TiPS- April 1991 [Vol. 121 27 McEwen, B. S. et at. (1982) Recent Prog. Horn. Res. 38.41-92 26 Schumxber, M. and McEwen, B. S. (1989) Mot. Nrurobiol. 3,27!%304 29 Romano, G., Mobbs, C., Howells. R. and Pfaff, D. (19W) Mol. Brain Res. 5, 51-58 30 Gould, E., Woolley, C., Frenkfint, M. end McEwen, 8. S. (1990) \. Neurosci.10,

147 1286-1291 31 McEwm, B. S. et al. (1990) in NruroemiocrinePnspectiun fIrof. 81(Muller, E. and MacLeod, R., eds), PP. 93-131, Springer-Vedag 32 McEwen, B. S. and Could, E. (1990) Biochem.Phurm~col.40,~2402 33 E~lkar, S. and Weizel. D. (1989) /. Neurophysiol.61,1036-1052

Pharmacologicalapproachesto appetitesuppression John Blundell It is relatively easy to demonstrate drug-inducedanorexia in animals, but the significance of such suppression of eating is often doubtful. Of the many age&s shown to be ‘active’in animals, only u very few are genuine appetite suppressants with clinical potential. Drup t.‘tatincrease central 5-HT Ieuels, or thaf a&ate petipherally acting pephdes, are currently among the most promising candidates. John BhmdeU adrtocatesII systems approach to the study of appetite control. Drug-induced changes in feeding should be interpreted according to a system wkick involves behaviour, peripheral physiology and brain neural pathways. Appetite involves more than alterations of food intake; the concept should take into account changes in hunger, food preferences, responses to taste and changes in macronutrient prefirences. Food is an excellent anorexic agent which is known to reduce hunger and to suppress eating for some time after administration. However, one major disadvantageous side-effect of food as an appetite suppressant is that it is also F to $4 to weight gain. By e!mta&ng how particular foods (and their nutritional components) influence the expression of appetite (in animals and humanu) it may be possible to

at present the pharmacological control of appetite remains a primary focus in the anti-obesity research pmgrammes of phannaceutical companies. Anyone m*ing a casual inspec tion of the researrh literature could be forgiven for thinking that rat + drug + food = paper on anorexia. It is true that a large number of chemicals suppress food consumption when given to rats in a standard anonxic sueening test (food-deprived rat, large ~~~~~~?:2%: dose of drug, brief exposure to the mechanisms responsible for food). One methodoiogical problem is to decide whether the the anorexic characWstics of number of grams of food left unfood, or that oppose the processes eaten by rats is due to a drug mediating the weight-inducing properties. This is another way of intervening in the pmces%s that match food intake to nutritional saying that studies on the requirements, or whether it is due pharmacology of feeding should to some nonspecific blockade or have the best chance of success if impediment of eatin . This probthey adcnowledge the complexity of the psychobiological system lem can largely %e resOlV@Zd by identifying the natural bewhich controls appetite (see haviourai satiety sequence which Centrefold diagram). The develfollows the inhibition of eaYng”, opment of safe and effective antiobesity drugs involves far more detecting an~mai~~~ contamithan contml of appetite; it innants of behaviour during eating itself3 and comparing the drugcludes inter alia the intention to induced suppression of eating alter processes concerned with with that produced by a known energy expendihue, fat synthesis aversive agent’. In departures and storage, and the digestion and from the basic anorexic test, rats absorption of nutrients. However, in JJiol~#a/Psychofogy have been offered earthworms, 1.Btrndcll is Rrrdrr spaghetti, potatoes, carrots and al theUnfoenity of Leeds, Lrrrk LSl 9/T, UK.

34 Kelly. M.. Moss. R. and Dud& C. (1977) Exp. Brein Rn. 30.5344 35 Scbunuchrr. M., Coirini, H., Pfaff, D. and McEwen. 8. S. (1990) Science250, 691-694 36 $ ~~fu&l9$) \. Pharmacol.EI~. 37 Ran&,’ V. and Dl~:en, D. (1987) I. Strroid Biochm. 27,~S96

dog food in order to assign special meaning to a form of eating that was subsequently curbed by a drug. Table I gives examples of chemicals reported to inhibit food intake in rats and contains proven or potential clinically relevant appetite suppressant drugs. See Ref.5foralistofdmgsthatenhance eating and whose action may be useful in elucidating pharmacological modulation of appetite. Nahuc of the appetite control The biopsychologicai system concerned with the expression of appetite can be conceptualized on three levels (see Centrefold diagram): (1) psychological events (hunger perception, cravings, hedonic sensations) and behavioural operations (meals, snacks, eneruv and macronutrient intakes); (2) bripheral physiology and metabolic events; and (3) neurotransmitter and metabo& interactions in the brain. This article advocates that appetite can best be rmderstood by adopting a systems view in which the expression of appetite refMs the synchronous operation of events and processes at all three levels. Neural events trigger and guide behaviour, but each act of behaviour involves a response in the peripheral physiological system; in turn these physiological events are translated into brain neurochemical activity, This brain activity represents the strength of motivation and the willingness to feed or refrain from feeding. Eating is a form of behaviour that has a definable structure and pattern. The feeding of mammals is a discontinuous process in which periods of eating are interspersed with periods of noneating. These may be regarded as meals and inter-meal intervals, an analysis which applies equally well to rats and human#. It is useful to distinguish between the processes of satiation and satiety. Satiation is the process which

Q IWI. ,O.mk

Schvc6 l’ub”,hm

‘Id.

IUKI

0163 - 614WWW2.m

I.R.I.S.

CAUDATE PUTAMEN

profile of neurotransmitter activity gives charactor to food-seeking behaviour am drtve for nutrients/taste

I

INSTITUTDE RECHERCHES INTERNATIONALES SERWER

I

Pharmacology John Blundell

of appetite

control Trends in Sciences

pllaeicar

-

I

weak

J

-

cephalic phase of appetite

OPERATIONS ,$F’$?&

bhaviour

physiology with

m

SATIATION eerly

SATIEN

inhi$bm of further _--__________-_-_-_-~~~~-~-.----

IOGU lnlake

fare

M

I

SATIATiON

TiPS -April

150 TABLE I. A@&

1991 [Vol. 221

brings

that reduoe food intake in animals References

Substance

Comments

Satiated blood

Davis, J. D. era/. (1967) Blood from free-feeding rats. Science 156,1247-l 240 26 ml iniected in 2 ml portions r~uc~i,itake of sweetened milk (30min lest) of rats fed 30 min every day for 24 days.

Saiietin

Pepiide extracted from h~an olasma iniaciedi.v. 0ri.c.v. Feduces food intake of rats deprived for 96 h.

Knoll, J. (1979) Phyla. Behav. 23,497-602

Anorexic urine

Peplide (oyroG!u-Hi?&-OH) extracted from urine of anorexia nervosa patients. Injected into female freefeeding mice. 50% decrease in daily lo& intake. Effect persists for year.

Trygsiad, 0. ef al. (1976) Acfa EndocrinoL 69, 196-208

Glucose and glycerol

40% glucose by gastric iniubation decreases intake ai 2,7 and 24 h. 40% glycerol decreases intake over 24 h.

Glick, Z. (1980) Physiol. Behav. 25,621-626

Ro220654 (inhibilor of hepaiii faiiy acid synthesis) Ro200063 (inhibitor of pancreatic lipase)

Zucker rals - obese and lean. Com~~ds adminisi~~ as diet admixtures. 24 h intakes reduced in lean rats lo 75% and in obese by 57%. Meal size and meal frequency decreased.

Drewnowski. A. efal. (1986) Fhafma~. Biochem bhav. 23.61 l-622

(-)-tiydroxyckrate

Female rats. daily 3 h feeding. 0.33 nmoies ka- . oral& twice daily. flecreasid intake accounts lor reduction in body weight and body lipids.

Sullivan. A. C. elal. (1974) L@&S, 124-134

Slows gaslric emptying. Oral administration reduces food intake in rals and dogs.

Sullivan, A. C. efal. (1961) in Anorecfic Agents, otA&on and of ~~ha~i~s Tolerance (Garaitini, S. and Blundell, J., eds), pp. 143-I 58. Raven

Atropine

Rats17 h food deprived. Sham feeding with gasiric fistula (liquid diet). Dose-related decrease (2-250 @gkg-‘) in intake.

Lorenz, 0. efal. (1976) PharmacoL Biocham. Behav. 8.405407

Adrenaline/ noradrenaline

Rats, high-carbohydrate diet for 1 h per day. Adrenaline 0.1.0.15 and 0.2 mg kg-‘. Noradrenaline. 0.1,0.15 mg kg”’ 5 min before. 0.15 dose reduces intake by 71% and 34% r~~i~e~,

Aussek, M. sl a/. (I 967) Physic/. R&au.2.429-433

Rats, 6 h feeding per day, 2 h test. Drugs given immediately before. Arn~~arn~~, I .25 mg kg-’ and mazindo17.5 mg kg-‘. Effects blocked by ventral noradrenergic bundle k&ons.

Garaitini, S. and Samanin, R.(l976)~f~/nf~ea~ Apm3file (Sifversione, T,, ed.), pp. 62-206, Dahlem Konferenzem

Mazindol, lisuride, piribidel, n~en~~, apomorphine

Rats, 4 h per day leeding. Drugs iniecied Lo. at various times bhfora s&l of 1 h test. All~rugs reduce intake; effect blocked by pimozide.

Carruba, M. 0. ef al. (1960) Eur. J. Pharmacol. 64,

5-HT

tucker rat and lean rat:. VMH-lesioned rals. 14 g locd per day belween 9 a.m. and 2 p.m. 12.5 mg per 100 g. 5 min prior to 2 h test. Decreased eating in all groups.

Bray, G. A. and York. D. A. (1972) Am. J. Physiol.223,

50 mg kg-’ l~ptophan i.p. Raiseatomeier-Noyes pellets. Freefeeding rats, decrease in meal size and 21 h intake. I6 h deprivation, decrease in size of first large meal and inctease io posl-meal interval.

Latham,C.J. and Blundell, J. E. (1979) LMe Sci. 24, 1971-1976

133-141

176-179

a period of eating (meal) to an end, while snticty refers to the inhibition of hunger and eating brought about by food cwsumption itself. The capacity ot food to induce satiety is known ai satiating efficiency’ and this phenomenon is markedly influenced by the total energy and composition of the food consumed’. Satiety is initiated and maintained by a series of overlapping mediating processes, the ‘satiety cascade’s. Satiation (control of meal size) and satiety (control of post-meal interval) are influenced separately by the nature and timing of physiological processes. Even before food touches the mouth, physiological signals are generated by the sight and smell of food. These events constitute the cephalic phase of appetite’. Cephalic phase responses are generated in many parts of the gastrointestinal tract and their function is to anticipate the ingestion of food. Afferent information provides the major control over appetite both during and immediately after eating. It has been noted that ‘Affewnt ~~for~u~jo~

from ingested food acting in the mouth provides primarily posifive feedback for eating; that from fhe stomach and small intestine primariiy negative feedbuck. . ,‘*‘. Initially

the brain is informed about the amount of food ingested and its nutrient content via afferent input. The gastrointestinal trart is equipped with specialized chemowhich and mechanoreceptors monitor physiological activity and pass info~ation to the brain mainly via the vagus nerve”. This afferent information constitutes one class of ‘satiety signal’ and forms part of the post-ingestive control of appetite. It is usual to identify a post-absorptive phase which arises, naturally enough, when nutrients have undergone digestion and cross the wall of the intestine to enter the circulation. These products, which reflect the nature of the food consumed, may be metabolized in peripheral tissues or organs or may enter the brain directly. In either case, they constitute a further class of metabolic ‘satiety signal’. It has been argued that the degree of oxidative metabuiisol of glucose and free fatty acids in the liver consti:ULcS J sigilifiiant h~~urce \)i illformation useful for !he crp!rot of

TiPS -April 1991 [Vol. 121 appetite”. Additionally, products of digestion and peptide frag ments that activate their metabolizing enzymes may reach the brain and bind to specific chemoreceptors, or influence neurotransmitter synthesis or alter some aspect of neuronal metabolism. In each case the brain is informed about some aspect of the metabolic state resulting from food consumption. It has also been hypothesized that the blood carries specific substances that reflect the state of depletion or repletion of energy reserves and directly modulate critical brain mechanisms. These substances could indude satietin”, adipsin” (which is now thought more likely to be a regulator of fat than appetite) and the sugar acids 3,4-dihydroxybutanoic acid-y-lactone, 2-buten-4-olide and 2,4,5trihydroxy pentanoic acid-yla&one”. From an evolutionary perspective it is possible to envisage that many peripheral regulators of the handling of ingested nutrients could be exploited as potential signals of food-~&ted activities or bodily needs. One such possibility is the activation peptide of pancreatic procolipase16. Traditional views of neural control have been based on hunger and satiety centres in the hypothalamus. These concepts are now out of date. It may be useful to recognize distinct roles for the hindbrain - particularly the nucleus of the solitary tract (NTS) and the closely associated area postrema, and the forebrain, and to consider separate processes of and reghrtration, transcription integration (see Centrefold diagram). Changes in the gastrointestinal tract resulting from food consumption are registered in the hindbr.*in. This information is transcribed onto neurotransmitter pathways (amines and associated peptides) and projected to primarily hypothalamic zones where integration with neuroendocrine and metabolic activity is organized. Many hypothalamic nuclei are involved in this activity, some of which (such as the supraoptic and suprachiasmatic nudei) have not been included in the diagram for the sake of darity. Information arriving from the periphery via neural thways is complemented by qua p” itatively different types of

151 AgelltsttllltreducefOOdintdcehanimds(U3litd) Rats,15hdqnived30,50w Bundell,J.E.endLatham. 90 mg kg-'i.p..dm-mle!ed C.J.(1979)PhammA decrees4.FM&UM@th Bitxh8m.&Jhav.11, eabnlebr3omgkp-'d 431-w mealsizeand24hbtalh‘lteke.

Smith,G.P.efrd.(lS34) fBptldm5,1149-1157

MaM,C.F.aml0iM,J. (1950)Pk?pwes1,131-134

5chaliy,Av*etaL(la57) science157,210-211

Loam,E.C.del.(ls5l)

JkT7

phydol.95.

vfJgd.R. A et&. (lB79)

J.PMlt&M.Exp 205.151-165

TiPS- April 1991 /Vol. 121

1X! Agents thaf rfxluce food intake inanimals(Centi)

-s3b8Mcc Nabxone(opioid

comments Ftats.48hdetxivation.2h Food i&ke mcepbr antagonisl) measmnent. reduced by 1.o-lo.0 mgh9-‘.No effectin mouse (24h deprived). Malerats,6 h feeding per day. 2.5 Tetrahydm-

Hottzman. S. G.

(1974)J. Phamlawl.EXL-I-7%. 189, 51-60

Solia.IX D. arid Sarry, H. (1974)P 39.213-222

cannabnd

ad 5.0 rng kg-’ martWy decrwsedfocdintakeinfirst2h &I carry-over lo next 4 h.

(WhenyMylamii

Rats(5I)orlOOmgkg-‘).20% reduction in 24 h focd intake.

Douish,C.T. (1962)in 7?re MlmlBE&sd~#rd R~(Hc0bet, 6.0. and Novin, D.. eds). pi. 543549, Haer Inst.

(-)Cathinone

Reduces mitk intake in 15 min lesl in rats.

Fonin,R.w.ala!. (1982)J. Pharmaccf. Ex&r.Ther. 226, 411-416

4 mg kg-’ decreases carrot cunsumptkm (5 h tests) in fooddeprived rats.

Zeiger. J. C. and Cadini, E. A. (1960) phemreco. Bbchern. eehav. 12.701-706

Anorexia produced by systemic in;$ctionsandbkckedby perifomii propnvalol.

Leibwitz. S. F. (1970) Proc IWW” USA 67,

Rats, 4 h leedii schedule 2.5. 5.0,lO.O. 20.0 mg kg-‘, 15 min priwtotest.Attdosesreduce intakeinl htest.

Somini, F.eta/. (1962) Life Sci. 30.90.5-911

NaldwMdratsledtri~

Cooper, S. J. and Eatalt. LB.(l966)Mlrmsci. Bbbehav. Rev. 9,5-19

(e.g.CGS6216)

&u&onin3Omintest.

t-lisww

Rats, 560 mg k& i.p. suppressed intakeinlirs12hofl2hfeeding regime,tutwtlhdaily4hbeding.

GluCagon

Rats,patatabteliquidtestmealin tii phase,i.p. injecMs reduced meal size. Rats, i.p. injecWns suppress sucrose sham Mding.

~,S.&&(&965, Behav. 23.721-726

Schnbder, L. H.efa/. (1966) fwnRes.fJM. 17,605-611

Rat, sweet mash; 30 min lest. 3.0 BZ:Omgkg-

-load

r&a and rale, 0.34.0 rngkg-’ (i.p.) reduce intake sweet mash.

ltil6.7

-’

Rwk, I. N. efd. (1966) PhyaM &rev. 44,545-S53

[email protected] titueeffect:M91512decremes ratedfeadtngbutbeasesmeat size. Zucker rats. Redwes food intake by reducing meal size. VPDPR (V&Pro. Asp-Prow

McLaughttn,c. L eta/. (1993)Physu..31. 467-491

FW6hfeedingdaitylO and2Opgdoeedecwses intakeby29%and34%. respeclively.

o-FeMU~ine

FllJoxeline

intake,seladlvelyIn earlyderk.

Suppt. I) w-S57

Rats,1omgkg-‘dewasesiood intakeofsoMpz&ts,P16mg k9-’ reduces mitk Me.

Lucki.I.a~(l966) -96.

Rata,freefeedtqlOmgkg-’ redwesraboffe&lgandmeal stze.

CtiM,P.G.efel.(l999) -97.

Rats, milkd&t, 6 h daily. i.p. ~daae-re@=wuctedudim

!Mechler, L. E. and Sbansky, K. J. (1966) -94, 342-356

‘ThlstsMtsrepresentaUve, notexhaesthfe.

information which can be detected in blood and cerebrospinal fluid. These include the polypeptides acidic fibroblast growth factor (aFGF), interleukin-lg and tumour necrosis factor (cachectin)“, together with brain insulin. Another feature of the brain’s detection system is the presence of glucose-monitoring neurons” which are also sensitive to other nutrients. These are located at strategic sites in the hindbrain and forebrain (as well as in the periphery). A large number of neurotransmitters, neuromodulators, pathways and receptors are implicated in the central processing of information relevant to appetite. The profile of this activity reflects the flux of physiological and biochemical transactions in the periphery and represents the pattern of behavioural events and associated motivational states. Pharmacologicaltargeta for appetlta control A consideration of the various components of the biopsychological system suggests many pharmacological targets, both central and peripheral, that might be exploited to suppress appetite. For example, in the periphery drugs could blunt positive afferent information or intensify inhibitory afferent information; they could stimulate chemoreceptor activity in the gut or modulate gastrointestinal functioning via the network of neurotransmitters in the enteric plexus. Drugs could also mimic or substitute for proposed appetite regulating factors in blood, alter oxidative metabolii in the liver, adjust metabolic satiety signals or change amino acid profiles. Finally, drugs could affect steroid levels mllecting energy metabolism which in turn influence neuronal function, for example cortlcosteroids upregulate a*-adrenoceptors in the paraventricular nucleus (PVN). Drugs affecting digestion or absorption would be expected to alter the timing and pattern of nutritional information reaching the brain. Within the bnin drugs can alter appetite via a number of neurotransmitter and neuromodulator systems at a variety of specific sites. This complex pattern of neumchemical activity reveals the vulnerability of the

TiPS - April 2992 [Vol. 22J appetite system to pharmacological action, and this is reflected in the large number of chemicals reported to inhibit food intake (Table I). The probable site and mode of action of many of these chemicals can be located on the Centrefold diagram. Despite this abundance of pharmaceutical activity safe and effective appetite controlling drugs have been difficult to develop. Peripheral action Much of the interest in peripheral sites of action for the suppression of appetite has focused on peptidergic inhibition of food intake. Many peripherally administered peptides lead to an anorexic response and good experimental evidence for an endogenous role exists for cholecystokinin (CCK), pancreatic glucagon, bombesin and somatostatirGs. Recent research has confirmed the status of CCK as a hormone mediating satiation and earlyphase satiety. The consumption of protein or fat stimulates the release of CCK which activates CCK,+ receptors in the pyloric region of the stomach. This signal is transmitted via vagal afferents to the NTS from where it is relayed to the medial zones of the hypothalamus including the PVN and the ventromedial hypothalamus (VMH). The anorexic effect of systemically administered CCK can be blocked by vagotomy” and by the selective CCKA receptor antagonist, devazepide (MK329)20. Significantly, there now exist many reports demonstrating that CCr