Serotonin ‘ohn

and the biology of feeding1’2

E Blundell

ABSTRACT

There

manipulation and

that

adjustments

bring

about

data

suggest

that

input

and

the drive

responses

sidering

and

or activity

systems

in the body

a central

nisms,

and

brain

nutritional

cascade),

the nature

tribution which

to coordinate

formation,

information.

peripheral

may food

by con-

processes

Two

key

onto

brain

an

(operamecha-

issues

are

5-HT

how

systems

neuroanatomical appropriate

physiological features,

AmfClinNutr

which between

physiological

The

occupy

environmental

response.

feeding

systems.

neurons

nutritional

that serotonin

can be developed

is transcribed

of this

of 5-HT

These

mediate

peripheral

serotonin

supply

in the relationship among

information

nutritional ofserotonin.

it is known

A framework

satiety

behavior

neurotransmitter,

role

Criteria appetite

the experimental

in feeding

in the

to feed. In addition,

organization.

of the

and

in feeding in the level

the interrelationships

tions

that

changes

primitive

occupy

and brain

causes

5-HT

is a phylogenetically therefore

evidence

is good

of serotonin

dis-

position

and and

in

metabolic

the

in-

behavioral

for establishing control

for

any

lowing

candidate

Experimental One

Serotonin,

appetite

control,

satiety,

anorexia,

diet

The involvement good

ofserotoninergic

has been

evidence

reviews

have

derived

from

has

neurons

in the expression

noted

for more

than

20 years

(eg,

1, 2) and

existed

for more

than

10 (eg,

3-5).

Various

collected

the

experimental

evidence,

much

of it

ofthe pharmacology ofanorexia (610). Experiments have been conducted largely on three types of animals: the leech, rat, and human. In the leech the large Retzius

cells

investigations

in the subesophageal

the cycle

of arousal,

ganglia food

contain

seeking,

serotonin

ingestion,

and

and satiation

regulate (11).

This description indicates that the association between serotonin and feeding is phylogenetically ancient. The bulk of investigations have been carried out on the rat and have included the use of electrical

and

chemical

stimulation

of the

brain,

electrolytic-

and neurotoxin-induced lesions, correlations of energy intake and brain serotonin concentrations after knife cuts, lesions, and in genetically obese animals, pharmacologic agonism and antagonism, neurotransmitter precursors, and nutrient-transmitter interactions. In humans serotoninergic agents are being employed as treatments for obesity and eating disorders and can be used as experimental tools for the investigation of human appetite Am iC/in

control Nutr

(12,

neurotransmitter

list provides

the basis

manipulations

may

be assessed.

The

fol-

of an evaluation. should

effectively

adjust

intake

is that

experimental

l992;55:l55S-9S.

Introduction

ofappetite

in

There are many chemical compounds that, when administered to experimental animals either parenterally or topically to the brain, produce short-term adjustments in food consumption (for list see references 14, 15). It has long been argued that such effects do not establish a biological role for the neurotransmitters or neuromodulators with which the applied chemicals interact. One ofthe tasks ofa rational methodology is to distinguish those agents that intervene naturally in the physiological processes and match feeding to nutritional requirements from those that disrupt or impede the system (16). Accordingly, it is worth considering what criteria should be adopted against which the case

of the most

nipulation KEY WORDS nutrition, receptors,

a role for neurotransmitters

13).

1992;55:155S-9S.

in USA.

© 1992 International

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important

criteria

neurotransmitter

should

produce

ma-

increases

and

decreases in food consumption. For serotonin it has been known for many years that agents leading to increased postsynaptic receptor activity (serotonin itself, releasers, reuptake blockers, precursors, direct agonists) give rise to a prompt and substantial anorexia. Indeed serotonin-induced anorexia has become a model against which other potential anorexic agents can be compared. However, the opposite effect, increase in food intake due to inhibition in serotonin systems, has been more difficult to demonstrate physiological agent

experimentally. and methodological

involved

(CCK),

it has

in

the

been

The

control

of

extremely

reasons for this are (17). Considering food

intake,

important

probably another

cholecystokin

to demonstrate

that

blockade ofCCK receptors could lead to increases in consumption. This has now been demonstrated many times due to the advent of specific antagonists for CCK-A type receptors, and this disclosure has been instrumental in confirming a physiological role for CCK in feeding(l8). Similarly, there are a number of reports showing an enhancement of food intake in rats by broad-spectrum serotonin antagonists such as methysergide, methiothepin, mesulergine, and metergoline (19-22). In addition,

about

during

‘From of Leeds,

2Addr

chology Printed

ofthe

Association

a dozen

treatment

reports

indicate

with serotonin

the BioPsychology Leeds, UK. reprint requests Department, for the Study

increased

receptor

Group,

Psychology

to JE Blundell,

University of Obesity

appetite

blockers.

of Leeds,

Department,

BioPsychology Leeds

in humans

Another

im-

University Group,

Psy-

LS2 9JT, UK. 1 55S

1 56S

BLUNDELL

portant

piece

of evidence

has

been

the

demonstration

necessary to indicate how visceral information, metabolic processing of nutrients, or physiological conditions associated with starvation and/or repletion are reflected in altered neurotransmitter activity. In other words, the theory must account for the representation of nutritional information in serotonin systems or for the impact of serotonin neurons on brain cells sensitive to nutritional status. For the serotonin system there are a number of routes that permit intimate associations between nutritionally relevant information and serotoninergic function. 5-HT and g/ucosensitive neurons. Glucosensitive neurons exist at different levels ofthe processing of ingested nutrients: within the periphery in the liver, within the brainstem in the nucleus ofthe solitary tract, and within the forebrain in the hypothalamus

of en-

intake after the administration of the 5-HT,A agonist as 8-OHDPAT (23) and the accompanying evidence

hanced

food

known suggesting

a mediation

via 5-HT,A

autoreceptors

on the

raphe

nuclei cell bodies (24). The reason why an enhanced intake serotonin postsynaptic receptor blockade is still a relatively

after elu-

sive phenomenon is probably due to the fact that the interaction of receptor subtypes responsible for feeding control has not yet been

fully

worked

receptors

and

gether

with

means

that

subtypes

out

the

Serotonin

When

and feeding

the

system (27). neuromodulators

Here

relationships

in the

sites

periphery

cells.

the

Consequently,

rostral

groups

superior nucleus

these

consists

on the

peripheral

of four

(B5, B7, and prosupralemnisus

dorsomedial

nucleus.

of Olszewski

and

main

nuclei

and

ulate

sensory send

B8),

main

This nomenclature (30). The caudal descending projections

5-HT

nuclei:

the nucleus

is based on the work group consists of five from this group mod-

to be important hypothalamus

integrative is innervated

In the paraventricular to be intimately related of 5-HT give rise to anorexia

nucleus 5-HT activity to feeding. Microinjections (31), whereas use of the

alysis

a release

has disclosed

of 5-HT

has

been here microdi-

contingent

that

creases)

5-HT-induced

are likely

effects

to be found

to be implicated feeding. However, upon

at other

eating

upon

sites

it is very

within

the

and

41, 42), protein

is that release)

The

behavioral for that

nutritional

demonstration

output neurotransmitter

state that

and

brain

de-

ence

forebrain

covaries

is not sufficient

in the expression

to identify

of appetite.

with

circulating

although there that abolishes demonstrated

this

a

a role It is also

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ratio

of 5-HT,

in lateral

hypothalamic

neu-

(Glucose-insen5-HT2 receptors

metabolites.

is some debate about the proportion this effect. This altered ratio, which after

pure

carbohydrate

intake,

could

of is act

to the brain the composition of the position adopted by some researchers

actually

drives

the

which

in turn

leads

synthesis to an

(and

ultimately

adjustment

in the

The experimental evidence for this end stage of the (see reference 43 for review) is not strong. However,

availability

remains

activity

a neurotransmitter

(ie, feeding)

in activity

the monitoring

It has been demonin the dorsal raphe

5-HT through 5-HT, receptors. are also modulated, excited via

and

behavior.

of tryptophan

one

brain Visceral

logical between

between

Diet composition and plasma amino acid profiles. More than 15 years ago it was proposed that “serotonin containing neurons appear to function as ratio sensors” (36) that “inform the brain about plasma amino acid patterns, and, possibly, about general nutritional state” (37). Similar theoretical positions were put forward (38-40). The basis for these postulations was the observed relationship between the tryptophan-large neutral amino acid (T-LNAA) ratio in plasma and the proportion of carbohydrate to protein in the diet. High-carbohydrate diets raise the T-LNAA ratio in plasma, which in turn increase brain tryptophan levels which leads to increased synthesis and release of 5HT. There are a number of reports indicating raised plasma ratios resulting from a high carbohydrate content in the diet (38,

the

and hindbrain. Links

link

via 5-HT, receptors.) In addition it has been argued is a close association in the paraventicular nucleus between glucoreceptor neurons, a2 adrenoreceptors and anorexic agent binding sites (35). This neurochemical complex is also activated by circulating corticosterone. Consequently, these mechanisms illustrate ways in which 5-HT activity modulates the output ofa chemosensing neuronal system sensitive to energy

hypothesis

in the brain

(increases

changes

as a signal that represents diet. However, the strong

(32). Activation of 5-HT,A autoreceptors in the region of B7 also produces an increase in food intake (24). Consequently, experimental techniques have shown 5-HT terminals to be active

likely

some

or inhibited that there

clearly

eating

and functional at some sites known network of pathways controlling

inhibitory neurons

mobilization

periventricular tract and the medial raphe In addition, the hypothalamus contains an of 5-HT in the dorsomedial hypothalamic

nucleus. shown

procedure

neurons

Within the nine distinct groups (28,

in the spinal cord. The rostral projecting into the forebrain

processing pathways

to make contact with zones known sites for the control of feeding. The by the dorsal raphe forebrain tract (28). endogenous source

state

secreentero-

the raphe dorsalis (B6 and (B9), and the hypothalamic

Baxter

and motor long axonal

with other sensory re-

information

produces

ceive sitive

nervous

effectors in musculature, blood vasculature; and

are implicated in many aspects of visceral function. brain 5-HT cell bodies can be divided into at least nuclei separated into rostral and caudal brainstem

group

that

enteric

act in collaboration network that links

moment-to-moment

to disclose

rons (34). This situation has been used to investigate the modulation ofthis activity by serotoninergic agents. It was concluded that 75% of lateral hypothalamic glucose-sensitive neurons re-

biological

fundamental

within

tract with epithelium,

It is important

nuclei in the

it is of course

5-HT neurons in a complex

generating

The

(33).

of glucose and the serotoninergic system. strated electrophysiologically that stimulation

for a neurotransmitter

appetite,

of the gastrointestinal tory, and absorptive

29).

become

pathways should exist at central and/or peripheral to be crucial for feeding. A good deal of serotonin exists

centralis B7), the

block

antagonists

to identify

to-

antagonists

to selectively

these

for feeding.

a role

body

endocrine

impossible

receptor.

of autosubtypes

receptor-specific

relevant

controlling

ceptors

of

be easier

systems

in the

lack

association

of differing

subtypes

In establishing transmitter sites known

close

certainly

receptor

network

The

receptors

it is experimentally it will

among

26).

current

of the 5-HT,

available

(25,

postsynaptic

way

in which

serotoninergic information

control

of feeding

to the

brain

nutritional

systems. and 5-HT. must

(via

T-LNAA

information

Any account

consider

the

ratio)

could

influ-

of the physio-

position

of the

nu-

cleus of the solitary tract (NTS). This key area in the hindbrain, together with the closely associated area postrema (AP), receives both sensory vagus nerve.

and The

visceral adjacent

information most prominently via the dorsal motor nucleus is the source of

SEROTONIN vagal

efferent

istration

pathways.

The

of visceral

following

information

picture

occurs

tegration in forebrain areas cleus). There is anatomical volved in this system. The

THE

is suggested.

in the

AP); this information is transcribed carried forward by means of long

and and

AND

Reg-

hindbrain

tions

neurons for in-

(particularly the paraventricular nuevidence that 5-HT neurons are inrole of catecholaminergic pathways

has been well described (44) and it is of fundamental importance that the A2 cell cluster is located in the NTS (45). There are considerable links between these noradrenergic nuclei and the dorsal 28,

and 29).

nuclei

medial

Direct

have

efferent

inputs

exist.

Efferent

been

described

like the CA systems, information brain noting

nuclei

also

may

NTS

raphe

from

(B6/B7, from

and

the

NTS

pathways

(29).

B8,

respectively;

B7 and

Consequently,

5-HT

the

classical

pharmacologic

procedure

of agonist-antagonist

in-

teractions, two pieces of evidence for this postulation are now available. First, it has been demonstrated that the nonspecific 5-HT receptor blocker metergoline blocked the inhibitory effect of exogenously administered CCK on food intake (46). Second, fenfluramine-induced anorexia was attenuated by the CCK-A receptor blocker MK-329 (47). These data suggest that one of the

pathways

from

the

stomach

hypothalamus is shared the case, it follows that release of CCK, such potent 5-HT-mediated ditional route through linked

to 5-HT

via the

vagus

and

NTS

to the

by CCK and 5-HT neurons. If this is nutritional factors that strongly elicit the as dietary fat (48), may also promote a anorexia. Consequently, this is one adwhich nutritional information could be

neurons

via visceral

afferent

pathways.

under

all circumstances. variables.

potency including

that

and

Modulation

implications

lines

is intimately

and role

with the of 5-HT

expression

that

“the

neurons

ascending

component

now of the

that

with feeding

system

behavioral

5-HT

nutritional drive.

be characterized?

serotonin

of specific

confirm

concerned

How

offood

intake; factors

ables (14). In human nection

It has been

or endocrine

events,

studies

between

plasma

ratios

is altered

and in certain adequately dence

types corrected

by a glucose central

5-HT

and the expression

between

nutritional

pattern

of eating.

through

which

relevant

carry

significant for the

nutritional

maintenance

(57).

time

There

metabolism

(56)

it is not

is also in eating

eviand

the review of5-HT and feedoperate to modulate the re-

input

(and

processing)

and

func-

5-HI

systems

is handled

operations suggests at every stage in the

are implicated by the body.

in the processes In keeping

with

this

but serves

petite.

this

proposed

factor

and

information

balance

nervosa

which

structural

function.

visceral

anorexia

during

picture, it would be expected that the exploitation of this cornprehensive modulatory role of 5-HI for therapeutic purposes would produce substantial adjustments in the expression of ap-

of the total of energy

and

For example, the esmeals upon T:LNAA

and in postabsorptive could be implicated

food

Accordingly,

are strengthened

highly

con-

information

The involvement of 5-HT systems during the acprocess (microdialysis studies) in postingestive (but

and

HT systems

of a sensitive

of appetite

The picture which emerges from ing is that various 5-HT pathways

processing

peptides,

neurochemical

van-

(58, 59). Moreover, it has been demonstrated response to a tryptophan challenge is significantly elevated in women after adherence to a 1000 kcal/d diet for 3 wk (60). This sex-specific neuroendocrine response indicates a shift in the sensitivity of 5-HT-mediated processes caused by a relatively mild dietary adjustment. Taken together, these findings indicate a sensitive connection between nutrition and various aspects of 5-HT metabolism in the periphery and brain.

duced

and other neuromodulators, no single likely to be critical to the maintenance

inhi-

is modulated contextual

dietary

load

5-HT

indicate

weight disorders that the prolactin

satiety

of amines,

other

with

(57),

data

a mechanical

evidence of

in patients

of obesity

of disordered

These

anorexia

physiological variables implicating 5-HT. tablished effect ofcarbohydrate and protein

balance

network

55).

with

is also

anorectic

ofseparate macronutrient (53), and the circadian

ofthe

processing

to nutri-

the

by nutritional variables, available (49, 50), the

(54,

together

there the

5-HI and to block ger and in energy

by a complex

manipula-

is linked

studies

is not simply

the intensity acting

to modulate their expression” (28). This statement seems to apply quite well to the role of 5-HT in appetite. Because of the extent to which overall integration of all facets of appetite and energy is maintained

nutrients

anorexia

(at various should

is not an essential

of 5-HT

in animal

is modulated ofcarbohydrate

for particular

5-HT-induced

bition

action

example,

preabsorptive) events that 5-HT components

of evidence

sites)

5-HT

in feeding.

ofthe diet (5 1), the availability (52), the degree of hydration

tional output. tual ingestive

or control

Many bodily

clinical

The

For

of5-HT activation the proportion

lationship

Theoretical

is not marginal; adjustments

sensitivity

by dietary

Postulated CCK-5-HTconnections. One further way in which 5-HT neurons could mediate in the transmission of postingestive information from its visceral origin to critical forebrain sites close to the pituitary is via the hormone CCK. Several years ago the possibility of such a relationship was postulated (JR Harper, JE Blundell, unpublished observations, 1987). Making use of

modulation

to sizeable

tional

preference

and to modulate the output of the NTS. It is also worth that clusters of 5-HT cell bodies exist in the AP (29).

157S

However the role of 5-HT in the control of feeding is characterized, it is evident that experimental alterations in 5-HT do not lead to automatic adjustments in all aspects of eating or

neurons,

are in a good position to both relay visceral the NTS to the integrative centres in the fore-

rise

Nutritional

texture sources

raphe

FEEDING

The

give

B8 to the

or AP onto

from

OF

suppressed.

(NTS

onto aminergic axonal pathways

BIOLOGY

and

is

5for

the organization of an appropriate level of feeding behavior in response to physiological requirements. This modulation of the flow of neural information between input and output is clearly evident when 5-HT neurons are experimentally activated or

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the

use

of pharmacologic

agents

to release

its reuptake produce clear reductions in hunintake (6 1). The processes of satiation and

the satiety

(62).

In animal

studies,

meal

size

is re-

ratio (meal size:postmeal interval) is increased (63), whereas in human experiments meal size is reduced by 10-15% and the postmeal suppression of hunger is preserved, leading to an elimination of some snacks from the eating repertoire (13). These clear effects (leading to a reduction of 1015% in daily energy intake) appear to be brought about by the activation of 5-HI systems intensifying the satiating power of food through both postingestive and postabsorptive components of the satiety cascade (64, 65).

1 58S

BLUNDELL

Ihe

evidence

from laboratory

and therapeutic

studies

that there is noticeable retical role for 5-HI

agreement between the in feeding and the clinical

upon

the

propositions.

tems

in the

bution linked

theoretical body

(the

disclose

actions potent

and

therapeutic

disorders.

of the itself

and

details

lead

to the

tools

of the

for the

sys-

the distri-

means that 5-HI is intimately in a number ofdifferent ways

operations

development treatment

between research

of these

of more

precise

of eating

and

progress towards CNS therapeutic targets. London: Oxford University Press (in press). 19. Blundell JE, Latham CI, Leshem MB. Biphasic action of a 5-hydroxytryptamine inhibitor on fenfluramine induced anorexia. J Pharm Pharmacol l973;25:492-4. 20. Fletcher PJ. Increased food intake in satiated rats induced by the 5HI antagonists methysergide, metergoline and ritansenn. Psychopharmacology l988;96:237-42. 21. Dourish CT, Clark ML, fletcher A, Iversen SD. Evidence that blockade ofpost-synaptic 5-HT, receptors elicits feeding in satiated rats. Psychopharmacology 1989;97:54-8. 22. Stallone D, Nicoladis S. Increased food intake and carbohydrate preference in the rat followingtreatment with the serotonin antagonist metergoline. Neurosci Lett l989;l02:3l9-24. 23. Dourish CT, Hutson PH, Curzon G. Low doses ofthe putative serotonin agonist 8-hydroxy-2 (Di-n-propylamino) letralin (8-OH. DPAT) elicit feeding in the rat. Psychopharmacology 1985;86: 197204. 24. Hutson PH, Dourish CT, Curzon G. Neurochemical and behavioural evidence for mediation of the hyperphagic action of 8-OH-DPAT by 5-HT cell body autoreceptors. Eur J Pharmacol 1986; 129:34751. 25. Garattini 5, Bizzi A, Caccia S, Codegoni AM, Mennini I. Progress report on the anorexia induced by dregs believed to mimic some of the effects of serotonin on the central nervous system. Am J Clin Nutr 1992;55(suppl): l6OS-6S. receptors:

theobased

5-HI

function). The sensitive association and 5-HI suggests that further

additional also

nature

of 5-HI

ofneurons and pathways) to feeding-related processes

(and not via a single nutritional variables will

The

metabolism

indicates

proposed outcome

interand weight

B

References 1. Soulairac A. Neurological factors in the control ofappetite. In: Pfeiffer CC, Symthies JR. eds. International review of neurobiology. New York: Academic Press, 1963:203-346. 2. Singer G, Sanghvi I, Gershon S. Exploration ofcertain behavioural patterns induced by psychoactive agents in the rat. Commun Behav Biol l97l;6:307-l4. 3. Blundell JE. Is there a role for serotonin (5.hydroxytryptamine) in feeding? Int J Obes 1977;1:l5-42. 4. Coscina DV. Brain amines in hypothalamic obesity. In: Vigersky RA, ed. Anorexia nervosa. New York: Raven Press, 1977:97-107. 5. Hoebel BG. The Psychopharmacology of feeding. In: Iversen LL, Iversen SD, Snyder SH, eds. Handbook of psychopharmacology. Vol 8. New York: Plenum, 1977:55-129. 6. Blundell JE. Serotonin and feeding. In: Essman WB, ed. Serotonin in health and disease. Vol 5. New York: Clinical Applications Spectrem, 1979:403-50. 7. Blundell JE. Serotonin and appetite. Neuropharmacology 1984;23: 1537-52. 8. Blundell JE. Serotonin manipulations and the strecture of feeding behaviour. Appetite 1986;7:39-56. 9. Garattini S. Importance of serotonin for explaining the action of some anorectic agents. In: Bray GA, ed. Recent advances in obesity research: II. London: Newman, 1978:433-41. 10. Nicolaidis 5, ed. Serotoninergic system, feeding and body weight regulation. London: Academic Press, 1986. 1 1. Lent CM, Dickinson MH. The neurobiology of feeding in leeches. Sci Am 1988;26l:98-l03. 12. Blundell JE, Hill AJ. Influence of tryptophan on appetite and food selection in man. In: Kaufman 5, ed. Amino acids in health & disease: new perspectives. New York: Alan Liss 1987:403-19. 13. Blundell JE, Hill AJ. Serotoninergic modulation of the pattern of eating and the profile of hunger.satiety in humans. mt J Obes l987;l 1(suppl 3):141-55. 14. Blundell JE. Systems and interactions: an approach to the pharmacology of eating and hunger. In: Stunkard AJ, Stellar E, eds. Eating and its disorders. New York: Raven Press, 1984:39-65. 15. Blundell JE, Hill AJ, Lawton CL. Neurochemical factors involved in normal and abnormal eating in humans. In: Shepherd R, ed. Handbook of the psychophysiology of human eating. Chichester, England: Wiley, 1989:85-112. 16. Blundell JE, Latham CJ. Pharmacological manipulation of feeding behaviour: possible influences of serotonin and dopamine on food intake. In: Garattini 5, Samanin, R, eds. Central mechanisms of anorectic dregs. New York: Raven Press, 1978:83-109. 17. Blundell JE. Strecture, process and mechanism: case studies in the psychopharmacology of feeding. In: Iversen LL, Iversen SD, Snyder SH, eds. Handbook of psychopharmacology. Vol 19. New York: Plenum 1987:123-82. 18. Smith GP. The cholecystokinin hypothesis of satiety. In: Dourish CT, Cooper Si, Iversen SD, Iversen LL, eds. Multiple cholecystokin

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26.

27.

28.

29.

30. 31. 32.

33. 34.

35.

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