Neuroscience and Biobehavioral Reviews 33 (2009) 95–106

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Neuroscience and Biobehavioral Reviews

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Review

Central 5-HT receptors in cardiovascular control during stress

Eugene Nalivaiko a,*, Andrea Sgoifo b

a Department of Human Physiology, Centre for Neuroscience, Flinders University, Adelaide, Australiab Stress Physiology Laboratory, Department of Evolutionary and Functional Biology, University of Parma, Parma, Italy

A R T I C L E I N F O

Keywords:

Serotonin

Psychological stress

Sympathetic

Brainstem

Heart rate

Arterial pressure

5-HT1A

5-HT2A

5-HT3

A B S T R A C T

Our aim is to consolidate recent data on relationship between central serotonergic neurotransmission

and stress-elicited cardiovascular changes. Activation of central of 5-HT1A receptors attenuates

tachycardic and pressor changes elicited by a wide range of stressors (airjet, restraint, open field, fear

conditioning, social defeat), supporting the previous view of these receptors as ‘‘sympathoinhibitory’’.

Their likely location is the medullary raphe. It is still unknown whether 5-TH1A receptors are

sympathoinhibitory in physiological condition, as 5-HT1A antagonists do not affect basal or stress-

altered cardiovascular parameters. In contrast to the established view that central 5-HT2A receptors are

‘‘sympathoexcitatory’’, experiments with new selective antagonists indicate that these receptors do not

mediate stress-induced pressor and tachycardic responses, and are not involved in cardiovascular control

at rest. The exception is control of cutaneous vascular bed, both at rest and during stress, likely at the

spinal level. 5-HT3 receptors located in the nucleus tractus silitarius (NTS) contribute to stress-induced

suppression of the baroreflex. 5-HT3 receptors located in sympathetic ganglia possibly contribute to the

development of sustained hypertension in chronically stressed rats.

� 2008 Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96

2. 5-HT1A receptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96

2.1. Activation of 5-HT1A receptors attenuates stress-induced tachycardic and pressor responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96

2.2. Anatomical location of sympatho-inhibitory 5-HT1A receptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96

2.3. Activation of 5-HT1A receptors inhibits stress-induced cutaneous vasoconstriction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97

2.4. Physiological role of sympatho-inhibitory 5-HT1A receptors is still unclear . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98

2.5. Clinical perspectives of new applications for 5-HT1A agonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99

3. 5-HT2A receptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100

3.1. Activation of 5-HT2A receptors reduces stress-induced thermogenic but not tachycardic or pressor responses . . . . . . . . . . . . . . . . 100

3.2. Stress-induced thermogenesis in the iBAT is mediated via 5-HT2A receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100

3.3. Anatomical location of 5-HT2A receptors responsible for cutaneous vasoconstriction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100

3.4. Cardiovascular effects of 5-HT2A receptor activation in humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101

3.5. 5-HT2C receptors: involvement in stress-elicited hypertension? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102

4. 5-HT3 receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102

4.1. Stress-induced suppression of the baroreflex: role of 5-HT3 receptors in the NTS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102

4.2. Stress-induced long-term potentiation in sympathetic ganglia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103

5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105

* Cor

E-m

0149-7

doi:10.1

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105

responding author at: School of Biomedical Sciences, University of Newcastle, Callaghan NSW 2308, Australia. Tel.: +61 2 4921 5620; fax: +61 2 4985 4200.

ail address: eugene.nalivaiko@newcastle.edu.au (E. Nalivaiko).

634/$ – see front matter � 2008 Elsevier Ltd. All rights reserved.

016/j.neubiorev.2008.05.026

E. Nalivaiko, A. Sgoifo / Neuroscience and Biobehavioral Reviews 33 (2009) 95–10696

1. Introduction

Serotonin (5-HT) has a wide spectrum of physiological,behavioural and cognitive actions. This is not surprising as theseactions are mediated via at least 14 different subtypes of 5-HTreceptors (Hoyer et al., 2002). Structure, anatomical location,pharmacology and cellular effects of these receptors are coveredin a comprehensive reviewed by Barnes and Sharp (1999). 5-HTwas initially characterized by Rapport et al. (1948) as a vasoactivesubstance, and since then, the knowledge about its cardiovasculareffects continuously expands. The plasma level of 5-HT is verylow, and its peripheral vascular effect occur when the substance isrelease from the platelets (e.g. during hemostasis). Severalexcellent reviews cover the issue of the neurally mediatedcardiovascular effects of 5-HT (Saxena and Villalon, 1990b;McCall and Clement, 1994; Ramage, 2001). The body of knowledgepresented in these reviews as well as in some more recent paperscould be summarised as the following: within the central nervoussystem, the two principal 5-HT receptor subtypes involved inmodulation of cardiac and vascular control are 5-HT1A and 5-HT2A receptors. Activation of central 5-HT1A receptors causessympatho-inhibitory effects (fall in the arterial pressure (AP) andthe heart rate (HR)), whereas activation of 5-HT2A receptorsprovokes sympatho-activatory actions (pressor, tachycardic, risein lumbar sympathetic, renal and cardiac nerve discharge). Thesephysiological effects are in good accord with cellular electro-physiological studies of these two receptor subtypes: activation of5-HT1A postsynaptic or autoreceptors evokes outward currents/hyperpolarization whereas activation of 2-HT2A receptors hasopposite effects (see Barnes and Sharp, 1999 for review). Fewstudies that have focussed on anatomical location of relevantreceptors point to medullary vasomotor and cardiomotor centers(rostral ventro-lateral medulla and/or medullary raphe) aspotential candidates.

Psychological stressor facilitate serotonergic neurotransmis-sion in the brain (Chaouloff et al., 1999). Meanwhile, most earlierinformation about cardiovascular effects of 5-HT receptoragonists and antagonist was collected either in anesthetizedstate or during quiet waking of experimental animals. It is onlyrecently that several research groups focussed on 5-HT receptor-mediated cardiovascular changes in stressed rats and rabbits,and it is our aim to summarise this work. The review isspecifically focussed on neurally induced effects, and isstructured as the following: in Section 2 we describe newfindings complementing previous knowledge about cardiovas-cular effects of 5-HT1A receptors. Section 3 summarises relevantstudies with relation to 5-HT2A receptors, and also containssome results related to the stress-induced thermogenesis.Section 4 deals with central 5-HT2C receptors, and Section 5covers the contribution of central 5-HT3 receptors in stress-elicited suppression of baroreflex and in stress-induced hyper-tension. Where possible, we provide available evidence about theanatomical location of receptors in question.

2. 5-HT1A receptors

2.1. Activation of 5-HT1A receptors attenuates stress-induced

tachycardic and pressor responses

In two recent studies conducted in conscious rabbits and rats,Nalivaiko and colleagues addressed two questions: whetheractivation of 5-HT1A receptors affect stress-induced cardiovas-cular changes, and if yes, what is the anatomical location of therelevant receptors. They found that systemic administration of 8-OH-DPAT (a selective 5-HT1A receptor antagonist) suppressed, in a

dose-dependent manner, tachycardic and pressor responses topsychological stressors—airjet stress in rabbits and restraint stressin rats (Nalivaiko et al., 2005; Ngampramuan et al., 2008) (Fig. 1A).Systemic administration of the drug could be mimicked by itsmicroinjection into the medullary raphe (see below), as shown inFig. 1B. Using peripheral autonomic blockade, the authorsdemonstrated that during stress, sustained sympathetic activationis associated with a transient vagal withdrawal, and thatsystemically administered 8-OH-DPAT reduces both these auto-nomic components (Fig. 1C and D).

These findings appeared in a very good accord with the work ofvan den Buuse and Wegener (2005) who examined effects ofseveral 5-HT1A receptor agonists (8-OH-DPAT, buspirone andMDL73,055) on basal AP and HR and on AP and HR changes elicitedby the open field test. The additional value of this laborious study isthat it was conducted in four different strains of rats—Wistar-Kyoto, spontaneously hypertensive rats, Fawn-Hooded and Spra-gue–Dawley. While there were some differences in drug actions ina single strain as well as between-strain differences, the generalconsensus was that activation of 5-HT1A receptors reducescardiovascular responses to the acute psychological stress.

More recently, Vianna and Carrive (2008) confirmed Nalivaiko’sobservation in restrained rats, and extended the study to theconditioned fear paradigm where systemically administered 8-OH-DPAT also substantially and significantly attenuated pressorand tachycardic responses. In this study and in the cited abovework from Nalivaiko’s laboratory (Nalivaiko et al., 2005; Ngam-pramuan et al., 2008), effects of the drug were clearly receptor-specific as they were suppressed by a selective 5-HT1A receptorantagonist WAY-100,635.

Thus, anti-tachycardic and/or anti-pressor effects of thesystemically administered 5-HT1A agonists during stress couldbe considered quite consistent as they were independentlyobserved by three different groups in two mammalian species,and in stress paradigms as diverse as airjet, restraint, novelty andconditioned fear. Furthermore, in our own studies that arecurrently in progress, we found that 8-OH-DPAT is also veryefficient in suppressing not only tachycardia but also cardiacarrhythmias in rats subjected to social defeat stress (unpublishedobservation). Consistently with pharmacological studies, stressfulstimuli (footshock and novel environment) produced largertachycardic responses in 5-HT1A receptor-knockout mice com-pared to the wild-type conspecifics (Gross et al., 2000; Pattij et al.,2002).

Systemic administration of 8-OH-DPAT also reduced stress-activated vagal withdrawal observed at the beginning of therestraint (Ngampramuan et al., 2008); see Fig. 1D. Potentialmechanisms underlying this effect are covered in the review byJordan (2005) and suggests activation (or more likely disinhibitionin our case) of cardiomotor vagal neurons. Indeed, localiontophoretic application of 8-OH-DPAT activated cardiac vagalneurons, and this effect was suppressed by WAY-100,635 (Wangand Ramage, 2001). As 5-HT1A receptors are inhibitory ones,Jordan (2005) suggested that they could be located on theinhibitory GABA-ergic interneurons in the nucleus ambiguus (N.Amb.). The source of serotonergic innervation of this nucleus ismedullary raphe (Haxhiu et al., 1993).

2.2. Anatomical location of sympatho-inhibitory 5-HT1A receptors

In order to reveal location of relevant 5-HT1A receptors, weperformed brain microinjections of 8-OH-DPAT in rats duringrestraint and in rabbits during airjet stress. The target for themicroinjections was the medullary raphe region as evidenceaccumulates that this could be a location of presympathetic

Fig. 1. Activation of 5-HT1A receptors with the selective agonist 8-OH-DPAT attenuates tachycardia elicited by restraint stress in rats. (A) Systemic pretreatment with 8-OH-

DPAT attenuates tachycardia in a dose-dependent manner. Graphs show mean group data (n = 7) for changes in HR in animals pretreated, on different days, with vehicle or 8-

OH-DPAT (10, 30, and 100 mg/kg s.c.). Arrowhead—drug injection; grey rectangle indicated duration of the restraint stress. (B) Microinjection of 8-OH-DPAT into raphe/

parapyramidal area mimics systemic effects of the drug. Graphs show mean group data (n = 8) for changes in HR in animals pretreated, on different days, with vehicle or 8-

OH-DPAT (1 nmol in 100 nl). The inset shows the injection site (drawing from the microphotograph). (C) Tachycardia during restraint is predominantly sympathetically

mediated, and this sympathetic component is suppressed by 8-OH-DPAT. Graphs show mean group data (n = 6) for changes in HR in animals pretreated, on different days,

with either methyl-scopolamine (1st drug) and Ringer (2nd drug) solution or methyl-scopolamine (1st drug) and 8-OH-DPAT (2nd drug) combination prior to restraint. (D)

The initial transient component of stress-induced tachycardia is due to the vagal withdrawal. The latter is attenuated by 8-OH-DPAT. Graphs show mean group data (n = 6) for

changes in HR in animals pretreated, on different days, with either atenolol (1st drug) and Ringer (2nd drug) solution or atenolol (1st drug) and 8-OH-DPAT (2nd drug)

combination prior to restraint. Modified from Ngampramuan et al. (2008), with permission.

E. Nalivaiko, A. Sgoifo / Neuroscience and Biobehavioral Reviews 33 (2009) 95–106 97

cardiomotor neurons, that these neurons are silent at rest butcould be activated during stresses (Samuels et al., 2002; Zaretskyet al., 2003), and that activation of the medullary 5-HT1A receptorsattenuates centrally induced tachycardia in anesthetized rats(Morrison, 2004). Administration of 8-OH-DPAT mimicked anti-tachycardic effects of systemically injected drug (Fig. 1B), support-ing the idea that cardiac presympathetics are indeed located in theraphe (Nalivaiko et al., 2005; Ngampramuan et al., 2008). Incontrast, intra-raphe microinjection of the drug did not prevent orreduce stress-induced rise in AP (Nalivaiko et al., 2005) suggestingthat the anti-pressor action of must be mediated by 5-HT1Areceptors with different anatomical location (possibly in the RVLMvasopressor region). Furthermore, intra-raphe 8-OH-DPAT alsoattenuated tachycardia elicited by immune stressor (iv LPS),suggesting that during both psychological and immune stresses,cardioacceleration is mediated by the same descending sympa-thetic pathway (Nalivaiko et al., 2005).

Many bulbospinal presympathetic neurons located in themedullary raphe are serotonergic. Like their midbrain counter-parts, medullary raphe neurons have inhibitory 5-HT1A auto-receptors on their perikarya and dendrites (Helke et al., 1997).Older literature suggests that activation of these receptors causeshypotension (Valenta and Singer, 1990; Nosjean and Guyenet,1991). Our microinjection studies in conscious rats and rabbitsclearly demonstrated that anti-tachycardic but not anti-pressoreffects of systemically administered 5-HT1A receptor agonistscould be mediated by activating corresponding receptors locatedin the presympathetic cardiomotor region in the medullary raphe.

In contrast, recent work from Dampney’s laboratory demonstratedthat systemic or intra-cisternally administered 8-OH-DPATreduces not only tachycardia but also rises in AP and in renalsympathetic activity elicited in anesthetized rats from thedorsomedial hypothalamus (a principal ‘‘defence area’’ thatmediates stress-induced cardiovascular alterations) (Horiuchiet al., 2005). Once again, the discrepancy is likely to be due to adifferent location in the brainstem of cardiomotor and vasomotorpresympathetic neurons expressing 5-HT1A receptors. Interest-ingly, activation of 5-HT1A receptors had no significant effect onchanges in sympathetic nerve activity evoked by chemoreceptor orbaroreceptor stimulation, suggesting that these receptors are notinvolved in neural circuits that mediate sympathetic reflexes(Horiuchi et al., 2005).

Obviously, described above systemic effects of 5-HT1A agonistscould be also mediated by receptors other then those located in themedullary raphe. 5-HT1A agonists are renowned for theiranxiolytic properties and are used in clinical practice for thispurpose (e.g. buspirone), and thus it is entirely possible thatreceptors located upstream from the lower brainstem (in corticalor subcortical areas) also contributed to the reduction ofcardiovascular responses to psychological stresses.

2.3. Activation of 5-HT1A receptors inhibits stress-induced cutaneous

vasoconstriction

In both experimental animals and in humans, psychologicalstressors increase body temperature. Temperature homeostasis

E. Nalivaiko, A. Sgoifo / Neuroscience and Biobehavioral Reviews 33 (2009) 95–10698

reflects a balance between heat production and heat dissipation. Inrats and rabbits, the latter process occurs due to the heat loss fromnon-haired skin—ear pinna (rabbits) and tail (rats). Both vascularbeds possess an extensive network of arterio-venous anastho-moses that can be constricted by sympathetic neural activity.Studies conducted during the last decade in Blessing’s laboratoryprovide evidence that various stressors cause very robustsympathetically mediated cutaneous vasoconstrictor responses(Yu and Blessing, 1997, 2001; Garcia et al., 2001; Nalivaiko andBlessing, 2003; Blessing, 2005; Ootsuka and Blessing, 2005b;Ootsuka et al., 2008). These reactions are essentially similar tohuman stress-induced vascular responses (‘‘becoming pale withfright’’). Such responses are illustrated in Figs. 2A and 3B and C.

Blessing’s group also contributed to the localization ofcutaneous presympathetic vasomotor neurons, in both the rabbit

Fig. 2. (A) In a conscious rabbit, sudden noise elicits a fall in the ear pinna blood flow

approximately 2 s after onset of theta rhythm in hippocampal EEG. Modified from

Yu and Blessing (1997), with permission. (B) In an anesthetized rabbit, electrical

stimulation of the dorsomedial hypothalamus causes falls in the ear and mesenteric

blood flows, in mean vascular conductances for these vascular beds, and rises AP (a).

Inhibition of raphe neurons by microinjection of GABAA agonist muscimol totally

suppresses cutaneous (ear) vasoconstriction, without affecting DMH-elicited

changes in the mesenteric conductance and in AP (b). From Nalivaiko and

Blessing (2001), with permission.

(Blessing et al., 1999) and the rat (Blessing and Nalivaiko, 2001).Transneuronal retrograde tracing following pseudorabies virusinjection into the rat tail revealed that these cells are located in themedullary raphe/parapyramidal area (Smith et al., 1998; Tothet al., 2006). This finding was confirmed in a pharmacological studyin anesthetized rabbits, where we found that stimulation of thedorsomedial hypothalamus, in addition to such well describedcardiovascular changes as rise in AP and HR, also provokes adramatic cutaneous vasoconstriction—to much larger extent thenvasoconstriction in the mesenteric vascular bed (Fig. 2B, left panel).This DMH-elicited cutaneous, but not mesenteric vasoconstrictionbas completely suppressed by inhibition of the raphe/parapyr-amidal region by microinjections of the GABAA agonist muscimol(Fig. 2B, right panel), suggesting that integrity of neurons located inthis area is necessary for transmitting neural activation from thehypothalamus to spinal sympathetic cutaneous vasomotor neu-rons (Nalivaiko and Blessing, 2001). This was further confirmed inexperiments in conscious rabbits, where inhibition of the raphe/parapyramidal region muscimol completely abolished stress- andcold-induced vasoconstriction in the ear pinna vascular bed(Ootsuka and Blessing, 2005b).

Relevant to our review, Blessing and colleague demonstratedthat stress-induced sympathetic cutaneous vasomotor responsesare significantly reduced by systemically administered 8-OH-DPAT(Blessing, 2005). Activation of 5-HT1A receptors also prevented orreversed cold-induced cutaneous vasoconstriction (Ootsuka andBlessing, 2003, 2006) suggesting a common neural pathway forthermoregulatory and stress-related cutaneous vascular effects.Ootsuka and Blessing (2006) have already demonstrated thatduring cold exposure, cutaneous vasodilatory (or rather anti-vasoconstrictory) effects of exogeneous 8-OH-DPAT are mediatedby activation of 5-HT1A receptors in the raphe/parapyramidalarea—the same brainstem region that contains presympatheticcardiomotor neurons (see above). In the experiments describedabove, effects of 8-OH-DPAT were reduced or blocked by WAY-100,635, indicating that they were receptor-specific.

Consistently with rat and rabbit pharmacological studies, in 5-HT1A receptor-knockout mice acute stressors provoked largerhyperthermic responses compared the wild-type animals (Grosset al., 2000; Pattij et al., 2002). While authors interpreted theseresults as a reflection of elevated anxiety, it is entirely possible thatenhanced hyperthermia was due to the excessive activation ofcutaneous presympathetic vasomotor neurons in the medullaryraphe, due to elimination of inhibitory effect of 5-HT1Aautoreceptors. This could lead to more potent cutaneous vaso-constriction in the tail artery (and thus heat conservation), similarto stress reaction in rats (Vianna and Carrive, 2005).

2.4. Physiological role of sympatho-inhibitory 5-HT1A receptors is still

unclear

Presented above data allows to suggest that endogeneousrelease of 5-HT could be cardioprotective, by reducing stress-activated cardiac sympathetic tone. However, studies with theselective 5-HT1A antagonist WAY-100,636 left one puzzling issue:while the drug efficiently suppressed effects of exogenouslyadministered 5-HT1A agonists, it did not have any action whengiven alone—neither at rest nor during restraint (Nalivaiko et al.,2005; Ngampramuan et al., 2008). This may indicate thatsympatho-inhibitory effects of 5-HT1A agonists are purely anexperimental phenomena, and that endogeneous 5-HT is notreleased in the vicinity of relevant 5-HT1A receptors. Analternative – and more speculative – possibility is that thesereceptors belong to a different subtype, sensitive to 5-HT1Aagonists but insensitive to WAY-100,635.

Fig. 3. Effects of selective blockade of 5-HT2A receptors on stress-elicited autonomic responses. (A) SR-46349B attenuates rises in the iBAT temperature during restraint stress

in rats. Left panel shows averaged traces from 8 rats obtained after injection of either vehicle (*) or SR-46349B at a dose of 1 mg/kg (*) 15 min prior to the restraint. Right

panel—mean values for stress-induced changes in the iBAT temperature for 4 different conditions (vehicle or SR-46349B at doses of 0.01, 0.1 and 1.0 mg/kg s.c.). (B) SR-

46349B increases basal blood flow in the rat tail artery and attenuates stress-induced tail vasoconstriction elicited by restraint. Left panel shows averaged traces from 8 rats

obtained after injection of either vehicle (*) or SR-46349B at a dose of 1 mg/kg (*) 15 min prior to the restraint. Right panel—mean values for stress-induced changes in the

tail blood flow for 4 different conditions (vehicle or SR-46349B at doses of 0.01, 0.1 and 1.0 mg/kg s.c.). Panels A and B are from Ootsuka et al. (2008), with permission. (C) SR-

46349B (1 mg/kg i.v.) attenuates sudden falls in the rabbit ear pinna artery elicited by an acoustic stimulus (cage tap). Modified from Blessing (2005), with permission.

E. Nalivaiko, A. Sgoifo / Neuroscience and Biobehavioral Reviews 33 (2009) 95–106 99

2.5. Clinical perspectives of new applications for 5-HT1A agonists

It must be noted that the described above controversy does notdiminish the value of the previous work as it suggests that 5-HT1Aagonists might be valuable pharmaceutical agents. Several decadesago Bernard Lown, a great scientist and great physician, hadwritten: ‘‘. . . if arrhythmias are to be controlled and prevented byinterventions aimed at modifying neural cardiac traffic, bluntingthe genesis at their source within the brain is an attractivechallenge.’’ (Blatt et al., 1979). We believe that our recent findingsform a solid evidence for the idea of using 5-HT1A agonists as

central sympatholytic cardioprotective drugs. In fact, buspirone (apartial 5-HT1A agonist currently used clinically as anxiolytic)attenuates stress-induced changes in heart rate and arterialpressure in healthy volunteers (Taylor et al., 1989). The idea ofusing 5-HT1A agonists as centrally acting anti-hypertensive drugsis not new (see Saxena and Villalon, 1990a for review), and therewas already an attempt to introduce another 5-HT1A agonistflesinoxan into clinical practice (Van Zwieten and Bruning, 1994).Unfortunately the attempt was not successful, presumably due toundesirable side effects. In a more recent human study comparingcardiovascular effects of urapidil and idazoxan (a1-adrenoreceptor

E. Nalivaiko, A. Sgoifo / Neuroscience and Biobehavioral Reviews 33 (2009) 95–106100

antagonists), it has been found that both drugs producedhypotension, but only in the case of idazoxan was it associatedwith tachycardia (presumably baroreflex-mediated) (Stoschitzkyet al., 2007). Authors suggested that 5-HT1A agonist properties ofurapidil could be the explanation of its more beneficial therapeuticprofile.

It is also possible that central 5-HT1A receptors are involved inthe pathogenesis of cardiac malfunction during mood disorders.Mental disorders associated with chronic stressors are establishedrisk factors for cardiac morbidity and mortality (Rozanski et al.,1999; Bunker et al., 2003), but there is no satisfactory explanation ofthe mechanistic link between mental and cardiac disorders.Abnormal functioning of the brain serotonin (5-HT) neurotransmis-sion in human mental disorders is now firmly established, andinvolvement of the 1A subtype of 5-HT receptors in the pathogenesisof depression is well documented (Rickels, 1990; Lucki, 1991; Blierand Ward, 2003). Earlier postmortem studies of brains of depressedpatients failed to demonstrate any deficiency of 5-HT1A receptors(Matsubara et al., 1991; Lowther et al., 1997). However, severalrecent brain imaging studies reported a reduced binding potency of5-HT1A receptors in several brain areas of depressed and panicpatients (Nash et al., 2003; Meltzer et al., 2004; Neumeister et al.,2004). These human results are supported by observations in animalexperiments where prolonged chronic stress caused reduction in thedensity and desensitisation of brain 5-HT1A receptors (Flugge, 1995;Lanfumey et al., 1999). Of particular interest is the recent report byShively et al. (2006) demonstrating global brain reduction of 5-HT1Areceptors in depressed primates. Importantly, the authors found acorrelation between this reduction and resting values of the HR. It isat present unknown whether the anomaly in the 5-HT1A receptorsfunction is restricted to just those brain areas that are involved inemotional processing/arousal, or it is a more global dysfunction,with involvement of the receptors located in other regions. This leadto a suggestion that if in anxiety/depression 5-HT1A receptorsfunction is also altered in brain areas that control the heart, suchareas may then be the origin of inadequate (or even maybepathological) neural influences to the heart (see Nalivaiko, 2006 forreview).

3. 5-HT2A receptors

3.1. Activation of 5-HT2A receptors reduces stress-induced

thermogenic but not tachycardic or pressor responses

As noted in Section 3, central 5-HT2A receptors are generallyconsidered as ‘‘sympatoexcitatory’’. This view was formedpredominantly based on results obtained with central adminis-tration of 5-HT2A agonists that indeed produced robust sympa-toexcitatory effects; see McCall and Clement (1994) and Ramage(2001) for reviews. While these experiments provided valuableresults, they did not address the question of whether activation ofcentral 5-HT2A receptors contributes to cardiovascular control inphysiological conditions. Attempts have been made to clarify thisquestion using ketanserin, a powerful 5-HT2A receptor antagonist.Indeed, some animal and human studies demonstrated hypoten-sive action of ketanserin, but it was not taken into account thatketanserin is also a noradrenergic-a1 antagonist, and thus itsaction was likely due to the peripheral vascular sympatheticblockade. Consistent with this idea, administration of ketanserinalone caused moderate hypotension associated with either nochange or with an increase in heart rate (e.g. Bolte et al., 1998;Bunag et al., 2002). This indicates that the drug did not affectsympathetic outflow to the heart, at least at rest.

Attempting to evaluate whether 5-HT2A receptors participatein cardiovascular control during stress, we have recently studied

the effects of selective blockade of these receptor on tachycardicand thermogenic responses elicited by restraint in rats. Systemicadministration of SR-46349B (a selective 5-HT2A antagonist)affected neither basal heart rate nor the tachycardia elicited byrestraint (Ootsuka et al., 2008). The lack of anti-tachycardic effectwas clearly not due to any drug-related problems as at theconcentration used (1 mg/kg) it efficiently suppressed thermo-genesis in the interscapular brown adipose tissue and cutaneousvasoconstriction in the tail artery as illustrated in Fig. 3A and B. Incurrently ongoing experiments using a more potent stressor (socialdefeat), we reconfirmed both the lack of anti-tachycardic effect ofthe drug and its efficient anti-hypertermic action and, additionally,found that SR-46349B does not affect AP—neither at rest norduring stress (Beig and Nalivaiko, 2008).

Consistent with the idea that 5-HT2A receptors do notparticipate in the neural control of HR and AP, lack of anycardiovascular effects have been reported for several selective 5-HT2A antagonists (Saydoff et al., 1996; O’Connor et al., 2001;Setoguchi et al., 2002). Thus, surprisingly, we have here quite asimilar situation to that described for 5-HT1A receptors: potentsympatoexcitatory effects of exogeneous agonists but lack of anyeffect of selective antagonists, suggesting that 5-HT is not naturallyreleased in the vicinity of central 5-HT2A receptors located insympathetic cardiomotor and vasomotor areas (except cutaneousvasomotor pathway—see next paragraph).

3.2. Stress-induced thermogenesis in the iBAT is mediated via 5-HT2A

receptors

While stress-induced thermogenesis is beyond the scope of thisreview, we would like to include this section as the data presentedhere is closely related to another stress-induced thermogenicvascular effect, namely cutaneous vasoconstriction. As alreadynoted, SR-46349B very efficiently suppressed iBAT thermogenesisand cutaneous vasoconstriction in rats during restraint (Fig. 3A andB) (Ootsuka et al., 2008) and attenuated stress-induced falls in theear pinna blood flow in conscious rabbits (Fig. 3C) (Blessing, 2005).The drug also dilated rat tail and rabbit ear vascular beds at rest(compare pre- and post-drug blood flow levels in Fig. 3B and C.Both cutaneous vasodilator and iBAT anti-thermogenic effects of 5-HT2A receptor blockade are consistent with well establishedhyperthermic effects of central 5-HT2A receptors activation(Gudelsky et al., 1986). In the previous section we have brieflycovered the physiology of the sympathetic cutaneous vasocon-strictor pathway that regulates heat dissipation. iBAT is one ofbodily areas where thermogenesis occurs; it could be enhanced byneural sympathetic influences, via peripheral adrenergic-b3

receptors. Amasingly, descending sympathetic pathway control-ling iBAT also relays in the medullary raphe/parapyramidal region,similar to cardiomotor and cutaneous vasomotor pathways.Furthermore, medullary presympathetic neurons that controliBAT are also sensitive to and could be inhibited by 5-HT1Aagonist 8-OH-DPAT (Morrison, 2004).

3.3. Anatomical location of 5-HT2A receptors responsible for

cutaneous vasoconstriction

Whereas previous studies suggested that 5-HT2A receptorsresponsible for hyperthermia are located in the brain, more recentexperiments, including our own, indicate that at least some ofthese receptors are located at the spinal level; so far this evidencewas obtained only in anesthetized rabbits. We have initially foundthat SR-46349B potently suppresses cutaneous (ear pinna)vasoconstriction elicited from the medullary raphe but not fromthe cervical sympathetic trunk (Fig. 4A) (Ootsuka et al., 2004). This

Fig. 4. Evidence for spinal location of 5-HT2A receptors that mediate cutaneous vasoconstriction in rabbits. (A) Electrical stimulation of the medullary raphe or of the cervical

sympathetic trunk elicit vasoconstriction in the ear pinna artery before blockade of 5-HT2A receptors (a). After administration of SR-46349B (1 mg/kg i.v.), raphe stimulation

has no effect; the response stimulation of sympathetic preganglionic fibers remains unaffected (b). Modified from Ootsuka et al. (2004), with permission. (B) Application of

SR-46349B to the thoracic level of the spinal cord substantially attenuates discharge in the rabbit ear sympathetic nerve elicited by the electrical stimulation of the medullary

raphe. Upper panel shows raw data obtained before and after receptor blockade. Bottom panel—dose-dependence of the antagonist action. Note that SR-46349B-resistant

part of response was further reduced by the glutamate receptor antagonist kynurenic acid. From Ootsuka and Blessing (2005a), with permission.

E. Nalivaiko, A. Sgoifo / Neuroscience and Biobehavioral Reviews 33 (2009) 95–106 101

indicates that intra-spinal neurotransmission was the onlypossible target for the drug. In a subsequent study, Ootsuka andBlessing demonstrated that stimulation of the medullary raphecauses increase in ear pinna sympathetic vasomotor nervedischarge and that this increase is substantially attenuated by atopical application of SR-46349B to the thoracic, but not to thelumbar area of the spinal cord (Fig. 4B) (Ootsuka and Blessing,2005a). It is tempting to speculate that spinal 5-HT2A receptorsmay also mediate activation of spinal sympathetic neuronscontrolling iBAT thermogenesis; crucial experiments that willclarify this issue are still to be performed. Consistent with ourfindings, 5-HT2A receptors are expressed by spinal sympatheticneurons (Doly et al., 2004). The source of endogeneous 5-HT thatactivate these receptors is most likely serotonergic raphe-spinalneurons (see above).

It may be thus concluded that, contrarily to existing opinion, 5-HT2A receptors do not mediate central cardiac and vascular effectsof 5-HT, with the exception of the cutaneous thermoregulatoryvascular bed. Vasoconstriction in the latter occurs, at least in part,due to 5-HT release from the raphe-spinal sympathetic terminalsand subsequent activation if spinal cutaneous sympatheticneurons. The same mechanism is likely involved in cutaneousvasomotion associated with the temperature regulation and withalerting or stressful stimuli.

3.4. Cardiovascular effects of 5-HT2A receptor activation in humans

In humans, 5-HT2A receptors are renowned for their halluci-nogenic properties, and for these reason the 5-HT2A receptorantagonism of atypical antypsychotics (e.g. olanzapine, clozapine,

ritanserin) is believed to contribute to their action. These drugs arewidely used at present, and their autonomic effects have also beenreported. However, because none of these agents is a pure 5-HT2Aanatagonist, interpretation of these results is complicated.

Ketanserin was previously used for the treatment ofhypertension in humans (Wenting et al., 1982; Andren et al.,1983), and whereas its hypotensive effect was believed to bemediated via 5-HT2A receptor antagonism rather then vianoradrenergic-a1 anatgonism (Ball and Robertson, 1985),‘‘relative contributions of at least these two, and perhaps other,mechanisms to the hypotensive effect of ketanserin during long-term oral treatment remain obscure’’ (Ball and Robertson, 1985).Of much larger interest and practical significance is theobservation that ketanserin is efficient in the treatment ofReinaud’s disease (Lagerkvist and Linderholm, 1986; Arosio et al.,1991)—a disorders characterised by profound vasoconstriction infingers. There are anatomical similarities between vasculature ofhuman fingers, rat tail and rabbit ear: in all three areas, the bloodsupply is predominantly to the skin, with a well-developedsystem of arterio-venous anasthomoses. Furthermore, fearfulstimuli produce strong vasoconstriction in human fingers(Kistler et al., 1998), just in the same way as stressful or alertingstimuli provoke vasoconstriction in the rat tail and rabbit ear(see above). This allows to suggest that the neural pathwaycontrolling these cutaneous beds also share some similarities. Itmay be that selective finger vasodilatory effect of ketanserin inhumans is mediated by the blockade of 5-HT2A receptorsexpressed by spinal cutaneous vasomotor neurons, and bysubsequent reduction of sympathetic outflow to the fingervasculature.

Fig. 5. In conscious rats, activation of 5-HT3 receptors in the NTS attenuates

baroreflex-induced bradycardia. (A) Changes in heart HR and AP in response to

intravenous injection of phenylephrine (PE) before and 1, 3, 10 and 20 min after

sequential bilateral microinjection of 5-HT3 agonist 2-methyl-5-HT into the NTS.

(B) 2-Methyl-5-HT has no effect when it is microinjected after selective blockade of

the 5-HT3 receptors with granisetron. From Callera et al. (1997), with permission.

E. Nalivaiko, A. Sgoifo / Neuroscience and Biobehavioral Reviews 33 (2009) 95–106102

3.5. 5-HT2C receptors: involvement in stress-elicited hypertension?

Data regarding potential involvement of central 5-HT2Creceptors in cardiovascular adjustments during stress are currentlylimited. That activation of these receptors elevates arterialpressure was convincingly demonstrated by Ferreira et al.(2005): icv administration of selective 5-HT2C agonist mCPPelevated, in a dose-dependent manner, the mean arterial pressure(but not HR) in conscious rats, and this effect was completelyprevented by central administration of the selective 5-HT2C

Fig. 6. During defence reaction, baroreflex-induced bradycardia is suppressed due to act

rats. (A) In animal injected with saline, phenylephrine (PE, i.v.) produces powerful baro

baroreflex is activated after prolohged excitation of the dPAG area (b). (B) Intra-NTS ad

bradycardic response (c), but completely prevents suppression of this bradycardia by d

antagonist SDZ SER 082. Importantly, the antagonist had no effecton the basal AP and HR, but greatly attenuated pressor, but nottachycardic response to the restraint stress. This interestingobservation indicates that activation of central 5-HT2C receptorsis responsible for the large component of the pressor responseduring psychological stress. Anatomical locations of relevant 5-HT2C receptors remains to be elucidated; described above datasuggest that they must be located relatively low in the hierarchy ofthe descending sympathetic vasomotor pathway, after its separa-tion from the sympathetic cardiomotor pathway. In contrast to thisrat study, mCPP had no effect on AP and HR in conscious mice,suggesting that there might be inter-species differences in the 5-HT2C receptor function (Stiedl et al., 2007).

4. 5-HT3 receptors

In frame of this review, 5-HT3 receptors represent interest intwo aspects—firstly, because of the evidence obtained in Laguzzi/Sevoz-Couche’s laboratory that activation of these receptors in thenucleus tractus silitarius (NTS) modifies cardiac baroreflexsensitivity and secondly, due to the findings of Alkadhi’s groupthat 5-HT3 agonist may affect long-term potentiation in sympa-thetic postganglionic vasopressor neurons.

4.1. Stress-induced suppression of the baroreflex: role of 5-HT3

receptors in the NTS

Laguzzi and colleagues initially discovered that in anesthethe-tized rats, microinjection of 5-HT3 agonists phenylbiguanide or ofits derivative CPBG reduces the cardiovagal component of thebaroreflex and of the chemoreflex in anesthetized rats (Merahi andLaguzzi, 1995; Sevoz et al., 1997). These effects were prevented bythe pre-injection into the NTS of 5-HT3 antagonists zacopride orondasetron, but not by 5-HT1 or 5-HT2 antagonists, and thus likelywere mediated via 5-HT3 receptors. These finding were thensuccessively reproduced in non-anesthetized rats (Callera et al.,1997) (Fig. 5).

ivation of 5-HT3 receptors in the NTS. Experiments were conducted in anesthetized

reflex-induced bradycardia (a). This bradycardia is substantially suppressed if the

ministration of the selective 5-HT3 antagonist granisetron does not affect control

PAG activation. From Comet et al. (2004), with permission.

E. Nalivaiko, A. Sgoifo / Neuroscience and Biobehavioral Reviews 33 (2009) 95–106 103

Psychological stressors cause alteration in baroreflex gain/sensitivity, and in the subsequent study authors tested whetherthese changes could be mediated by the above-describedmechanism. They found that activation of the dorsomedialhypothalamus or the dorsal periaqueductal gray matter (a wellknown ‘‘defence areas’’) inhibits baroreflex bradycardia, and thatthis effect could be markedly reduced by the selective blockade of5-HT3 receptor in the NTS, as shown in Fig. 6 (Sevoz-Couche et al.,2003; Comet et al., 2004, 2005). In these works, authors unveiledquite complex sequence of events: excitation of 5-HT3 receptorcauses activation of downstream-located tachykinin NK1 recep-tors that in turn activate inhibitory postsynaptic GABAA receptors.In the latest work from this laboratory, authors advanced to thenext step and in a very elegant work identified the serotonergicpathway causing baroreflex inhibition associated with the defensereaction (Bernard et al., 2008). Using c-Fos labeling, they initiallyfound that stimulation of the dorsal periaqueductal gray sub-stantially increases the number of activated neurons (includingserotonergic cells) in the B3 group that, interestingly, corresponds

Fig. 7. (A) Ganglionic long-term potentiation (gLTP) requires activation of 5-HT3 recep

amplitude of postganglionic population spike that occurs in response to preganglionic

stimulation (20 Hz for 20 s, arrowhead). Open circles—control; selective 5-HT3 agonist m

was substantially attenuated in the presence of the selective 5-HT3 receptor antagonist

hypertension is stressed rats. In non-stressed rats, AP remain an normal level throughout

stressor (cage switch), AP raised by about 40 mmHg within a week, and remained at thi

receptor antagonist tropisetron, stress did not provoke hypertensive changes until the

establishing stress-induced hypertension (not shown). (C) Differences found in the in vi

from control rats. (a) There was a leftward shift of the input-output curve in ganglia isol

with ondasetron substantially reduced ganglionic transmission only in stressed rats (cl

animals (open circles). (c) In ganglia from control animals, gLTP was readily inducible (clo

only minor effects (open circles. Note that graphs (b) and (c) show normalized, not ab

to the cardiomotor medullary region described above. They thendemonstrated that local pharmacological blockade of neuronalactivity in this area prevented the inhibitory effect of dPAGactivation on the baroreflex-induced bradycardia. Conversely,neuronal activation by local application of D,L-homocysteic acidinto B3 region caused baroreflex inhibition that was suppressed bymicroinjection of granisetron into the NTS (Bernard et al., 2008).Taken together, these results convincingly demonstrate thatduring defense reaction, baroreflex inhibition occurs due toactivation of serotonergic neurons in the medullary-raphe/para-pyramidal area, with subsequent release of 5-HT and activation of5-HT3 receptors in the NTS.

4.2. Stress-induced long-term potentiation in sympathetic ganglia

The idea that chronic stress may lead to a sustained elevation ofthe AP currently regains popularity (Steptoe, 2000; Strike andSteptoe, 2004). Underlying mechanistic links between chronicstress and hypertension are currently unknown, and in this regard

tors in rat sympathetic ganglia (in vitro study). The graph shows changes in the

fibers stimulation. Original traces are shown in C (c). gLTP was induced by tetanic

-CPBG caused significant increase in the gLTP (closed circles), and this potentiation

MDL 72222 (closed squares). B. Evidence that 5-HT3 receptors mediated sustained

the experiment (closed triangles). In untreated animal that were subjected to daily

s level (closed circles). In contrast, in rats that were treated with a selective 5-HT3

drug was interrupted. Tropisetron also reversed hypertension if it was given after

tro studies between sympathetic ganglia obtained from stressed/hypertensive and

ated from stressed animals (open circles). (b) Selective blockade of 5-HT3 receptors

osed circles—cage switch stress; closed triangles—swim stress), but not in control

sed circles) whereas in ganglia from stressed animals, tetanic stimulation provoked

solute values. Modified from Alkadhi et al. (1996, 2005b), with permission.

E. Nalivaiko, A. Sgoifo / Neuroscience and Biobehavioral Reviews 33 (2009) 95–106104

a series of provoking and insightful studies have been published byKarim Alkadhi and colleagues during last decade. These research-ers demonstrated that repetitive psychological stressors may leadto sustained elevation of the AP by up-regulating long-termpotentiation (LTP) in the peripheral sympathetic ganglia, withsubsequent increase of sympathetic vascular tone. This ganglionicLTP (gLTP) is similar to much better known cortical LTP, andmanifests as long-lasting increase in the population spike of thesympathetic postganglionic nerve following tetanic stimulation ofpre-ganglionic fibers (Fig. 7A). The history of discovery of gLTP andits properties are comprehensively covered in the introduction tothe Alkahdi’s seminal paper (Alkadhi et al., 1996) and in twosubsequent reviews (Alkadhi et al., 2005a; Alkadhi and Alzoubi,2007). The major contribution of these authors that is relevant toour current discussion is the discovery that activation of 5-HT3receptors is an essential and sufficient requirement for theexpression of gLTP. This was first proved in the in vitro preparation,by demonstrating that 5-HT and m-CPBG (a selective 5-HT3agonist) facilitates gLTP; that selective blockade of 5-HT3 receptorprevents or reverses gLTP (Fig. 7A); that gLTP cannot be elicited inmonoanine-depleted ganglia obtained from reserpinized rats; andthat activation of 5-HT3 receptors by exogenous agonists in these5-HT depleted ganglia restores gLTP to the normal level.Sympathetic preganglionic terminals do not synthetise 5-HT,and the most likely source of intrinsically released 5-HT insympathetic ganglia is the small intensity fluorescent (SIF) cells(Hadjiconstantinou et al., 1982; Happola, 1988).

That 5-HT3 receptor-mediated facilitation of ganglionic LTPunderlies stress-induced hypertension was shown in a more recentstudy from the same group (Alkadhi et al., 2005b). Repetitivetreatment with 5-HT3 receptor tropisetron prevented a sustainedincrease in the AP elicited in rats by a chronic cage-switch stress(Fig. 7B). Importantly, the drug also reversed stress-inducedhypertension if it was administered after development of the

Fig. 8. Summary of data presented in this review. Psychological stresses cause activati

periaqueductal grey (PAG). These neurons, in turn, activate 5-HT-containing neurons in th

5-HT from the raphe neurons may activate their inhibitory 5-HT1A autoreceptors, thus

activated raphe neurons has several effects: at the level of the lower brainstem, it attenua

the solitary tract (NTS) to the nucleus ambiguus that contains parasympathetic cardioin

also activate these vagal neurons via direct projection to the N. Amb.; this effect is mediate

medullary raphe activates sympathetic neurons that innervate the heart, the cutaneou

outflows (but not the outflow to the heart) are mediated via 5-HT2A receptors located po

the spinal cord (IML). It may be that midbrain 5-HT-containing neurons from median

forebrain, also contribute to the development of stress-induced autonomic changes (gre

stress-induced hypertension, by facilitating long-term potentiation in the sympathetic

latter. In vitro studies of sympathetic ganglia obtained from non-stressed and stressed animals strongly supported results obtainedin vivo: firstly, the input/output curve for sympathetic gangliafrom stressed rats was shifted to the left (Fig. 7C(a)), indicating thatganglionic transmission was enhanced (in other words, at anygiven strength of preganglionic stimulation, the amplitude of thepostganglionic population spike was higher). Secondly, selectiveblockade of 5-HT3 receptors reduced synaptic transmission only inganglia from stressed animals, suggesting that only in this casethere was a substrate for the blockade (Fig. 7C(b)). Thirdly, high-frequency stimulation of preganglionic fibers induced gLTP only inganglia from control unstressed rats (Fig. 7C(c)), probably becausein stressed animals gLTP was already saturated.

It is not easy to prove that in the described above in vivoexperiments, the site of anti-hypertensive action 5-HT3 antago-nists was indeed restricted to sympathetic ganglia. Two lines ofevidence suggest that it was not in the CNS: firstly, centraladministration of ondasetron caused opposite effect (rise in the AP)in conscious rats (Ferreira et al., 2004). Secondly, both tertiary formof tropisetron (blood–brain barrier-permeant) and its non-permeant quaternary form were equipotent in reducing AP inthe spontaneously hypertensive rats (Alkadhi et al., 2001). Thislater observation, in conjunction with appropriate in vitro studies,suggests that SHR and chronically stressed rats may share the samemechanism for elevated arterial pressure.

In future, it certainly would be of major interest to elucidatewhether 5-HT3 receptors also contribute to the stress-inducedelevation in cardiac sympathetic tone and to other autonomicdisturbances elicited by chronic stresses. There is presently apaucity of human data with regard to involvement of 5-HT3 incardiovascular control. In healthy volunteers, administration of aselective 5-HT3 receptor antagonists affected neither basal levelsof AP and HR nor changes produced by head-up tilt (Upward et al.,1990; Matzen et al., 1993). This suggests that 5-HT3 receptors do

on of neurons in ‘‘defence areas’’—the dorsomedial hypothalamus (DMH) and the

e medullary raphe magnus (RMg) and raphe pallidus (RPa). Local dendritic release of

limiting excessive neuronal activation. 5-HT released from neuronal terminals of

ted baroreflex-induced bradycardia, by inhibiting excitatory link from the nucleus of

hibitory neurons. This effect is mediated via 5-HT3 receptors. Raphe neurons could

d via 5-HT1A receptors. At the level of the spinal cord, descending pathway from the

s vascular bed and the interscapular brown adipose tissue (iBAT). These two latter

stsynaptically on the spinal sympathetic neurons in the intermediolateral column of

/pontine raphe (MnR/RPn), via their projections to the hypothalamus and to the

y arrows). At the periphery, 5-HT3 receptors may contribute to the pathogenesis of

ganglia (SG). (+) Excitatory effects; (�) inhibitory effects.

E. Nalivaiko, A. Sgoifo / Neuroscience and Biobehavioral Reviews 33 (2009) 95–106 105

not contribute to cardiovascular regulation at rest; whether theyare involved in the genesis of stress-induced pressor changes inhuman’s remains to be clarified.

5. Conclusions

5-HT is an important central neurotransmitter mediatingstress-elicited cardiovascular changes. Brain 5-HT-containingneurons are segregated in the raphe nuclei in the medulla andthe pons, and it appears that it is medullary raphe that is particularrelevant for integrating numerous autonomic functions duringpsychological stresses, likely because it represents a finalmedullary relay for relevant descending pathways. At least 3subtypes of 5-HT cereptors (5-HT1A, 5-HT2A and 5-HT3) may beinvolved in stress-induced and raphe-mediated cardiovascular andthermogenic effects. Presented in this review information issummarised in Fig. 8. It may be that the midbrain raphe, via itsprojections to the hypothalamus and the forebrain, also contributeto the development of stress-induced autonomic changes; this isyet to be evaluated.

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