3, 4, and 9 of this book). Such sensory information reaches the brain to facilitate or inhibit responses that correct changes in body fluid–mineral balance and control cardiovascular function, thus activating a neural network of noradrenergic, cholinergic, angiotensinergic, GABAergic, vasopressinergic, oxytocinergic, and serotonergic pathways (Johnson 2007).

10.2. OVERVIEW OF BRAIN SEROTONERGIC SYSTEM

Serotonin [5-hydroxytryptamine (5-HT)] is among the most ancient signaling molecules in the phylogenetic scale and has been identified in the central nervous system (CNS) of invertebrates since Coelenterata (Hydra), Platyhelminthes (flatworm, Bipalium sp.), Annelida (Pheretima Communissima), Arthropoda (sea louse, crayfish, crab and cricket), Mollusca and Echinodermata, and Protochordata (Fujii and Takeda 1988). The first identification of 5-HT in the CNS of mammals was made by Twarog and Page (1953), findings considered an important landmark in neuroscience. In vertebrates, especially in humans and rats, different effects of serotonin on the CNS have been observed, controlling, for example, sleep–wake cycle, appetite, nociception, stress, sexual behavior, blood coagulation, blood pressure, and hydroelectrolytic balance (Peroutka 1994). Changes in serotonin metabolism are associated with several disorders, including obsessive–compulsive disorder, panic disorder, depression, anxiety, eating disorders, social phobia, drug abuse and addiction, migraine, hypertension, pulmonary hypertension, emesis, and irritable bowel syndrome (Hoyer et al. 2002; Saxena 1995).

Serotonin-containing neurons in the dorsal raphe nucleus (DRN), median raphe nucleus (MRN), and raphe centralis superior (B7–B9 groups) provide extensive serotonergic innervations to telencephalon and diencephalon, whereas the intermediate and posterior groups (B1–B6 groups) send local projections at the pons, and descendent projections to the mesencephalon, medulla and spinal cord (Jacobs and Azmitia 1992; Molliver 1987).

Serotonin receptors are found in platelets, lungs, heart, gastrointestinal tract, and vascular endothelium, and are widespread throughout the peripheral and central nervous systems. They are grouped into seven distinct families (5-HT₁ to 5-HT₇), including 15 structurally and pharmacologically distinct subtypes (Barnes and Sharp 1999; Green 2006; Hoyer et al. 1994, 2002). Most of the serotonin receptors act through G-protein coupling, with the exception of the 5-HT₃ receptor, which is a ligand-gated ion channel (Barnes and Sharp 1999). The G-protein–coupled receptors induce changes in the intracellular levels of cAMP, with the exception of the 5-HT₂ receptor family, which modulates C-phospholipase function (Hoyer et al. 2002). It is noteworthy that the high expression of serotonin receptors in brain areas is related to hydroelectrolytic balance and cardiovascular control (Saxena 1995).

The 5-HT₁ serotonin receptor family is composed of five different subtypes negatively coupled to adenylate cyclase via G-protein: 5-HT_1A, 5-HT_1B, 5-HT_1D, 5-HT_1E, and 5-HT_1F (Hoyer et al. 2002; Barnes and Sharp 1999; Saxena 1995). These receptors are found in various regions of the CNS, including the septum, amygdala (AMY), hippocampus, basal ganglia, thalamus, frontal cortex, raphe nuclei, and hypothalamus (Barnes and Sharp 1999; Bruinvels et al. 1994; Hoyer et al. 2002; Lanfumey and Hamon 2004; Pazos and Palacios 1985). The receptor subtypes 5-HT_1A, 5-HT_1B and 5-HT_1D may act either as autoreceptors, reducing the synthesis and release of serotonin, or as heteroreceptors, controlling the release of other neurotransmitters such as glutamate, gamma-aminobutyric acid (GABA), acetylcholine (ACh), dopamine (DA), and norepinephrine (NOR) (Barnes and Sharp 1999; Bockaert and Pin 1998; Hoyer et al. 2002; Pauwels 1997).

The family of 5-HT₂ receptors is composed of three different subtypes—5-HT_2A, 5-HT_2B, and 5-HT_2C—positively coupled to C-phospholipase and A2-phospholipase that change intracellular calcium levels (Barnes and Sharp 1999; Bockaert and Pin 1998; Hoyer et al. 2002; Saxena 1995; Van Oekelen et al. 2003). The 5-HT_2A and 5-HT_2C receptors subtypes are found in several brain areas such as the cortex, hippocampus, hypothalamus, nucleus accumbens (NAc), cerebellum, AMY, basal ganglia, and thalamus (Barnes and Sharp 1999; Hoyer et al. 2002; Leysen 2004; Van de Kar et al. 2001; Van Oekelen et al. 2003), whereas the 5-HT_2B receptors are found in the medial amygdala (MeA), the cerebellum, the septum, and the lateral hypothalamus (Hoyer et al. 2002; Duxon et al. 1997). In addition, there is a strong expression of 5-HT_2C receptor subtypes in the choroid plexus (Barnes and Sharp 1999; Hoyer et al. 2002; Leysen 2004; Van de Kar et al. 2001; Van Oekelen et al. 2003). Some studies have shown that activation of these receptors in the brain can interfere with the control of food intake (Foster-Schubert and Cummings 2006; Nonogaki et al. 2006), locomotion (Landry and Guertin 2004), anxiety (De Mello Cruz et al. 2005; Hackler et al. 2006; Wood 2003) and hormone secretion of ACTH, corticosterone, oxytocin (OT), renin, and prolactin (Bagdy et al. 1992; Van de Kar et al. 2001).

Unlike other serotonin receptors, 5-HT₃ receptors belong to the superfamily of ligand-gated ion channels (Barnes and Sharp 1999; Boess and Martin 1994; Faerber et al. 2007; Gaster and King 1997; Hoyer et al. 2002; Joshi et al. 2006; Melis et al. 2006; Saxena 1995). The 5-HT₃ receptor is a pentameric protein, and the five subunits have been cloned and classified from A to E (Hayrapetyan et al. 2005; Joshi et al. 2006; Maricq et al. 1991; Melis et al. 2006; Reeves and Lummis 2006), although only the subunits A and B appear to be present in functional 5-HT₃ receptors, constituting 5HT₃ receptors homo-pentamers 5-HT_3A subunit [i.e., (5HT_3A)] and heteromers 5-HT_3A and 5-HT_3B subunit [i.e., 5-HT_3AB] (Maricq et al. 1991; Niesler et al. 2003). Activation of 5-HT₃ receptors leads to rapid depolarization by opening nonspecific cation channels allowing the entry of Na⁺ and Ca²⁺ and the output of K⁺ (Hoyer et al. 2002). These receptors are found in various regions of the CNS such as hippocampus, nucleus of the solitary tract (NTS), area postrema (AP), AMY, nucleus of the vagus dorsomotor, and cerebral cortex; all the same their physiological role remains elusive (Barnes and Sharp 1999; Hoyer et al. 2002; Morales et al. 1998).

The 5-HT₄ receptors are coupled to G-protein and positively coupled to adenylate cyclase increasing the intracellular levels of cAMP (Saxena 1995; Uphouse 1997; Barnes and Sharp 1999; Hoyer et al. 2002). Currently, 10 isoforms (A to J) of the 5-HT₄ receptor have been identified in three different species: rats, guinea pigs, and monkeys (Alex and Pehek 2007; Vilaró et al. 2005). In the CNS, these receptors are distributed heterogeneously with the highest expression being in the limbic and nigrostriatal areas (Alex and Pehek 2007; Patel et al. 1995; Vilaró et al. 2005; Waeber et al. 1996). The information about the physiological responses induced through activation of the central 5-HT₄ receptor are still scarce; however, it seems that these receptors may modulate the release of various neurotransmitters such as ACh, DA, GABA, and serotonin (Barnes and Sharp 1999; Hoyer et al. 2002).

The family of 5-HT₅ receptors is composed of two putative subtypes, referred to as 5-HT_5a and 5-HT_5b (Hoyer et al. 2002; Nelson 2004; Wesolowska 2002), which are G-protein–coupled (Carson et al. 1996; Hoyer et al. 2002; Nelson 2004; Wesolowska 2002). These receptors are found in the hippocampus, hypothalamus, AMY, striatum, thalamus, cerebellum and cortex, habenula, and DRN (Hoyer et al. 2002; Matthes et al. 1993; Oliver et al. 2000; Pasqualetti et al. 1998; Wesolowska 2002). The physiological function and the pharmacological characteristics of 5-HT₅ receptors remain to be clarified.

The 5-HT₆ receptor is coupled to the G-protein and positively coupled to adenylate cyclase, increasing the intracellular cAMP levels (Barnes and Sharp 1999; Hoyer et al. 2002; Mitchell and Neumaier 2005; Wesolowska 2002). These receptors are highly expressed in areas such as the striatum, NAc, olfactory tubercle, and cortex, and moderately expressed in the AMY, hypothalamus, thalamus, cerebellum, and hippocampus (Hoyer et al. 2002; Mitchell and Neumaier 2005; Wesolowska 2002). Some studies have shown that the blockade of 5-HT₆ receptors may modulate the release of other neurotransmitters such as DA, ACh, NOR, GABA, and glutamate (Mitchell and Neumaier 2005).

The 5-HT₇ receptor family is the most recently identified. These receptors are also positively coupled to G-protein and increase intracellular cAMP levels. The density of these receptors is high in the hypothalamus, thalamus, AMY, hippocampus, cortex, and DRN (Hoyer et al. 2002; Thomas and Hagan 2004; Wesolowska 2002). Four different isoforms of the 5-HT₇ receptor are expressed in rodents and humans. However, up to the present, these isoforms do not seem to differ in their pharmacological profile, signal transduction, or distribution. The 5-HT₇ receptors appear to play a physiological role in thermoregulation and circadian rhythm (Glass et al. 2003; Guscott et al. 2003). In addition, these receptors are present in glutamatergic neurons at the raphe nuclei, suggesting that they modulate the activity of serotonergic neurons (Harsing et al. 2004).

Although there are a large number of drugs for different subtypes of serotonin receptors, there is still much controversy regarding the selectivity of the agonists and antagonists so far described. The lack of strict selectivity of serotonergic agents has hampered a clear definition of the physiological role of many serotonin receptor subtypes. However, these pharmacological tools have contributed to identify the functional role of central serotonin in the CNS. Table 10.1 summarizes the data on serotonergic agonists and antagonists that have been used to investigate the participation of serotonin receptors in the control of thirst, salt appetite, and blood pressure.

TABLE 10.1

Pharmacological Data about the Agonists and Antagonists Serotonergic Presented in this Review Summarizing the Effects of Central Injections of Each Serotonergic Agent on Water Intake, Salt Intake and Blood Pressure

10.3. SEROTONIN AND FLUID INTAKE

10.4. SEROTONIN AND BLOOD PRESSURE

Blood volume, cardiac output, arterial resistance, and blood pressure (BP) adapt to different metabolic situations ensuring adequate blood flow for microcirculation. An important factor controlling effective circulating volume is the amount of sodium in the ECF. Changes in blood volume may result in alterations in BP and tissue perfusion. Thus, central integrated mechanisms to control water and sodium intake and BP are essential for life (Stachenfeld 2008; Stricker and Sved 2000). Indeed, an overlapping brain network controlling water and sodium intake and blood pressure has been shown (Dampney et al. 2002; De Gobbi et al. 2008). Among the brain neurotransmitters, serotonin has been implicated in the control of all these parameters. In this section, we review the role of the different types of serotonin receptors in the control of cardiovascular function and present a summary of the results produced in our laboratory on this subject.

In the periphery, serotonin affects cardiovascular system targeting the heart and blood vessels. The effects of the systemic administration of serotonin on the cardiovascular system are mediated mainly by five serotonin receptors: 5-HT₁, 5-HT₂, 5-HT₃, 5-HT₄, and 5-HT₇ (De Vries et al. 1996; Martin 1994; Saxena 1995; Saxena and Villalón 1991; Villalón et al. 1996, 1997a). Usually, an intravenous injection of serotonin induces a triphasic response characterized by initial hypotension followed by an increase in BP and then a stable hypotension (Côté et al. 2004; Villalón et al. 1997b). The initial hypotension is induced by a bradycardic reflex (von Bezold-Jarisch reflex) mediated by activation of 5-HT₃ receptors present at afferent cardiac nerve endings of the vagus (Yusuf et al. 2003). The pressor phase seems to be a result of the vasoconstriction induced by activation of 5-HT₂ receptors in blood vessels and of the positive ionotropic and chronotropic effects mediated by 5-HT₄ receptor activation in cardiac myocytes (Côté et al. 2004). The final hypotensive phase may involve the activation of different serotonin receptors at both central and peripheral level (Villalón et al. 1997b). The increase in BP obtained by intravenous administration of serotonin may be dependent on the integrity of circumventricular organs such as the SFO and the OVLT. In fact, a lesion in the anteroventral region of the third ventricle attenuates the hypertensive response induced by peripheral administration of serotonin (Muntzel et al. 1996).

Brain administration of serotonin and its analogs produces variegated responses: bradycardia or tachycardia, hypotension or hypertension, and vasodilatation or vasoconstriction (Kuhn et al. 1980). The effect of central serotonin stimulation on the cardiovascular system is mediated mainly by 5-HT₁, 5-HT₂, and 5-HT₃ receptors (Ramage and Villalón 2008).

Some contradictory findings have been published in the literature concerning the effect of 5-HT_1A receptors on cardiovascular control. Stimulation of brain 5-HT_1A receptor produces hypotension and bradycardia in normotensive and spontaneously hypertensive rats (Buisson-Defferier and Van de Buuse 1992; Dabiré et al. 1987). The hypotension and bradycardia induced by central activation of 5-HT_1A receptor may be the result of either the stimulation of heteroreceptors in the rostral–ventrolateral medulla (RVLM) (Clement and McCall 1990; Valenta and Singer 1990) or autoreceptors in the DRN (Connor and Higgins 1990). Additionally, the hypotension and bradycardia may be mediated by a decrease in sympathetic activity (Fozard et al. 1987; Gradin et al. 1985) and an increase in vagal tone to the heart (McCall and Clement 1994; McCall et al. 1987). Depending on the brain area, the stimulation 5-HT_1A receptors may trigger different sympathetic responses. Indeed, injections of the agonist 8-OH-DPAT into raphe magnus and pallidus, dorsal raphe, and rostral ventrolateral medulla inhibit sympathetic activity and decrease blood pressure (McCall and Clement 1994), whereas injections into the raphe obscurus (Dreteler et al. 1991) and preoptic area (Szabo et al. 1998) promote an increase in sympathetic activity and blood pressure.

The importance of 5-HT_1A receptors in the control of cardiac function has been reevaluated. Some of the cardiovascular effects attributed to the stimulation of 5-HT_1A receptors may be attributable to the activation of other serotonergic receptors such as the 5-HT₇ receptors (Barnes and Sharp 1999; McCall and Clement 1994). The main agonist of 5-HT_1A receptors available, 8-OH-DPAT, may also interact with other receptors such as the 5-HT_1B/1D, 5-HT_2A/B/C, and 5-HT₇ serotonergic receptors (Hoyer et al. 1994; Knight et al. 2004; Krobert et al. 2001). The use of more selective procedures targeting serotonin receptors, such as drugs and genomic interventions, will help to clarify the role of 5-HT₁ receptors in cardiovascular function. The peripheral activation of 5-HT₂ receptors promotes generalized sympathoexcitation and a rise in blood pressure. Some results in the literature suggest that this may be attributable to an increase in total peripheral resistance, because stimulation of the 5-HT₂ receptors, located in the vascular endothelial cells, promotes arterial vasoconstriction (Chandra and Chandra 1993; Dabiré et al. 1990; Meller et al. 1992). Furthermore, peripheral activation of the 5-HT₂ receptors has been shown to induce positive chrono- and inotropic effects and to inhibit ANP secretion leading to an increase in cardiac output and blood volume that may also contribute to the increase in BP (Cao et al. 2003; Laer et al. 1998; Mertens et al. 1993).

The definition of 5-HT₂ receptors actions at the brain on cardiovascular control is difficult, because the data obtained in experiments using cats and rats are contradictory. In rats, 5-HT₂ receptor activation causes sympathetic inhibition, whereas in cats it enhances sympathetic activity (Anderson et al. 1992, 1995). Also, central 5-HT₂ receptor activation in rats, but not in cats, increases circulating vasopressin (AVP) levels (Brownfield et al. 1988; Montes and Johnson 1990; Steardo and Iovino 1986). In view of the fact that AVP enhances baroreflex sensitivity (Koshimizu et al. 2006; Oikawa et al. 2007), it seems that the initial conclusions of sympathoinhibition based on Anderson’s experiments in rats are precipitated. In fact, the 5-HT₂ receptors activation induces sympathoexcitation, which is masked by the concomitant AVP release and its consequent baroreflex-mediated sympathoinhibition.

The cardiovascular effects induced by central injection of 5-HT₂ receptor agonists have been attributed to the 5-HT_2A receptor subtype (Ramage 2001). However, it is not unexpected that many of the cardiovascular effects originally ascribed to 5-HT_2A receptors could be due to activation of the 5-HT_2C or 5-HT_2B receptors, because the 5-HT₂ receptor subtypes are to a great extent homologous, with pharmacological similarities (Giorgetti and Tecott 2004). Of the 5-HT₂ receptor agonists, DOI and mCPP have been frequently used in both experimental and clinical studies to investigate the functional role of 5-HT_2A and 5-HT_2C receptors, although they are not selective.

The 5-HT_2C receptors in the brain are widely distributed throughout the CNS (Clement et al. 2000), and activation of 5-HT₂ receptors located in prosencephalic areas is associated with a sympathoexcitatory and hypertensive response, whereas the opposite effect is seen after activation of the 5-HT₂ receptors located in the hindbrain. Third ventricle injections of 5-HT_2C receptor agonist, mCPP in rats produces an increase BP attenuated by the antagonist SDZ-SER 082. Also, third ventricle injections of SDZ-SER 082 significantly blunted stress-induced hypertension without modifying the increase in HR induced by the stress (Ferreira et al. 2005). Because the administration of the SDZ-SER 082 alone in nonstressed rats failed to induce any significant change in BP, it is worthwhile to suggest that 5-HT_2C receptors appear not to exert endogenous, tonic, modulatory role in the control of blood pressure, under nonstress conditions. On the other hand, under stress conditions, the activation of 5-HT_2C receptors became relevant to cardiovascular coping-stress response.

The increase in BP produced by mCPP was sustained for several minutes and accompanied by an initial sharp decrease followed by a sustained increase in HR (Ferreira et al. 2005). This probably means that the initial phase of mCPP-induced hypertensive response triggers baroreflex-mediated bradycardia. On the other hand, the coexistence of hypertension and tachycardia in the subsequent phase indicates a hypertensive, sympathoexcitatory drive, in which baroreflex inhibition of HR is suppressed. It is possible that such drive overcomes the baroreflex-mediated sympathoinhibition associated with AVP, which is also released in response to third ventricular injection of mCPP (Jorgensen et al. 2003; Knowles and Ramage 2000; McCall and Clement 1994).

Third ventricle injections of the selective 5-HT₃ receptor agonist, m-CPBG, in rats cause a significant decrease in BP without any change in HR. The opposed effects are observed with 5-HT₃ receptor blockade by third ventricle injections of the selective 5-HT₃ receptor antagonist, ondansetron. These data seem to indicate that the stimulation of brain 5-HT₃ receptors induces a fall in BP through a decrease in sympathetic activity. Indeed, central activation of the 5-HT₃ receptor inhibits the baroreflex-mediated tachycardia; conversely, baroreflex-mediated bradycardia is maintained, indicating normal parasympathetic activity in these animals. These data suggest that central serotonin acting on 5-HT₃ receptors promotes a tonic inhibitory drive on blood pressure.

The pharmacological activation of central 5-HT₃ receptors by m-CPBG was able to impair stress-induced hypertensive response and inhibit tachycardic response in a dose-dependent manner (Ferreira et al. 2004). This allows us to conclude that central 5-HT₃ receptor activation may efficiently exert an inhibitory drive on acute stress-induced changes in cardiovascular function. On the other hand, in stressed animals receiving a third ventricle injection of ondansetron, there was an increase in BP that was not significantly different from that found in saline-treated, stressed controls (Ferreira et al. 2004). This may mean that the endogenous inhibitory drive in blood pressure regulation exerted by serotonin via central 5-HT₃ receptors as observed in nonstressed rats is somehow suppressed during stress. Alternatively, during stress, the sum of the many integrated hypertensive drives exerted by different neurochemical components largely exceeds the 5-HT₃ receptor–dependent inhibitory effect on blood pressure. A similar inhibitory effect on hypertensive response to stress is observed after injection of m-CPBG into the medial septum/vertical limb of diagonal band (MS/vDB), but it failed to cause any significant change in resting blood pressure (Urzedo-Rodrigues et al. 2011). This suggests that, in this particular region, 5-HT₃ receptors generating a tonic inhibitory drive on blood pressure are already fully activated. Therefore, the inhibitory 5-HT₃ receptor–dependent drive exerted by the serotonergic pathways located in the MS/vDB plays a crucial role in maintaining blood pressure within its physiological range (Urzedo-Rodrigues et al. 2011). Typical behavior referred to as a defense reaction is triggered by different stressful conditions and the dorsomedial nucleus of the hypothalamus and the dorsal part of the periaqueductal gray appear to be the key sites in the brain involved in this response (for reviews, see Depaulis et al. 1994; DiMicco et al. 2002). 5-HT₃ receptors located at the NTS are essential for the bradycardic reflex observed during the defense reaction (Comet et al. 2004, 2005; Sévoz-Couche et al. 2003).

It appears that an increase in the sympathetic drive may explain the rise in blood pressure observed after blockade of the 5-HT₃ receptors in the MS/vDB by ondansetron. Indeed, administration of prazosin, an alpha1-adrenoceptor blocker, reverses the hypertensive response induced by the injection of ondansetron into the MS/vDB. An additional mechanism by which the blockade of 5-HT₃ receptors located in the MS/vDB induces a hypertensive response may be related to the increase in brain angiotensinergic activity. Injection of losartan, an AT1 receptor antagonist, into the MS/vDB blunted the previously detected hypertensive response induced by ondansetron (Urzedo-Rodrigues et al. 2011). Taken together, these data suggest that 5-HT₃ receptors at this brain level exert a tonic inhibition of local release of AII and sympathoinhibition.

The hypotension induced by central 5-HT₃ receptor activation may result from an interaction with different brain neurotransmitter pathways such as GABAergic, glutamatergic, and opiatergic (Chameau and Van Hooft 2006; Chu et al. 2009). Lateral ventricle injection of mu, kappa, or delta opioid receptor antagonists impairs the hypotensive response to central 5-HT₃ receptor stimulation (Fregoneze et al. 2011). These opioid receptors have been identified in the cell body, as well as in axon terminals and at synaptic terminals. Their activation may change the spike duration controlling Ca²⁺ influx, thus inhibiting neurotransmitter release (Chandra and Chandra 1993; Schoffelmeer et al. 1992a,b). It is possible that the release of opioid peptides induced by 5-HT₃ receptor activation inhibits neurotransmitter release that controls sympathetic tonus and normal blood pressure. However, the intrinsic cellular mechanism by which 5-HT₃ and opioid receptors interact remains to be established.

Another serotonergic receptor that has more recently been studied in cardiovascular function is the 5-HT₇ receptor. However, there is no selective 5-HT₇ receptor agonist available and the antagonist (SB269970) that has been used also binds to the 5-HT_5A receptors, alpha-adrenergic receptors, and dopaminergic receptors (Foong and Bornstein 2009; Lovell et al. 2000). The exact physiological role of the 5-HT₇ receptor remains to be clarified. It has been observed that central administration of SB269970 blocks the bradycardic reflex induced by baroreceptor, cardiopulmonary, and chemoreceptor stimulation (Damaso et al. 2007; Kellett et al. 2005). 5-HT₇ receptors may also exert a functional effect on sleep and thermoregulation (Hedlund and Sutcliffe 2004; Hedlund et al. 2003), as well as on antidepressant-like activity in the forced swim test (Guscott et al. 2003; Hedlund et al. 2005). Acute restraint stress up-regulates 5-HT₇ receptor messenger RNA in the rat hippocampus (Yau et al. 2001). In addition, a possible role of 5-HT₇ receptors at the NTS in cardiovascular control during stressful conditions has been suggested, because injection of SB269970 into the cisterna magna increased BP without altering HR (Ramage and Villalón 2008).

10.5. CONCLUDING REMARKS

Several studies have shown that central serotonergic pathways are important for the maintenance of hydroelectrolytic balance and cardiovascular function. The functional role of serotonin in these parameters seems to be dependent on the brain area stimulated and subtype of receptor activated. Furthermore, the physiological responses induced by serotonin may involve interaction with different neurotransmitters. Although many studies have been conducted in an attempt to clarify the role of serotonin and its receptors in cardiovascular function and hydroelectrolytic balance, several questions remain to be answered. The main problem concerns the lack of appropriate pharmacological tools for each subtypes of serotonin receptor and the use of different experimental protocols that make it very difficult to draw a clear picture of the role of serotonin receptors in the different brain areas on salt appetite, drinking behavior, and cardiovascular control. Although there are several limitations in the techniques used so far, important results have been obtained with serotonergic drugs selective for different receptors on the cardiovascular function and hydroelectrolytic balance.

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