ANRV367-ME60-26 ARI 4 December 2008 17:27

ANNUAL
REVIEWS Further The Expanded Biology
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Department of Psychiatry, 2 Department of Cellular and Molecular Biology, University of
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California, San Francisco, California 94143; email: miles.berger@ucsf.edu,

john.gray@ucsf.edu
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3
Departments of Pharmacology, Medicinal Chemistry, and Psychiatry, University of North
Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina 27599;
email: bryan roth@med.unc.edu

Annu. Rev. Med. 2009. 60:355–66 Key Words

The Annual Review of Medicine is online at 5-HT, receptor, SSRI, behavior, cardiovascular, gastrointestinal
med.annualreviews.org

This article’s doi: Abstract

10.1146/annurev.med.60.042307.110802
Serotonin is perhaps best known as a neurotransmitter that modulates
Copyright  c 2009 by Annual Reviews. neural activity and a wide range of neuropsychological processes, and
All rights reserved
drugs that target serotonin receptors are used widely in psychiatry and
0066-4219/09/0218-0355$20.00 neurology. However, most serotonin is found outside the central ner-
vous system, and virtually all of the 15 serotonin receptors are expressed
outside as well as within the brain. Serotonin regulates numerous bio-
logical processes including cardiovascular function, bowel motility, ejac-
ulatory latency, and bladder control. Additionally, new work suggests
that serotonin may regulate some processes, including platelet aggre-
gation, by receptor-independent, transglutaminase-dependent covalent
linkage to cellular proteins. We review this new “expanded serotonin
biology” and discuss how drugs targeting specific serotonin receptors
are beginning to help treat a wide range of diseases.

355
 ANRV367-ME60-26 ARI 4 December 2008 17:27

INTRODUCTION FROM BRAIN TO BEHAVIOR

Although serotonin (5-hydroxytryptamine, Serotonin modulates virtually all human be-
5-HT) was discovered 60 years ago (1), the havioral processes. This finding may seem sur-
study of serotonin and its receptors continues prising given that less than one in a million
to yield new biological insights of medical CNS neurons produce serotonin and the vast
relevance in virtually all major organ systems, majority of total body serotonin is found out-
including the cardiovascular, pulmonary, gas- side the CNS (8). However, brainstem sero-
trointestinal (GI), and genitourinary systems tonin neurons send ascending projections that
as well as the central nervous system (CNS) terminate in a defined and organized man-
(2). Serotonin and serotonin receptors are ner in cortical, limbic, midbrain, and hindbrain
important in the regulation of virtually all regions (Figure 1). Indeed, all brain regions
brain functions, and dysregulation of the express multiple serotonin receptors in a recep-
serotonergic system has been implicated in tor subtype-specific fashion (9). Additionally,
the pathogenesis of many psychiatric and individual neurons may express multiple sero-
Annu. Rev. Med. 2009.60:355-366. Downloaded from www.annualreviews.org

neurological disorders (3, 4). tonin receptors. For instance, Layer V pyrami-
A greater understanding of serotonin dal neurons express 5-HT1A and 5-HT2A recep-
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function has emerged during the last two tors, which exert opposing effects on pyramidal
decades with the cloning of at least 15 sero- neuron firing (10). CNS serotonin neurons are
tonin receptors, which are grouped into seven thus ideally positioned to modulate the activity
families based on signaling mechanisms (5). of a wide variety of human brain circuits, which
Other important advances have included the explains, in part, the pleiotropic behavioral ef-
subsequent development of receptor-specific fects of brain serotonin (9).
knockout mice, and the development of recep- The behavioral and neuropsychological
tor subtype-selective drugs. These advances processes modulated by serotonin include
have also shown us that serotonin has critically mood, perception, reward, anger, aggression,
important functions in many human organ appetite, memory, sexuality, and attention,
systems outside the CNS, including the regula- among others. Indeed, it is difficult to find a hu-
tion of energy balance and food intake, GI and man behavior that is not regulated by serotonin.
endocrine function, and cardiovascular and pul- (A full discussion of how serotonin modulates
monary physiology. These findings may help the neural circuitry of behavior and emotion
explain the diverse side effects of serotonergic is beyond the scope of this review; see, e.g.,
drugs—from diabetes and metabolic syndrome References 11–13.) Although the neural cir-
to valvular heart disease (6, 7). These recent cuitry responsible for each of these behavioral
findings also imply that developers of new sero- processes is still being elucidated, in many cases
tonin receptor subtype-selective drugs will need there is at least one specific brain region or
to consider the roles of a given receptor subtype nucleus that is critical for a given behavior.
in the physiology of multiple organ systems. In The expression pattern of each serotonin recep-
time, these advances may lead to therapies with tor within the human CNS is also known (9).
improved efficacy and side-effect profiles, and Thus, the question of how serotonin modulates
will enhance our understanding of a variety of each behavioral process can usually be framed
neuropsychiatric and medical disorders. in terms of how specific serotonin receptors
Here we review how serotonin and its cog- modulate the specific brain region(s)/nuclei in-
nate receptors regulate the function of multiple volved in producing the behavioral output.
human organ systems and disease processes. We Just as each behavior is regulated by multi-
also highlight specific settings where new sero- ple serotonin receptors, each serotonin recep-
tonergic drugs may be introduced to medical tor is expressed in multiple brain regions and
practice in the future. likely contributes to the modulation of multiple

356 Berger · ·
Gray Roth
 ANRV367-ME60-26 ARI 4 December 2008 17:27

Behavioral effects:
Mood
Perception
Memory
Anger
Aggression
Fear
Stress responses
Appetite
Addiction
Sexuality

Other CNS effects:

Motor control
Cerebellar regulation
Sleep/circadian rhythms
CNS vascular tone
Emesis
Respiratory drive
Annu. Rev. Med. 2009.60:355-366. Downloaded from www.annualreviews.org

Body temperature
Descending regulation of multiple organ systems
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Central serotonergic drugs:

SSRIs
Tricyclic antidepressants
MAOIs
Other antidepressants
Buspirone
Atypical antipsychotics
Triptans
5-HT3 receptor antagonists (e.g. ondansetron)
Fenfluramine
Ergotamine/methysergide
Hallucinogens

Figure 1
Central serotonergic pathways, effects, and drugs. In the central nervous system (CNS), serotonin is almost
exclusively produced in neurons originating in the raphe nuclei located in the midline of the brainstem.
These serotonin-producing neurons form the largest and most complex efferent system in the human brain.
The most caudal raphe innervate the spinal cord, while the more rostral raphe, the dorsal raphe nucleus and
the medial raphe nucleus, innervate much of the rest of the CNS by diffuse projections. Indeed, virtually
every cell in the brain is close to a serotonergic fiber, and nearly all behaviors as well as many other brain
functions are regulated by serotonin. Not surprisingly, serotonin receptors and transporters are a major focus
of CNS drug development, and many current medications modulate serotonin neurotransmission. 5-HT,
serotonin; MAOI, monoamine oxidase inhibitor; SSRI, selective serotonin reuptake inhibitor.

behavioral processes. For example, anxiety-like targeting central serotonergic activity and sero-
behavior is regulated primarily by 5-HT1A and tonergic receptors are currently used clinically
5-HT2C receptors, among others (14, 15), but or are in clinical development for the treat-
the 5-HT2C receptor regulates not only anx- ment of nearly every neuropsychiatric disorder
iety but also reward processing, locomotion, (17, 18).
appetite, and energy balance (16). This princi-
ple explains why drugs targeting a specific sero-
tonin receptor nonetheless have effects on mul- SEROTONIN AND VASCULAR
tiple behavioral processes (16). BIOLOGY
Despite this lack of a one-to-one correspon- Both within the CNS and throughout the body,
dence between specific serotonin receptors and serotonin plays a number of roles in vascular
individual behavioral processes, various drugs biology, ranging from the control of vascular

www.annualreviews.org • Expanded Biology of Serotonin 357

 ANRV367-ME60-26 ARI 4 December 2008 17:27

- Complex regulation of heart rate - Vasoconstriction/dilation

- Regulates sinus node (depending on vascular bed)
- Regulates AV node - Involved in systemic HTN
- Can induce atrial fibrillation in
high 5-HT states, e.g., carcinoid
- Involved in heart development - Released from dense granules
- Involved in valvulopathy - Facilitates platelet aggregation
- Ventricular remodeling in CHF - Induces local vasoconstriction

- Regulates respiratory drive

- May be involved in SIDS - Centrally modulates micturition
- Involved in pathogenesis of - Facilitates the guarding reflex
pulmonary hypertension - Role in stress incontinence

- Regulates gastric emptying - Mammary gland development

- Regulates intestinal peristalsis - Regulates epithelial tight
- Regulates intestinal secretion junctions and milk release
- Regulates colonic tone
Annu. Rev. Med. 2009.60:355-366. Downloaded from www.annualreviews.org

- Regulates pancreatic secretion

- May regulate beta cells - Uterine vasoconstriction
- Nausea/emesis - Uterine smooth muscle
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- Involved in IBS contraction (cervical > ovarian)

- Platelet-derived 5-HT involved - Uterine involution
in hepatic regeneration - Oocyte maturation
- Induces progesterone
secretion by granulosa cells
- Pain and nociception
- Complex effects on HPA axis
and stress responses - Inhibition of ejaculation
- Early embryonic development - Involved in control of penile
flaccidity and detumescence

Figure 2
Myriad effects of serotonin outside the central nervous system. 5-HT, serotonin; AV, atrioventricular; CHF, congestive heart failure;
HPA, hypothalamic-pituitary-adrenal; HTN, hypertension; IBS, irritable bowel syndrome; SIDS, sudden infant death syndrome.

resistance and blood pressure to the control striction of surrounding blood vessels, facili-
of hemostasis and platelet function (Figure 2). tating hemostasis. Selective serotonin reuptake
Serotonin causes vasoconstriction or vasodila- inhibitors (SSRIs) can increase bleeding time
tion in different vascular beds depending on the by inhibiting the uptake and storage of platelet
particular receptors that are expressed in each serotonin, so caution should be used in patients
vessel wall and surrounding smooth muscle tis- at high risk for bleeding or on anticoagulants.
sue (19). Indeed, activation of 5-HT1B receptors Indeed, platelets from individuals treated with
on cerebral blood vessels causes vasodilation, SSRIs, as well as platelets from serotonin trans-
which may partly explain the analgesic effects porter knockout mice, show decreased aggre-
of the triptan antimigraine drugs (20). gation responses (22).
Platelets have significant vesicular serotonin Accumulating data suggest that SSRI treat-
stores but lack the enzymes to synthesize sero- ment may decrease myocardial infarction (MI)
tonin (21); instead, they take up serotonin from risk. Several case-control studies have observed
the plasma via the serotonin transporter. Sero- lower MI rates among depressed patients taking
tonin is then secreted by the platelet dense gran- SSRIs versus controls, but not among patients
ules during platelet activation and plays a role taking tricyclic antidepressants (23). A retro-
in promoting platelet aggregation and vasocon- spective secondary analysis of post-MI patients

358 Berger · ·
Gray Roth
 ANRV367-ME60-26 ARI 4 December 2008 17:27

randomized to receive SSRIs or placebo showed

decreases in recurrent MIs and all-cause mor- SEROTONERGIC DRUGS AND VALVULAR
tality among patients on SSRIs (24). Although HEART DISEASE
depression is also an independent risk factor for
MIs that may be related to altered serotonin The drug combination of fenfluramine/phentermine was ex-
biology (25), the idea that SSRIs may actu- ceptionally effective for inducing weight loss in obese individ-
ally reduce MIs is intriguing and still awaits uals (80), although this advantage was offset by the induction
prospective testing (26). of valvular heart disease by fenfluramine (81), which led to the
Interestingly, recent studies suggest that in- withdrawal of fenfluramine. In 2000, we and others discovered
tracellular serotonin may also play a role in that a metabolite of fenfluramine—norfenfluramine, a potent
platelet activation through covalent linkage activator of 5-HT2B receptors—was likely responsible for the
to small G proteins via tissue transglutami- valvulopathy induced by fenfluramine and the “fen/phen” com-
nase. This modification constitutively activates bination (34, 82). We subsequently screened a small library of
G protein–dependent signaling pathways and available drugs and identified certain ergolines (pergolide
Annu. Rev. Med. 2009.60:355-366. Downloaded from www.annualreviews.org

stimulates platelet aggregation (27). In addi- and cabergoline) and amphetamine derivatives [methylene-
tion, serotonin is covalently cross-linked to a dioxymethamphetamine (MDMA; “Ecstasy”)] as potent 5-HT2B
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variety of adhesion proteins and clotting fac- agonists (35). We predicted that they too would be associated with
tors on the platelet cell surface (28), a pro- valvular heart disease with chronic use (for review see References
cess essential for the activation of a subset of 7 and 83). Subsequent clinical studies have indicated that per-
platelets. These findings have expanded the golide, cabergoline, and MDMA use are associated with valvular
classical paradigm, in which serotonin works heart disease indistinguishable from that induced by fenfluramine
by noncovalent interactions with membrane- (84–86). Based on these findings, we have recommended that all
bound receptors, and creates many new ques- approved and candidate medications be screened at 5-HT2B re-
tions about whether serotonin can exert biolog- ceptors for agonist actions prior to use in humans (7, 34).
ical activity by covalently attaching to cellular
proteins in other organ systems, including the
brain. ity that awaits clinical trials in humans. Mean-
while, 5-HT2A antagonists may have utility in
treating vasospastic angina and ischemic heart
SEROTONIN AND CARDIAC disease, and 5-HT3 antagonists have been re-
FUNCTION ported to be useful in treating post-MI pain
Serotonin regulates several different aspects of (33).
cardiac function, ranging from electrical con- Serotonin also plays a pathological role in
duction to valvular closure to post–MI remodel- the cardiac valvulopathy caused by the appetite
ing (Figure 2). Studies of cardiac abnormalities suppressant fenfluramine (see sidebar, Seroton-
in patients with serotonin-producing carcinoid ergic Drugs and Valvular Heart Disease) (7, 34).
tumors provided early evidence that serotonin 5-HT2B receptor activation on valvular inter-
modulates heart function. High serotonin lev- stitial cells is mitogenic (35), increasing valve
els in these patients can cause atrial fibrillation leaflet area and causing the poor valve closure
(29), an effect that may be mediated by cardiac seen in patients exposed to these drugs. It has
5-HT4 receptors (30). been suggested that the valvulopathy and fi-
Aside from this role in the atria, 5-HT4 re- brosis resulting from carcinoid syndrome may
ceptor expression increases in failing cardiac have a similar etiology (7). Mice lacking the 5-
ventricles (31), and this may play a role in HT2B receptor either die of cardiac defects or
ventricular remodeling. Animal studies suggest develop dilated cardiomyopathy in adulthood
that 5-HT4 antagonists may help improve car- (36). Thus, the 5-HT2B receptor plays an im-
diac function and block pathological remodel- portant role in cardiac development as well as
ing in congestive heart failure (32), a possibil- adult cardiac valvular function.

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 ANRV367-ME60-26 ARI 4 December 2008 17:27

SEROTONIN, BREATHING, Serotonergic abnormalities have also been

AND PULMONARY ARTERY found in roughly 50% of infants who have died
HYPERTENSION from sudden infant death syndrome (SIDS)
(45). These infants have significantly more
Serotonin helps control breathing and respira-
medullary serotonin neurons but significantly
tory drive through effects on brainstem respi-
less expression of serotonin transporter and 5-
ratory control centers as well as on the pul-
HT1A receptor in these cells (46). Medullary
monary vasculature (Figure 2). In pulmonary
serotonin neurons are highly pH sensitive and
artery hypertension (PAH), hypoxia elevates
serve as central chemoreceptors (47), suggest-
plasma serotonin levels (37) and likely increases
ing that these abnormalities may cause a de-
mitogenic 5-HT2B receptor signaling on pul-
fective respiratory response to hypercapnia that
monary artery endothelial cells. Increased
may underlie SIDS. Mice with defective devel-
5-HT2B receptor signaling increases vascular
opment of serotonergic neurons have a SIDS-
resistance (38) and is necessary for the develop-
like syndrome (48).
ment of PAH, since mice deficient for 5-HT2B
Annu. Rev. Med. 2009.60:355-366. Downloaded from www.annualreviews.org

do not develop PAH (39). One patient with a

heterozygous activating 5-HT2B receptor mu- SEROTONIN, ENDOCRINOLOGY,
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tation developed PAH (40), suggesting that AND METABOLISM

increased 5-HT2B receptor signaling may be The functions of serotonin in the endocrine
sufficient to cause PAH. Indeed, 5-HT2B antag- system and metabolism range from the cen-
onists can prevent the development of increased tral control of energy balance and central mod-
pulmonary vascular resistance, suggesting that ulation of the hypothalamic-pituitary-adrenal
these drugs could be useful clinically in treating (HPA) axis to the direct regulation of mam-
early PAH (38). mary gland development (Figure 2). Several
Serotonin may also induce pulmonary artery lines of evidence suggest an important role
remodeling by direct covalent attachment to in- for hypothalamic 5-HT2C receptors in regu-
tracellular signaling proteins in vascular smooth lating energy balance and modulating glucose
muscle cells (41), similar to the way sero- homeostasis (49). In particular, hypothalamic 5-
tonin influences platelet function by receptor- HT2C and 5-HT1B receptors act by modulating
independent covalent attachment to proteins. melanocortin pathways, and serotonin release
Indeed, acute blockade of the serotonin trans- into the hypothalamus stimulates sympathetic
porter by SSRIs can block the development of nerves that innervate brown adipose tissue (50).
PAH and subsequent right ventricular hyper- Because of these mechanisms, 5-HT2C recep-
trophy in animal models (42), suggesting that tor agonists may be useful for treating obesity
intracellular rather than extracellular serotonin and diabetes (51). Serotonin also plays a role in
may be an etiological factor in PAH. setting overall metabolic rate and temperature
Serotonin also modulates the activity of control. Serotonin-deficient mice show a rapid
rhythm-generating respiratory neurons in the hypothermic response when placed in a cold
brainstem pre-Boetzinger complex via the 5- environment (52), a response that may be me-
HT4 receptor. Opioid analgesic drugs cause diated by hypothalamic 5-HT1A and 5-HT7 re-
respiratory depression by suppressing the ac- ceptors (53). Serotonin regulates the HPA axis
tivity of these cells via mu opioid receptors, at multiple levels (54) and thus has complex
whereas activation of the 5-HT4 receptor is ex- effects on the overall stress response.
citatory (43). These findings have led to the in- Serotonin has also been implicated in the de-
triguing idea that 5-HT4 agonists could be used velopment and regeneration of metabolic and
to block opioid-induced respiratory depres- endocrine organs. For example, serotonin is
sion while still leaving opioid-induced analgesia synthesized within the developing mammary
intact (44). gland, where it is part of an autocrine-paracrine

360 Berger · ·
Gray Roth
 ANRV367-ME60-26 ARI 4 December 2008 17:27

loop that is essential for mammary gland devel- the central and peripheral nervous systems
opment (55). In the adult mammary gland, sero- (Figure 2). Within locally inflamed tissue, sero-
tonin regulates epithelial tight junctions and tonin release sensitizes peripheral nerve fibers
milk release (56). In the liver, serotonin is im- that carry nociceptive information to the CNS
portant in regeneration following transection (62). Brainstem serotonin neurons send de-
or volume loss. In particular, platelet-derived scending projections into the spinal cord that
serotonin signals through 5-HT2A and 5-HT2B modulate incoming nociceptive information
receptors to promote liver regeneration (57). (63). Finally, brainstem raphe serotonin neu-
rons send ascending projections to cortical and
limbic regions that may modulate the psycho-
SEROTONIN AND THE logical perception of pain (64).
GASTROINTESTINAL SYSTEM Serotonergic abnormalities have been re-
Serotonin regulates digestion at multiple lev- ported in patients with mood disorders, and
els within the human GI system and through- altered serotonergic modulation of pain pro-
Annu. Rev. Med. 2009.60:355-366. Downloaded from www.annualreviews.org

out the phylogenetic spectrum (Figure 2) (58). cessing at these multiple levels may explain in-
Roughly 95% of total body serotonin is released creased pain perception in these patients (64).
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into the gut by intestinal enterochromaffin cells The multiple levels at which serotonin mod-
(8), but serotonin is involved at the very mo- ulates nociceptive processing and pain per-
ment that food enters the body. Activation of ception may also explain the efficacy of sero-
taste-bud cells on the tongue causes serotonin tonergic drugs in treating pain disorders. For
release onto sensory afferent nerves (59) that example, triptan drugs are thought to re-
transmit taste information to the CNS. Once lieve migraine symptoms by activating thalamic
food enters the GI tract, it is propelled along 5-HT1B and 5-HT1D receptors (20), whereas
by peristaltic waves; these waves, as well as in- tricyclic antidepressants and combined sero-
testinal motility and secretion, are modulated tonin/norepinephrine reuptake inhibitors such
by serotonin (reviewed extensively in Reference as duloxetine may work via the serotonergic
8). For example, intestinal serotonin regulates modulation of incoming nociceptive informa-
pancreatic enzyme secretion (60), a mechanism tion in the spinal cord (64).
by which the gut may communicate exocrine The serotonin system also plays an impor-
enzyme needs to the pancreas based on GI tant role in anesthesia response. Inhalational
contents. anesthetic agents may work in part by suppress-
Altered serotonin signaling has been impli- ing serotonin release, and patients taking sero-
cated in functional bowel disorders, including tonergic antidepressants may require increased
irritable bowel syndrome (IBS) (8). Drugs tar- dosage of these agents (65).
geting both the 5-HT3 and 5-HT4 receptors Patients taking serotonergic antidepressants
have been used to treat IBS. In addition, exces- are also at increased risk of developing sero-
sive GI serotonin release can activate 5-HT3 re- tonin syndrome, a poorly understood syndrome
ceptors on afferent vagal nerves that innervate involving altered mental status, autonomic in-
brainstem vomiting centers (61), which may stability, and neuromuscular rigidity, when ex-
partly explain why 5-HT3 antagonists such as posed to multiple drugs in an inpatient setting
ondansetron are effective antiemetics. (66).

SEROTONIN AND PAIN SEROTONIN AND

CONTROL, ANESTHESIA, GENITOURINARY FUNCTION
AND SPINAL NOCICEPTION Serotonin plays a variety of roles in the central
Serotonin modulates pain perception and no- and peripheral control of genitourinary func-
ciceptive processing at multiple levels within tion within both the brain and the spinal cord

www.annualreviews.org • Expanded Biology of Serotonin 361

 ANRV367-ME60-26 ARI 4 December 2008 17:27

(Figure 2). Serotonin increases ejaculatory la- hemorrhage risk, recent data show that preg-
tency and delays orgasm through 5-HT2C and nant women taking SSRIs are not at increased
5-HT1B receptors but also decreases ejaculatory risk of postpartum hemorrhage (74). However,
latency through the 5-HT1A receptor (67). The exposure to SSRIs during pregnancy may in-
net effect of serotonin is to prolong ejaculatory crease the newborn’s risk of developing persis-
latency and to delay orgasm, and thus SSRIs tent pulmonary hypertension (75).
are often prescribed off-label to treat prema- Serotonin also regulates uterine contrac-
ture ejaculation (68). Although all SSRIs pro- tion through 5-HT2A receptors (Figure 2) (76).
long ejaculatory latency to some degree, this 5-HT2A receptor–induced uterine contractions
effect is most pronounced with paroxetine, and favor the cervical end of the uterus, suggest-
there is no direct correlation between antide- ing a role in promoting sperm transport to-
pressant efficacy and antiejaculatory latency. ward the oviduct (77). In addition, serotonin has
Serotonin modulates micturition in a sim- been shown to induce uterine collagenase ex-
ilar fashion as it does ejaculation. It controls pression after delivery, which promotes uterine
Annu. Rev. Med. 2009.60:355-366. Downloaded from www.annualreviews.org

urinary function via actions in the brain and involution (78).

spinal cord, and it regulates parasympathetic
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neural input to the bladder and somatic input to

the external urinary sphincter. 5-HT2C recep- CONCLUSIONS
tors prevent urination whereas 5-HT1A recep- As these examples show, serotonin is much
tors promote urination (69). The net effect of more than a neurotransmitter essential for the
serotonin on urination is likely inhibitory, since modulation of mood. It regulates a wide range
combined serotonin-norepinephrine reuptake of physiologic and pathophysiologic processes
inhibitors are used clinically to treat stress in- in most human organs. This explains why sero-
continence (70). tonergic drugs modulate phenomena ranging
from ejaculatory latency to hemostatic function
in addition to their more commonly appreci-
SEROTONIN, REPRODUCTIVE ated effects on mood and cognition.
FUNCTION, AND PREGNANCY Serotonin typically regulates a given phys-
Increased serotonin levels are found in the iologic process (such as digestion, pain per-
serum of pregnant women and may play a role ception, or energy balance) at multiple steps
in the altered vascular physiology of pregnancy through different and frequently opposing
(71). Roughly tenfold increases in serotonin mechanisms. For example, serotonin is not sim-
have been observed in the serum of preeclamp- ply pro- or antianalgesic; instead, it both po-
tic women, and serotonin levels correlate with tentiates and inhibits nociceptive processing at
the severity of preeclampsia. These findings led various levels of the nervous system.
some to propose nearly 50 years ago that el- Why is serotonergic modulation of these
evated serotonin may cause preeclampsia (re- processes so complex? One possibility is that
viewed in Reference 71). The elevated sero- this complexity allows wide modulatory ac-
tonin in preeclamptic patients likely stems from tivity of biological processes while preserving
increased platelet activation and aggregation as homeostasis even under diverse environmental
well as decreased metabolism by monoamine conditions. For example, depleting serotonin
oxidase. The altered vascular tone seen in acutely has little effect on mood in normal in-
preeclampsia in high-serotonin states may be dividuals (79), even though serotonin recep-
mediated by 5-HT1B and 5-HT1D receptors tors modulate a number of neural pathways that
(72); if so, blocking these serotonin receptors subserve mood. At the same time, serotonergic
or blocking platelet serotonin accumulation dysregulation is seen in multiple disease pro-
with SSRIs could help treat preeclampsia (73). cesses ranging from IBS to depression, and cor-
Interestingly, although SSRIs can increase rection of specific serotonin receptor signaling

362 Berger · ·
Gray Roth
 ANRV367-ME60-26 ARI 4 December 2008 17:27

abnormalities can often help treat the disease in tor is likely to have effects on multiple body
question. systems. For example, although 5-HT4 ago-
The richness and complexity of serotoner- nists may have rapid-onset antidepressant ac-
gic modulation of physiologic and pathophysi- tivity within the CNS, their clinical use may be
ologic processes discussed here provide both a tempered by their effects on other organ sys-
pharmacologic opportunity and challenge. On tems, such as on GI motility and on cardiac
the one hand, the involvement of specific sero- hypertrophy in heart failure.
tonin receptors in a given process provides an As research on the role of specific serotonin
opportunity to pharmacologically target these receptors in human physiology progresses, the
specific receptors in a related disease state. On difficulty of this challenge will become clear. In
the other hand, the fact that each individual the process, we will likely gain new serotonergic
serotonin receptor is involved in multiple phys- drugs and disease treatments as well as a deeper
iologic processes also presents a challenge, since understanding of the beauty and complexity of
even a drug targeting a single serotonin recep- human biology.
Annu. Rev. Med. 2009.60:355-366. Downloaded from www.annualreviews.org
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DISCLOSURE STATEMENT
M. Berger personally owns stock in Arena Pharmaceuticals. J.A. Gray has no conflicts. B.L. Roth,
since 2006, has consulted with the following pharmaceutical companies on 5-HT receptor phar-
macology: Merck, Johnson & Johnson, GlaxoSmithKline, AMRI, Supernus, Labopharm, Wyeth-
Solvay Alliance, Roche, Mediavation, and DaiNipponSumitomo. Dr. Roth is listed as coinventor
on several patents related to the use of 5-HT receptor subtype-selective drugs in treating human
disease.

ACKNOWLEDGMENTS
We thank Laurence Tecott for helpful discussions. Work on 5-HT receptor pharmacology is
supported by RO1MH61887 and U19MH82441 and by the National Institute of Mental Health
Psychoactive Drug Screening Program (all grants to B.L. Roth).

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NJ: Humana
3. Roth BL. 1994. Multiple serotonin receptors: clinical and experimental aspects. Ann. Clin. Psychiatry
6:67–78
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Annual Review of
Medicine

Contents Volume 60, 2009

Transcatheter Valve Repair and Replacement

Susheel Kodali and Allan Schwartz p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1
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Role of Endothelin Receptor Antagonists in the Treatment

of Pulmonary Arterial Hypertension
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Steven H. Abman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p13

Oral Iron Chelators
Maria Domenica Cappellini and Paolo Pattoneri p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p25
The Treatment of Hyperhomocysteinemia
Bradley A. Maron and Joseph Loscalzo p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p39
Stroke Rehabilitation: Strategies to Enhance Motor Recovery
Michael W. O’Dell, Chi-Chang David Lin, and Victoria Harrison p p p p p p p p p p p p p p p p p p p p p p p p55
Cardiomyopathic and Channelopathic Causes of Sudden Unexplained
Death in Infants and Children
David J. Tester and Michael J. Ackerman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p69
Bisphosphonate-Related Osteonecrosis of the Jaw: Diagnosis,
Prevention, and Management
Salvatore L. Ruggiero and Bhoomi Mehrotra p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p85
IL-23 and Autoimmunity: New Insights into the Pathogenesis
of Inflammatory Bowel Disease
Clara Abraham and Judy H. Cho p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p97
Necrotizing Enterocolitis
Marion C.W. Henry and R. Lawrence Moss p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 111
Cancer Screening: The Clash of Science and Intuition
Barnett S. Kramer and Jennifer Miller Croswell p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 125
Biomarkers for Prostate Cancer
Danil V. Makarov, Stacy Loeb, Robert H. Getzenberg, and Alan W. Partin p p p p p p p p p p p p 139
Management of Breast Cancer in the Genome Era
Phuong Khanh H. Morrow and Gabriel N. Hortobagyi p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 153

v
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MicroRNAs in Cancer
Ramiro Garzon, George A. Calin, and Carlo M. Croce p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 167
Erythropoietin in Cancer Patients
John A. Glaspy p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 181
Thrombopoietin and Thrombopoietin Mimetics in the Treatment
of Thrombocytopenia
David J. Kuter p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 193
Evolving Treatment of Advanced Colon Cancer
Neil H. Segal and Leonard B. Saltz p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 207
Barrett’s Esophagus and Esophageal Adenocarcinoma
Robert S. Bresalier p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 221
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Primary Myelofibrosis: Update on Definition, Pathogenesis,

and Treatment
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Omar I. Abdel-Wahab and Ross L. Levine p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 233

Nicotine Dependence: Biology, Behavior, and Treatment
Riju Ray, Robert A. Schnoll, and Caryn Lerman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 247
Food Allergy: Recent Advances in Pathophysiology and Treatment
Scott H. Sicherer and Hugh A. Sampson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 261
Immunomodulation of Allergic Disease
David H. Broide p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 279
Hypereosinophilic Syndrome: Current Approach to Diagnosis
and Treatment
Amy Klion p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 293
Extensively Drug-Resistant Tuberculosis: A New Face
to an Old Pathogen
Sheela Shenoi and Gerald Friedland p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 307
Polycystic Kidney Disease
Peter C. Harris and Vicente E. Torres p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 321
The Kidney and Ear: Emerging Parallel Functions
Elena Torban and Paul Goodyer p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 339
The Expanded Biology of Serotonin
Miles Berger, John A. Gray, and Bryan L. Roth p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 355
Advances in Autism
Daniel H. Geschwind p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 367
Chronic Consciousness Disorders
James L. Bernat p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 381

vi Contents
 AR367-FM ARI 15 December 2008 18:20

Goals of Inpatient Treatment for Psychiatric Disorders

Steven S. Sharfstein p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 393
Understanding and Reducing Variation in Surgical Mortality
John D. Birkmeyer and Justin B. Dimick p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 405
MRI-Guided Focused Ultrasound Surgery
Ferenc A. Jolesz p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 417
Genetic Testing in Clinical Practice
Steven W.J. Lamberts and André G. Uitterlinden p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 431
The HapMap and Genome-Wide Association Studies in Diagnosis
and Therapy
Teri A. Manolio and Francis S. Collins p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 443
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Prospects for Life Span Extension

Felipe Sierra, Evan Hadley, Richard Suzman, and Richard Hodes p p p p p p p p p p p p p p p p p p p p p p 457
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Emerging Concepts in the Immunopathogenesis of AIDS

Daniel C. Douek, Mario Roederer, and Richard A. Koup p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 471
Lessons Learned from the Natural Hosts of HIV-Related Viruses
Mirko Paiardini, Ivona Pandrea, Cristian Apetrei, and Guido Silvestri p p p p p p p p p p p p p p p p 485

Indexes

Cumulative Index of Contributing Authors, Volumes 56–60 p p p p p p p p p p p p p p p p p p p p p p p p p p p 497

Cumulative Index of Chapter Titles, Volumes 56–60 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 501

Errata

An online log of corrections to Annual Review of Medicine articles may be found at

http://med.annualreviews.org/errata.shtml

Contents vii