Serotonin and Appetite

G. CURZON
Institute of Neurology
Queen Square
London WCl N 3BG England

INTRODUCTION

Neurochemical research on relationships between tryptophan (TRP), 5-hydroxy-

tryptamine (5-HT) and feeding has centered on how feeding affects brain T R P
concentration and on the synthesis and availability of 5-HT. Pharmacologists have
focused on the control of appetite by 5-HTergic drugs. These findings lead to questions
such as whether effects of feeding on T R P and on 5-HT function are involved in the
normal control of appetite and in disorders such as anorexia nervosa. Research in this
area has been stimulated by recent evidence for numerous 5-HT receptor subtypes.
This chapter will mainly concern how drugs with selectivity towards these receptors
affect feeding in the rat. As a drug used clinically to decrease appetite (fenfluramine,
Ponderax@)acts by releasing 5-HT,' it is probable that other 5-HT-ergic drugs can
influence appetite in the rat and do not decrease food intake merely, for example, due to
general malaise. Before describing research on this topic the effects of feeding on brain
T R P and of T R P administration on feeding will be briefly indicated.

EFFECTS OF FEEDING ON BRAIN TRP AND 5-HT

Rat brain tryptophan increases on giving a large high carbohydrate-low protein

meal, because of a fall of plasma concentrations of amino acids which compete with
T R P transport to the brain.* A similar increase occurs on overnight fasting because
T R P is freed from binding to plasma albumin so that it becomes more available to the
brain.' While these mechanisms may normally have no more than slight effects under
normal dietary conditions,' it should be remembered that this conclusion is based on
data from relatively few subjects studied over short periods. As values obviously range
more widely within larger groups or over longer periods of study, subgroups could exist
with brain T R P concentrations that are highly sensitive to dietary influences. Such
T R P changes can influence 5-HT synthesis, but there is still no direct convincing
evidence that giving TRP, even at pharmacological dosage, increases 5-HT at receptor
sites. Nevertheless, T R P and 5-HT-ergic drugs affect feeding and it is particularly
interesting to note that feeding has recently been reported to increase extracellular
5-HT in the lateral hypothalamus of the rat.' These findings suggest that feeding may
lead to central T R P and 5-HT changes which normally mediate its termination and
that inappropriate relationships between feeding or food deprivation and changes of
brain indole chemistry and 5-HT function could be involved in disorders of appetite
such as anorexia nervosa.

EFFECT OF L-TRP ON FEEDING

As 5-HT-ergic drugs affect feeding' and brain 5-HT synthesis is increased by

~ effects of T R P on feeding have received much attention. Early work on rats
L - T R Pthe
521
522 ANNALS NEW YORK ACADEMY OF SCIENCES

failed to reveal changes” perhaps because the amino acid was given after food
deprivation as intake was decreased under other conditions, i.e. on the first day of
exposure to a diet to which L-TRP was added.” Similar results were obtained on
humans.” The association of anorexia in cancer patients with high plasma free T R P
and C S F T R P concentration^'^ may therefore be of causal significance.
L-TRP can also affect food choice as acute’4 or chronic” administration to rats
within meals decreased subsequent carbohydrate intake and increased protein intake.
Similarly, l g L-TRP given to humans in a high protein meal decreased carbohydrate
intake in a later, free choice meal.15 Conversely, if plasma T R P was decreased by
giving a T R P deficient amino acid mixture then protein intake in a later, free choice
meal was decreased.I6
These findings are consistent with an important role for 5-HT in feeding. However
the influence of other pathways of T R P metabolism on feeding remains largely
unexplored. Nevertheless evidence, summarized below, on the effects of 5-HT receptor
subtype agonists on feeding strengthens interpretation in terms of 5-HT.

EFFECTS OF 5-HT AGONISTS ON FEEDING

5-HT,AAgonists

The putative 5-HTI, agonists 8-hydroxy-2-(di-n-propylamino)tetralin(8-OH-

DPAT)’7,’8 buspirone, ipsapirone,” gepirone2’ and LY 165 163” increase food intake in
free feeding rats. Typical data is shown in TABLE1. As the anorexic effects of
non-selective, indirect 5-HT agonists (e.g. fenfluramine and 5-hydroxytryptophan)
and the hyperphagic effects of the 5-HT synthesis inhibitor p-chlorophenylalanine
(pCPA) suggest that 5-HT inhibits food intake,’.’ 8-OH-DPAT was proposed to cause
hyperphagia by activating presynaptic 5-HTl, receptors so that 5-HT release from
terminals is decreased.” This mechanism is supported”,” by the absence of 8-OH-
DPAT- and LY 165163-induced hyperphagia after depletion of 5-HT by pCPA.
Presynaptic 5-HT,, receptors do not occur on 5-HTI, terminals23but are found at high

TABLE I. Effects of 5-HTI,Agonists on Food Intake in Freely Feeding Rats“

Treatment 6 . C . I Food Intake (e. i SEM)

Two hours
Saline 0.8 & 0.3
8-OH-DPAT 0.125 mg/Kg 2.2 ? 0.4
8-OH-DPAT 0.250mg/Kg 2.1 i 0.4

Saline 0.4 & 0.1

LY165163 0.5 mg/Kg 1.5 t 0.5
LY165163 lmg/Kg 2.3 + 0.3
Four hours
Saline 1.6 & 0.4
Gepirone 4 mg/Kg 3.4 + 0.4
Gepirone 8 mg/Kg 4.4 k 0.3

Saline 1.5 2 0.3

Buspirone 4 mg/Kg 3.2i 0.5
Ipsapirone 5 mg/Kg 2.2 2 0.5
“Effects of drugs were all p 4 0.05
CURZON: SEROTONIN AND APPETITE 523

TABLE 2. Effects of Antagonists on the Hyperphagic Response to 8-OH-DPAT

(1 mg/Kg s.c.) in Normally Fed Rats"
Treatment Blockade Interpretation
Metergoline Srng/Kg Yes 5-HT receptor
Ketanserin 2.5mg/Kg No Not 5-Htz. a,
ICS-205-930 1mg/Kg No Not S-HT,
( - ) Pindolol4rng/Kg Yes 5-HT,,, 5-HT,,, or p
( + ) Pindolol4rng/Kg No Not
Spiperone O.OSmg/Kg Yes 5-HT,, or DA
Haloperidoi O.lmg/Kg No Not DA or a ,
Idazoxan 3mg/Kg No Not a2
"Data are from ref. 28.

density on 5-HT cell bodies in the raphe nuclei"; injecting 8-OH-DPAT therein
increased feeding."
Although 8-OH-DPAT has high affinity for 5-HTl, sites it also has lower affinity
for 5-HTlB,5-HT,,, 5-HTl,, and 5-HTz sitesz6 and also for a,-adrenergic" sites.
However, antagonist experiments2* point strongly to the hyperphagic effect being
mediated at 5-HTl, sites (TABLE2).
It is conceivable that 8-OH-DPAT affects feeding via a general activation of motor
and consumatory behavior due to a widespread decrease of 5-HT release a t terminals.
It is known that raphe lesions can enhance dopamine-dependent behavior such as
locomotion and gnawing." Therefore 8-OH-DPAT might increase feeding secondarily
to a release of these behavioral components. Indeed it has been s ~ g g e s t e d ~ "that
. ~ ' it
elicits eating merely as a consequence of gnawing. However, animals given a choice
between food pellets and wood blocks chose to eat the pellets17and both 8-OH-DPAT
and gepirone dose-dependently increased consumption of a liquid diet.32
TRP, which might increase 5-HT at postsynaptic receptors, decreases carbohy-
drate intake.".'4-'6Therefore it is of interest that 8-OH-DPAT, which decreases 5-HT
at these sites33had the opposite effect, increasing carbohydrate intake by rats given a
carbohydrate/protein choice (Sarna, Whitton, Curzon and Leathwood, unpublished).
These findings are consistent with the hypothesis that the choice depends on 5-HT
functionj4but it seems unlikely that this mechanism operates in the normal animal as a
result of normal patterns of food i r ~ t a k eeven
~ . ~though
~ it may occur on drug treatment.
Also, it has been speculated that the resultant changes at 5-HT receptors may not
influence discrimination between carbohydrate and protein as such, but instead some
unrelated sensory difference between the characteristics of the diet^.^^.^'

5 - H T , , and 5-HT,, Agonists

If decreased 5-HT at postsynaptic sites is responsible for the hyperphagic effects of

5-HTl, agonists then two questions arise: which 5-HT receptor subtypes are involved
and where do they occur? Postsynaptic 5-HTl, receptors are possibly implicated as the
5-HTIBagonist RU 24969 causes hypophagia.""" Also 1-(3-chlorophenyl) piperazine
(mCPP) and I -[3-(trifluoromethyl) phenyl] piperazine (TFMPP) which have substan-
tial affinityJ0.41for 5-HTlB5-HTl, and 5-HT2sites caused hypophagia in normally fed
and food-deprived Results on the above three drugs are given in TABLE 3.
RU 24969 also causes h y p e r a ~ t i v i t y ~whilst
~ , ' ~ mCPP and TFMPP cause hypoac-
tivity which is mediated by central 5-HTl, receptors.45 It therefore seemed possible
524 ANNALS NEW YORK ACADEMY OF SCIENCES

TABLE 3. Effects of 5-HT,,/5-HTl, Agonists on Food Intake in Freely Feeding Rats"

Treatment (i.p.) Food intake (g/4h i SEM)
Saline 1.14 0.18
RU 24969 1mg/Kg 0.55 2 0.12
RU 24969 2mg/Kg 0.30 * 0.10
RU 24969 5mg/Kg 0.07 f 0.16

Saline 1.21 i 0.16

mCPP lmg/Kg 0.31 t 0.17
mCPP 5mg/Kg 0.15 t 0.03
TFMPP lmg/Kg 0.52 2 0.07
TFMPP 5mg/Kg 0.15 f 0.03

"Data are from ref. 38. Effects of drugs were all p < 0.05.

that mCPP- and TFMPP-induced hypophagia also involved stimulation of 5-HTl,

receptors. Indeed, evidence45 suggested this was so for the hypophagia seen when
mCPP and TFMPP-treated rats were placed for 20 min in a novel cage. Responses to
RU 24969, mCPP and T F M P P were therefore investigated under conditions more
appropriate to the study of hypophagia, i.e., using animals previously deprived of food
and measuring intake over longer
When this was done, the effects of antagonists (TABLES4 and 5 ) indicated that
mCPP (and probably also TFMPP) caused hypophagia by stimulating 5-HTl, recep-
tors although functional 5-HT,, receptors were also needed for the response to occur.
However, RU 24969 acted solely by direct stimulation of 5-HT,, receptors. Since
completing this work, it was reported that both mCPP and TFMPP bind somewhat
more strongly to 5-HTl, receptors than to 5-HT,, sites in vitro.26
Affinities of the antagonists for non-5-HT receptors are unable to explain their
effects on hypophagias due to RU 24969 or mCPP. Thus although mianserin (but not
metergoline or mesulergine) has high affinity for histamine H 1 re~eptors,~'~''reduced
histaminergic activity reduces food intake.49 Mediation by a2 receptors for which
mCPP and mianserin have some affinity50.5'is also unlikely, since the specific a2
antagonist idazoxan did not oppose mCPP-induced hypophagia. The a l antagonist
phentolamine is also ineffective.J2 Lastly, mCPP has little affinity for dopamine
receptors.'2 Two anomalous findings must be mentioned. Firstly, cyproheptadine ( 1 0

Effects of Antagonists (S.C.) on the Hypophagic Response to R U 24969

TABLE 4.
(Smg/Kg i.p.)"
Treatment Blockade Interpretation
Metergoline 5mg/Kg Yes 5-HT receptor
Ketanserin 0.2 mg/Kg No Not 5-HT2, L Y ~
ICS 205930 lmg/Kg No Not 5-HT3
Mianserin Smg/Kg No Not 5-HT,,, 5-HT2, H ,
Mesulergine 0.2mg/Kg No Not 5-HTIc, 5-HT2, DA
1 - N P 2mg/Kg No Not 5-HTl,, 5-HT2
( k ) Cyanopindolol8mg/Kg Yes S-HTIA, 5-HTIB. P
(-) Pindolol 2mg/Kg Yes P
~ - H T , AS-HTIB,
,
( + ) Pindolol 2mg/Kg No Not p
Spiperone 0.1 Omg/Kg No Not 5-HTlA,5-HT2, DA
"Data are mostly on food-deprived rats (ref. 46); some on freely feeding rats (ref 39). I - N P =
1-Naphthyl piperazine.
CURZON: SEROTONIN AND APPETITE 525

mg/Kg, not shown), unlike other 5-HTIc antagonists, did not block the hypophagic
effect of either drug, although it antagonized mCPP-induced hypoloc~motion.~~ Sec-
ondly, unlike other 5-HTl, and 5-HT,, antagonists, (-) pindolol ( 2 mg/Kg, not
shown) did not block mCPP-induced hypophagia even though it prevented hypophagia
due to RU 24969.
Notwithstanding the above anomalies, antagonist experiments as a whole strongly
suggest that mCPP and TFMPP cause hypophagia by action at 5-HTlc receptors.
These together with our previous data on the hypolocomotor effect of mCPP45
and our subsequent findings on its anxiogenic effect” were of some potential impor-
tance as they were the first evidence for behavioral consequences of activating 5-HTIc
receptors. We have therefore paid particular attention to the fact that 5-HTlcsites and
5-HT2 sites have much in common. Thus, most antagonists with high affinity for
5-HTIc sites also bind strongly to 5-HT2 sites26and activation of both sites induces
phosphoinositide h y d r ~ l y s i s Furthermore,
.~~ activation of 5-HT2 sites has been sug-
gested to mediate fenfluramine-induced hypophagia, as it was blocked by ketan~erin.~’
This drug and two other 5-HT2 antagonists, LY 53857 and 1-naphthylpiperazine
(I-NP), also blocked hypophagia due to 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopro-

Effects of Antagonists (S.C.) on the Hypophagic Response to mCPP

TABLE 5.
(5mg/Kg i.p.)“
Treatment Blockade Interpretation
Metergoline Smg/Kg Yes 5-HT receptor
Ketanserin 0.2 rng/Kg No Not 5-HT2,
Ritanserin 0.6rng/Kg No Not 5-HT2
ICS 205930 Img/Kg No Not 5-HT3
Mianserin 5mg/Kg Yes 5-HT1c,5-HT2, HI
Mesulergine 0.2 mg/Kg Yes S-HT,,, 5-HT,, DA
1-NP 2mg/Kg Yes 5-HT,c, 5-HT2,
(+) Cyanopindolol 8mg/Kg Yes S-HTIA,S-HTIB,B
(-) Propanolol 16mg/Kg Yes S-HTiA, S-HT,,, P
Idazoxan 1mg/Kg No Not a2
“Data are on food-deprived rats (ref 46). 1-NP = I-naphthyl piperazine.

pane (DOI).S6These considerations may seem to cast doubt on our evidence that
activation of 5-HTIc sites causes hypophagia. On the other hand since 1-NP is also a
~ ~ DO1
potent 5-HTIca n t a g ~ n i s tand . ~ ~ and LY 53857 have high affinity for the 5-HTl,
site,26the evidence for the involvement of S H T , sites relies heavily upon the selectivity
of ketanserin. These problems were investigated (Kennett and Curzon, unpublished)
by determining the in vivo antagonist potencies of nine antagonists to both 5-HT2and
5-HTlc sites (ketanserin, ritanserin, mianserin, 1-NP, LY 53857, methysergide,
altanserin, metergoline and ( + ) propranolol) against 5-HT2-mediated head twitch
behavior” and mCPP-induced hypophagia. The ratios of the ID,, values obtained
correlated highly significantly ( p < 0.001) with the ratios of the affinities for 5-HTlc
and 5-HTl, sites as calculated from published data.26This strengthens our evidence
that mCPP-induced hypophagia is mediated by 5-HT,, rather than by 5-HT2 recep-
tors. Relating the in vivo effects of drugs to their in vitro binding affinities eliminates
uncertainties due to differences of metabolism of different drugs, as such differences
would comparably affect ability to inhibit both hypophagia and head twitch.
Other recent data are also consistent with 5-HTIc rather than 5-HT2 sites
mediating hyp~phagia.’~ Thus, a dose of ritanserin causing 50% occupation of 5-HT2
526 ANNALS NEW YORK ACADEMY OF SCIENCES

sites had no effect on D-fenfluramine-induced hypophagia while 4 x the dose inhibited

it about 50%. This suggests mediation by 5-HT,, sites as it can be calculated from the
affinity constantsz6that the above increase of ritanserin dosage would be sufficient to
half saturate 5-HTl, receptors but would have little effect on either 5-HT,, or 5-HT,,
sites.
Are RU 24969 or mCPP and TFMPP-induced hypophagias secondary to other
behavioral effects? Hypophagia due to RU 24969 is unlikely to be secondary to its
hyperlocomotor effect, as h a l o p e r i d 0 1 ~and ~ ~ ~p~i n~ d ~ l o block
~ ~(+) l ~ ~ this but not the
hyp~phagia.~' Conversely, metergoline blocks the h y p ~ p h a g i abut ~ ~ potentiates
.~~ the
h y p e r l o c ~ m o t i o nAlso,
. ~ ~ ~infusing
~~ R U 24969 into the hypothalamus caused hypopha-
gia only.39Evidence also points to mCPP (and TFMPP) hypophagia and hypoactivity
being separately induced since ( k ) cyanopindolol or ( - ) propanolol did not alter the
activity, yet prevented the h y p ~ p h a g i a , ~while
' . ~ ~ T F M P P caused hypophagia but not
hypoactivity on hypothalamic infusion.39 Lastly, while the 5-HTl, antagonists mian-
serin, 1-NP, cyproheptadine, and mesulergine opposed both mCPP-induced hypopha-
gia and hypoactivity they increased food intake, but not activity, when given alone.45,"
These increases were seen in normally fed but not in food-deprived rats. Therefore, the
hyperphagia may either be rate dependent or due to effects on appetite rather than
satiety. This may explain contradictory reports on the effect of cyproheptadine on rat
food i n t a k ~ ' ~ . ~ '
It is conceivable that 5-HTl, and 5-HT,, agonists cause hypophagia merely due to
drug-induced malaise. This was investigated6' using the antiemetic drug trimethoben-
zamide (TMB). This is a rational procedure, even though rats cannot vomit, as T M B
prevents both the putative malaise-induced hypophagic response to cholecystokinin6'
and lithium chloride-induced taste aversion." As it prevented the hypophagic response
of rats to acetyl salicylate (a known emetic in man and dogs) but did not affect
hypophagia due to R U 24969, mCPP and TFMPP, the latter effects probably do not
reflect a malaise-dependent mechanism.
As infusing 5-HT or norfenfluramine into the paraventricular nucleus (PVN) of
the hypothalamus causes h y p ~ p h a g i ait, ~seemed
~ likely that R U 24969, mCPP and
TFMPP had a similar effect at this site; as briefly mentioned above, this was shown.
Thus 0.5, 1.0 and 2.0 pg of both R U 24969 and TFMPP caused dose dependent
hypophagia on PVN infusion.39Similar infusion of 8-OH-DPAT was without effect.

SEX DIFFERENCES IN 5-HT DEPENDENT HYPOPHAGIA

The revelation of sex differences in the hypophagic effects of stress have led us to
similar studies on hypophagic 5-HT agonists. In the former work, a single 2 h restraint
stress caused hypophagia over the next 24 h. This was not merely a result of the gastric
lesions which can result from restraint as the histamine-H, antagonist ranitidine
decreased their number but not the hy~ophagia.~' On repeating the restraint daily for 5
day^,'^,^' food intake returned to normal in male but not in female rats. It has also been
reported that chronic fenfluramine infusion is more hypophagic in female rats than in
maleshxSubsequently, it was shown that the hypophagic effects of R U 24969 and
mCPP were greater in female than in male rats if they had been deprived of food for
24 h but not in freely feeding animals.69 These results suggest the existence of a 5-HT
dependent hypophagic mechanism which is more active in food-deprived female rats
than in males. This could conceivably have a role in the greater incidence of anorexia
nervosa in women.
CURZON: SEROTONIN AND APPETITE 527

SUMMARY

Feeding or food withdrawal can affect the supply of tryptophan to t h e brain and
hence (in some circumstances) 5-HT synthesis therein. Also fenfluramine which
releases 5-HT to postsynaptic receptors suppresses appetite, and there a r e reports that
tryptophan can have a similar effect. Furthermore, feeding is reported to release
hypothalamic 5-HT. Therefore 5 - H T could have a role in the normal termination of
feeding and perhaps also in disorders of appetite. T h e recognition of various 5-HT
receptor subtypes has stimulated research in this area. W e have now investigated the
involvement of the subtypes in the pharmacological control of feeding.
Thus, 5-HT,, agonists ( % O H D P A T , buspirone, gepirone, etc.) stimulate intake in
freely feeding rats, probably by activating autoreceptors on t h e cell bodies of 5-HT
neurons so that 5-HT release a t terminals is decreased. T h e hyperphagia is not
explicable by increased activity or gnawing and is strikingly manifest against carbohy-
d r a t e in carbohydrate vs. protein choice experiments.
Feeding in previously food-deprived rats is decreased by t h e 5-HT agonists
RU 24969, 1-(3-chlorophenyl) piperazine ( m C P P ) and 1-(3-trifluoromethyl) phenyl)
piperazine ( T F M P P ) . Effects of antagonists on these properties suggest that RU
24969-induced hypophagia depends on 5 - H T , receptors only, while mCPP a n d
TFMPP induce hypophagia a t 5-HT,, sites, though this effect also requires 5-HT,,
receptors for its expression. Responsible sites occur in t h e paraventricular nucleus of
the hypothalamus a s infusing either RU 24969 or TFMPP therein causes hypophagia.
On systemic injection, the hypophagic drugs a r e particularly active in female rats, an
effect of conceivable relevance to human anorexic illness.

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DISCUSSION OF T H E PAPER

R. MURPHY(New York University, New York City): A question with regard to

your hypophagia. I gathered from your slides that some of the animals are food
deprived and some of the animals are free feeding. I’m just curious if you’ve looked
systematically at food-deprived animals vs. the non-deprived animals in terms of the
effect.
CURZON: Yes. Hypophagia was seen in freely feeding or food-deprived rats. But
ED,, values are greater in the food-deprived ones.
CURZON SEROTONIN AND APPETITE 531

S . LIEBOWITZ (Rockefeller University, New York City): I agree with that com-
ment. In freely feeding animals we get lower threshold doses in terms of the effective-
ness of the drugs. I also wanted to ask if a circadian rhythm in the effects of serotonin
could be modulating nutrient intake.
CURZON:That’s a very important point. However, we have usually done our
experiments in the afternoon. It’s a real gap in our work that we haven’t looked at
different times of day. I think there’s been at least one paper in the literature where
DPAT was shown not to be hyperphagic when given during the night, which is when
the animals normally eat most. There seems to be a ceiling level of food intake and
DPAT can’t bring that up any higher.
LIEBOWITZ: I was particularly intrigued by your last slide in terms of showing, I
think it was a surge in the hypophagic effects of MCPP after puberty. Is that correct?
CURZON:Yes. The surge was very clear. The sex difference was maintained with
increasing age. We wondered whether it was merely due to a sex difference in
metabolism. This now seems unlikely because the hypolocomotor effect of MCPP is
identical in both male and female rats.
P. HARTIG(Neurogeneric Corporation, Paramus, N J ) : Just a quick technical
question. I think that we often overlook that a dirty old drug, spiperone, is a fairly good
differentiator between S H T , and IC. It’s got about 21/* log units difference higher
affinity for 5-HT2. Did you try that in your series?
CURZON:No. The other drugs we’ve looked at as well as the four mentioned in my
talk are LY-53857, methysergide, altanserine, metergoline and propranolol. ID,, data
on all nine antagonists strongly point to mCPP causing hypophagia by acting on
5-HTl, receptors.