Progress in Neurobiology Vol, 36, pp. 23 to 34, 1991 Printed in Great Britain.All rights reserved

0301-0082/91/$0.00 + 0.50 © 1990 PergamonPress pie

ROLE OF CCK IN REGULATION OF FOOD INTAKE ANDREW JAY SILVER a n d JOHN E. MORLEY Division of Geriatrics, St Louis University School of Medicine, St Louis, MO 63104, U.S.A. (Received 8 May 1990)

CONTENTS 1. Introduction 1.1. General comments 1.2. Structure of CCK 1.3. Historical perspective 1.4. Other roles for CCK 2. Effects on feeding--animals 2.1. Peripheral 2.1.1. Introduction 2.1.2. Species effect 2.1.3. Age effect 2.1.4. Mechanisms 2.2. Central 3. Effects on feeding--humans 4. Why study results differ 5. Evidence for a physiological role 5.1. Introduction 5.2. Use of antagonists 6. Future studies References

23 23 24 24 25 25 25 25 25 25 26 27 28 29 29 29 29 30 30

1. INTRODUCTION

to be involved in the regulation of feeding, making the concepts of a single feeding and/or satiety center obsolete. Food intake is regulated peripherally by the release of gastrointestinal peptides from the stomach and intestine as food passes through the gastrointestinal tract (Gibbs and Smith, 1985). These peptides appear to play a role in meal termination, thus the designation "the peripheral satiety system" (Morley et al., 1985a). The best studied of these putative satiety agents is CCK; however bombesin (Morley et al., 1980), glucagon (Van de Weele et al., 1980), somatostatin (Levine and Morley, 1982) and calcitonin (Levine et al., 1984a) have all been shown to decrease food intake. The combination of these peptides acting additively appears to be an important determinant of the duration of a meal. Absorption of food nutrients may also play a role in terminating the meal and may be responsible for creating the inter-meal interval (Fig. 2) (Morley, 1987). CCK affects food intake both centrally and peripherally and is referred to as a gut-brain peptide. CCK receptors have been classified into peripheral-type (CCK-A) or brain-type (CCK-B) (Dourish et al., 1989). CCK-A receptors are located in the stomach, pancreas, and medial nucleus tractus solitarius, while CCK-B receptors are in the lateral nucleus tractus solitarius, paraventricular nucleus, and ventromedial hypothalamus. CCK has been demonstrated to produce a variety of behavioral effects (Morley, 1980). This review will concentrate on the regulation of CCK on food intake.

1.1. GENERALCOMMENTS The regulation of food intake is an extremely complex process likely to involve the interactions between multiple peptides, hormones, and neurotransmitters (Morley and Levine, 1985; Morley, 1987). Although numerous agents have been shown pharmacologically to affect food intake (Table 1), only a small number have been demonstrated to be physiological regulators of feeding. Cholecystokinin is a gastrointestinal hormone that appears to play a physiological role in the termination of a meal. Morley et al. (1985a) have divided the modulation of feeding into two systems, the central feeding system and the peripheral satiety system (Fig. 1). The hypothalamus is the neuroendocrine transducer (Morley, 1980), regulating information from various neuropeptides and monoamines (Leibowitz, 1986) and playing the key role in the central feeding system. Much of the work in this area was first noted in studies by Brobeck et al. (1943) and Anand and Brobeck (1951) where lesions in the lateral hypothalamus (feeding center) or medial hypothalamus (satiety center) produced a characteristic behavior in food intake. Other brain regions have been demonstrated All correspondence should be sent to: Andrew Jay Silver, M.D., Division of Geriatrics, M-238, St Louis University School of Medicine, 1402 South Grand Boulevard, St Louis, MO 63104, U.S.A. JPN36/~--B

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24

A.J. SILVERand J. E. MORLEY TABLE 1. AGENTS THAT AFFECT FOOD INTAKE

Increase

Decrease

Alpha noradrenergic Diazepam Dopamine 5-Hydroxytryptamine GABA Galanin GHRH Glucocorticoids Growth Hormone NPY Opioid peptides Peptide YY Progesterone Testosterone Thyroid hormones

Amphetamines Beta-adrenergic Bombesin Caerulein Calcitonin CCK-8 CCK-33 CRF Dopamine Glucagon Insulin Insulin growth factor Neurotensin Somatostatin TRH VIP

~BBS~ SS/PG/ 100%'

\ nutnents~

Time

FIG. 2. The termination of a meal, as controlled through the release of gastrointestinal peptides and through the absorption of nutrients (CCK = cholecystokinin; BBS = bombesin; SS = somatostatin; PG = pancreatic glucagon).

i.2. STRUCTUREOF CCK Structural determinations have, in general, come from porcine studies. Several different enzymatic cleavage products have been isolated from preprocholecystokinin (for review see Baile et al., 1986) and include CCK-58, 39, 38, 22, 12, 10, 9, 8, and 4. The most active product is CCK-8 (Calam e t al., 1982; Rehfeld, 1978) with CCK-8S (sulfated tyrosine at the seventh position from C-terminus) demonstrating the

most biological activity especially with regard to feeding behavior. 1.3. HISTORICAL PERSPECTIVE Ivy and Oldberg (1928) were the first to note the effects of a substance (later termed cholecystokinin) in activating gallbladder contraction. Quigley and associates in a variety of studies (1932; 1934, 1955)

Opioids Opioids serotonin bombesin

Norepinephrine ~+ Serotonin CRF

-

Dopamine bombesin TRH NeuropeptideY Calcitonin

Glucagon Bombesin CCK somatostatir Motilin FIG. 1. The central and peripheral feeding systems (Morley et al., 1985a, with permission).

ROLE OF C C K IN REGULATIONOF FOOD INTAKE

noted that injection of intestinal extract (containing CCK) could inhibit activity of a denervated stomach. This substance could also stimulate pancreatic enzyme secretion (Harper and Raper, 1943). MacLagan (1937) was the first to note the effect of CCK on food intake using a crude duodenal extract. Mutt and Jorpes (1971) first isolated CCK from the gastrointestinal tract and over the next two years several investigators noted its effect during a meal (Glick et al., 1981; Jamieson, 1973). Sjodin (1972) demonstrated that CCK decreased food intake in dogs. He considered this a toxic effect. CCK was first proposed as a satiety agent by Gibbs and coworkers (1973) when they noted that the biologically active form of CCK (CCK-8S) decreased food intake in the rat. Vanderhaegen (1975) first discovered a CCK-like substance in the central nervous system which was later characterized by Dockray (1976). 1.4. OTHERROLESFOR CCK Numerous other roles for CCK have been described. Some of these may have an indirect if not direct role in food intake. CCK has been shown to inhibit gastric emptying (Debas et al., 1975; Moran and McHugh, 1982). However a direct relationship between its ability to inhibit food intake and inhibit gastric emptying has not been established. CCK plays a role in glucose homeostasis. Rushakoff and coworkers (1978) have shown that CCK potentiates amino acid but not glucose-induced insulin secretion in humans. CCK has also been shown in humans to slow the delivery of glucose to the duodenum and reduce postprandial hyperglycemia (Liddle et al., 1988). In fed mice, the CCK antagonist L-364,718 prevents the CCK-8-induced elevation of insulin (Reagan et al., 1987). CCK may play a role in the development of acute pancreatitis (Niederau et al., 1986). Shinya and Fujimura (1989) demonstrated that CCK-8 injected into rats increased levels of lipase, amylase, and the weight of the pancreas, and suggested a role for the CCK antagonist proglumide in the treatment of acute pancreatitis. Other roles for CCK include its ability to act as the transmitter for inhibition of gastric acid secretion (Davison and Najafi-Farashah, 1987), to increase non-REM sleep at the expense of wakefulness in rats (Kapas et al., 1988), to produce a conditioned taste aversion (Deutsch et al., 1976), and to enhance memory (Flood and Morley, 1987). Potential therapeutic modalities include the use in treatment of human cholangiocarcinoma as endogenous CCK has been shown to regulate growth of this tumor (Evers et al., 1989), and in the treatment of gastroparesis and the irritable bowel syndrome (Silverman et al., 1987). Finally, CCK acts as an antagonist to the opiates. In the classic paper by Faris et al. (1984a), rats immunized against endogenous CCK demonstrated potentiation to morphine analgesia. Since then, CCK antagonists have been found to potentiate opioid analgesia (Watkins et al., 1985; Dourish et al., 1988). CCK has been shown to interfere with the temperature regulating effect of opiates as well as with numerous other opioid properties (Kapas et al., 1989). Evidence also suggests that the opioid feeding

25

system and CCK may interact to control food intake (Baile et al., 1986).

2. EFFECTS ON FEEDING---ANIMALS 2.1. PERIPHERAL 2.1.1. Introduction The peripheral satiety feeding system is responsible for the termination of a meal (Section 1.1), that is, to create a sensation of fullness so that the animal slows down and stops the intake of food. (For a review of satiety and its phases, see Smith and Gibbs, 1979.) Since the concentration of CCK in plasma was noted to increase after a meal (with changes in the ratio of CCK-8:CCK-33-39 from a basal level of 1:1 to 3:1 ten minutes after feeding, as noted in dogs by Linden and Uvnas (1977)), studies were devised to look at the effects of peripheral CCK acting as a satietin. Doses necessary to reduce food intake were, in general, five times the amount needed to stimulate pancreatic amylase secretion (Reidelberger and Solomon, 1986). The classic study by Gibbs and coworkers in rats (1973) noted that cerulein, a CCK-like substance, decreased food intake as did CCK-33 in a dosedependent manner. There was no evidence of malaise or difficulty with locomotion and the effect was specific, i.e., there was no effect on fluid intake. The behavior typified that seen in usual satiety (Antin et al., 1975), feeding followed by grooming and exploratory behavior such as sniffing and locomotion, with activity ending in rest or sleep. It was later felt (Gibbs and Smith, 1985) that CCK acted mainly to shorten the duration of feeding. 2.1.2. Species effect CCK has been shown in pharmacological doses to decrease food intake in numerous species including the chicken, hamster, human, monkey, mouse, pig, rabbit, rat, and sheep (Morley et al., 1985b). Species differences exist in several rzspects. For example, when injected peripherally, CCK affects food intake in the pig, to a lesser extent in the chicken, and minimally in the sheep (Baile and Della-Fera, 1984), while high doses have no effect in the wolf (Morley et al., 1983a). Obese mice appear less sensitive to CCK's effect at low doses and are more or as sensitive at high doses (McLaughlin and Baile, 1981). In rats, peak levels of CCK are reached immediately after meals and return to baseline within 15 min (Liddle et al., 1984), while in dogs the peak effect is not seen until two hours after food intake (Lilja et al., 1982). This may explain why in some studies (Reidelberger et al., 1989), postprandial levels have not been found sufficient to produce satiety in the dog. 2.1.3. Age effect Elderly humans often complain of early satiety, that is, they have a sensation of fullness earlier during the course of a meal as compared to younger years. Our laboratory (Silver et al., 1988) looked at the effects of the gastrointestinal peptides on food intake

26

A.J. SILVERand J. E. MORLEY

in mice of different ages, theorizing that age-related differences in these effects might help to explain the pathophysiology of anorexia in the elderly (Morley and Silver, 1988). Although CCK-8, bombesin, glucagon, and calcitonin all reduced feeding in 8- and 25-month-old C57BL/6 Nnia mice, CCK-8 had the greatest age-related effects. Food was suppressed to a greater extent in old than in young mice and continued to suppress food intake in a dose-dependent manner for a longer period of time in the older mice. This "enhanced sensitivity" to CCK could potentially predispose older animals to develop early satiety with subsequent weight loss and proteincalorie malnutrition. 2.1.4. M e c h a n i s m s Numerous mechanisms have been proposed for the decrease of food intake by CCK (see Table 2). The most popular peripheral mechanism proposed is that gastric distention causes the release of CCK terminating food intake and limiting further distention. Gastric distention depends on the rate of feeding, rate of emptying, and the gastric tone (Hunt and Spurrell, 1951). Cannon and Washburn (1912) were the first to suggest that gastric distention causes satiety. Moran and McHugh (1982) felt that satiety was secondary not only to the increase in gastric distention but also to the decrease in gastric emptying which they attributed to the effects of CCK, as did Yamagishi and Debas (1978). In rats, a linear relation has been noted (Moran and McHugh, 1988) between the inhihition of gastric motility and inhibition of food intake by CCK (through a certain dosage). In baboons, Figlewicz and coworkers (1989) found that CCK-8 administration decreased gastric emptying and produced plasma levels consistent with normal prandial CCK levels, concluding that endogenous CCK plays a role in decreasing a meal by decreasing gastric emptying (although they noted that a direct CNS interaction may be required). Similar findings are noted in a monkey study (McHugh and Moran, 1986), where it was felt that the effect of CCK on feeding was not affected unless a distending load was present in the stomach. McHugh and Moran (1986) characterize gastric emptying into two phases: the first, a rapid emptying phase, is dependent on volume and gastric emptying; the second, a slower phase which is dependent on certain food types entering the intestine (Makhlouf, 1974) and CCK acting to inhibit gastric emptying. Proponents of the gastric emptying theory suggest that CCK exerts its effect by contracting the pyloric sphincter (Fisher et al., 1973) (in vh~o TABLE 2. PROPOSED MECHANISMS FOR CCK IN REGULATION OF FOOD INTAKE

Smooth muscle contractile effect Decrease in gastric emptying Direct vagal stimulation Direct NTS stimulation Induce hyperglycemic state Antagonize norepinephrine-induced feeding Antagonize opiate-induced feeding ? Nausea effect

evidence---Murphy et al., 1987), and by increasing the pressure in the pyloric canal (Scheurer et al., 1983). Supporting evidence is conflicting; in one study pylorectomy decreased satiation in rats (Moran et al., 1988), while in a second study, pyloroplasty had no effect on gastric emptying (Conover et al., 1989). Also, manometric measurements of gastric motility reveal a different motor pattern in the stomach when exogenous CCK is administered as compared to the postprandial pattern that is present when endogenous CCK is present (Shillabeer and Davison, 1987). In humans, no direct relationship between gastric emptying and food intake could be demonstrated (Shaw et al., 1985). Gastric distention does not appear to play a major role in accounting for CCK's satiety effect. Moran and McHugh (1988) demonstrated that the effect on feeding inhibition is always greater than that of gastric inhibition and estimated that gastric distention accounted for "64% the variability in satiation by CCK". Also, sham feeding (where gastric distention does not play a role) is inhibited by CCK with the typical satiety behavioral sequence noted in rats (Gibbs and Smith, 1986) and in cats (Bado et al., 1988). In the former study, it is suggested that food intake is decreased because of intestinal satiety which is mediated through the release of CCK after food reaches the intestine, while gastric satiety is bombesin mediated. The type of food necessary for this intestinal satiety is specific, i.e. is regulated primarily by protein, amino acids, and fats, not by carbohydrates (Forgacs et al., 1983). Schneeman and Lyman (1975) suggest that trypsin acts as a feedback signal to turn off the release of CCK. Also of interest is the fact that the duodenum and jejunum have the highest concentration of active CCK (Schneeman and Lyman, 1977; Larsson and Rehfeld, 1979). CCK may exert its effect on food intake by producing hyperglycemia (Section 1.4), by decreasing norepinephrine-induced eating (Morley et al., 1982a), or by antagonizing feeding enhancement induced by the opioid system (Wilson et al., 1983; Morley et al., 1983b). A nausea effect has been suggested (Deutsch and Hardy, 1977) as CCK stimulates a dose-related increase in oxytocin secretion which, in rats, is a marker for nausea (Verbalis et al., 1986). However, West et al. (1987) compared the effects of a known aversive agent, lithium chloride, to CCK. In the rat, the former decreased both meal size and number of meals per day, while the latter decreased only the meal size while increasing the number of meals per day (compensatory mechanism), suggesting that CCK does not primarily work through the induction of nausea. Billington and coworkers (1983) noted that CCK acted as a satiety agent as it inhibited food intake to a lesser degree as the period of food deprivation was increased. This compared with the effects of lithium chloride, an aversive agent, where food was inhibited independent of the length of deprivation. Flood et al. (in press) found that through the use of the lever press, CCK decreased the number of reinforcements (milk reward) but did not affect the number of lever presses, whereas lithium chloride decreased both. These results support the role of CCK as a satiety versus aversive agent.

ROLEOFCCK IN REGULATIOF ONFOODINTAKE Whatever the exact mechanism, CCK clearly do©s not act alone as the peripheral satiety agent to terminate the meal and suppress further food intake. Hinton et ai. (1986) noted an additive effect of bombesin and CCK in reducing food intake. We recently demonstrated (Silver et al., submitted) that CCK-8, somatostatin, and glucagon acted in an additive manner to decrease food intake when administered in combination. CCK-8 and bombesin when combined acted infra-additively, that is, less than what would be expected from the sum of their individual effects. This might be due to the fact that bombesin downregulates CCK receptors (Younes et al., 1989). Somatostatin inhibited the effects of bombesin and gastrin-releasing peptide. Thus, interactions exist between the gastrointestinal hormones of the peripheral satiety system resulting in the termination of a meal (Fig. 3). Once CCK is released, how does its message reach satiety centers in the brain? Zorbin et al. (1981) first noted CCK receptors to be present in the vagus nerve. Further work (Smith et al., 1981) found that the gastric branch of the vagus played an important role as it abolished CCK-induced decrease of food intake if severed, as compared to other branches of the vagus such as the celiac or hepatic. In particular, the afferent fibers appeared to play the dominant role as administration of atropine (which blocks efferent fibers) had no effect (Smith et al., 1983). In rodents, the effect of vagotomy is specific as it inhibits the satiety effect of CCK but not of bombesin (Morley et al., 1982b). The role of the vagus remains controversial, however, as vagotomy has no effect on CCK in rabbits and dogs (Levine et al., 1984b; Houpt et al., 1978), and as LeSauter et al. (1988), although finding that vagal fibers mediate C C K ' s satiety effect, were unable to support the role of the gastric branches of the vagus as the definitive mode of transport. However it should be noted that in mice Flood et al. (1987) found that low but not high doses of CCK-8 had their satiety effect mediated through the vagus. Whichever part of the vagus is involved relays the signal via the

u:o )i!

Bombesin

Ga~tdn~L S2matostatin releasing pepfide

FIG. 3. Proposed schema of the interrelationships between the gut peptides in controlling food intake. Bombesin and gastrin-releasing peptide decrease food intake through the release of CCK. Somatostatin, glucagon, and C C K act independently to decrease food intake, while sornatostatin act to block the effects of bombesin and gastrin releasing peptide.

27

nucleus tractus solitarius (NTS) to the hypothalamus (Crawley and Schwaber, 1984). In fact, the presence of CCK in the nucleus tractus solitarius (an important relay center for gastrointestinal and other functions) suggests its role as a neurotransmitter (Howe et al., 1989). In addition, the peripheral administration of CCK enhances firing in the NTS (Ewart and Wingle, 1983) and hypothalamus suggesting that the satiety effect may be occurring in the NTS itself. In summary, peripherally-administered CCK inhibits food intake in numerous species. The vagal afferents appear to play a role after receiving input either from a gastric distention mechanism or other mechanism(s) (Fig. 4). 2.2. CENTRAL The anatomic site determines what effect a particular hormone or peptide is going to have on food intake (Morley, 1989). For example, Rolls et al. (1981) found that the forebrain is important in sensory-specific satiety (repetition of the same food causes the animal to stop eating it eventually), the amygdala and hippocampus play a role in palatability and aversion, and the hypothalamus represents the main feeding center as lesions in the lateral hypothalamus cause weight loss, while lesions in the ventromedial hypothalamus cause weight gain. CCK has been localized in various regions of the brain including the cerebral cortex; median eminance; ventromedial, supraoptic, paraventricular, and dorsomedial nuclei; septum; basal ganglia; hippocampus; amygdala; substantia nigra; nucleus aceumbens; thalamus; periaqueductal grey; and spinal cord (Vanderhaeghen et al., 1980, 1981; Beinfeld, 1983). Some areas of the brain (cortex, hippocampus, and thalamus) are sites of CCK biosynthesis as measured by m R N A levels (Iadarola et al., 1989). The predominant form of CCK in the brain is CCK-8, with the sulfated type being the active form (Rehfeld, 1978). The exact role of CCK in the central control of feeding is more controversial compared to its peripheral effect. For example, when exogenous CCK is injected into the lateral ventricle, ventromedial hypothalamus, or paraventricular nucleus of the hypothalamus, in some studies food intake is decreased compared to vehicle injection (Stern et al., 1976) while in others there is no effect (Kulkosky et al., 1976). CCK-8 antibody has been shown to stimulate feeding when injected into the brain of sheep (DellaFera et al., 1981), and into the paraventricular nucleus of the hypothalamus of the rat (Faris et al., 1984b). Studies are also mixed with regard to the content of CCK in brains of lean and obese animals. Strauss and Yalow (1979) found that obese animals had lower brain CCK content compared to lean animals, while Schneider et al. (1979) noted no difference. Finally, studies differ as far as central CCK receptors is concerned. In one study (Saito et al., 1981) under fasting conditions, the number of CCK receptors increased in the hypothalamus, while another study (Hays et al., 1981) noted no effect on receptor number under fasting conditions. In general, CCK is less effective in decreasing food intake when injected centrally as compared to peripheral injections in rodents. However, in other species,

28

A.J. SILVERand J. E. MORLEY

CCK-8 may be more potent when given centrally. For example, in chickens intracerebroventricular injections decrease food intake by 87% compared to 30% when administered intraperitoneally (Savory and Gentle, 1980). Similar findings have been noted in pigs (Parrott and Baldwin, 1981), but in hamsters (Miceli and Malsbury, 1983) the effect of both central and peripheral administration are the same. One reason for these differences may be in the ability/inability of CCK to cross the blood-brain barrier (BBB). For example, the dog is another species where central effects are greater (Sakatani et al., 1986) and where it has been demonstrated that CCK does not cross the BBB (Zhu et aL, 1986). Various mechanisms responsible for CCK's central effect of food intake have been suggested. As in a peripheral mechanism (see Section 2.1.4), it may cause hyperglycemia. Because of the proximity in neurons with other feeding neuromodulators such as norepinephrine (Myers et al., 1986), dopamine (Stuler et al., 1981), and the opiates (Martin et al., 1983), CCK may exert its effects through enhancement or suppression of these peptides. Finally, it has been suggested that high central doses may act peripherally to induce satiety (Passaro et al., 1982).

/

In summary, CCK can decrease feeding centrally by a variety of mechanisms. Although the exact mechanism(s) remains unclear, CCK appears to act both peripherally and centrally to decrease food intake in all animal species.

3. EFFECTS ON FEEDING---HUMANS After a meal, endogenous CCK levels in the circulation have been found, in humans, to increase 1.5-3.0 times the level under fasting conditions (Byrnes et al., 1981; Becker et al., 1984) supporting a role for CCK in the regulation of human feeding. As in the animal studies, results are mixed as to the effect of exogenous CCK on food intake. In studies with nonobese humans, most suggest a decrease in food intake from 12-50% (Kissileff et al., 1981; Stacher et al., 1982; Shaw et al., 1985), although some have shown no effect (Greenway and Bray, 1977), or even an enhancement of food intake (Sturdevant and Goetz, 1976). Abdominal cramping and nausea and vomiting have often limited the doses tested to less than 0.05-0.1 #g/kg (Miaskiewicz et al., 1989).

CCK infusion ~ S ~ ,

decreasesfeeding " ~

\

l ~ ' / /

/

~

~"~"~

"

/' /

/

J

y~., ~ ~ . z ~" 1 ~ ~ { I~

I I:~

/ ~

Lesion of DMN inhibitsCCK

Lesion of NTS and areapostrema inhibits CCK "~

Afferent vagotomy inhibitsCCK

Vagotorny inhibits CCK

Selectivegastric vagotomy inhibits CCK

FIG. 4. Peripheral CCK having an effect on central feeding centers via vagal afferents (Morley et al., 1985a, with permission).

ROLEOFCCK IN REGULATIONOF FOODINTAKE The effects of CCK have been looked at in patients with various eating abnormalities. Pi-Sunyer et al. 0982) decreased a liquid lunch intake by 13% in obese patients; under similar experimental conditions in nonobese patients, the intake was decreased by 19% (Kissileff et al., 1981). A difference in satiation mechanisms may account for these differences as obese subjects are capable of overeating after being given preloads compared to leaner counterparts (Spiegel et al., 1989). Also, obese subjects have a decreased release of both insulin and glucagon after CCK injection, while leaner subjects have a decreased release of insulin only, with an increased release of glucagon (Hill et al., 1988). In a group of vagotomized patients given CCK, gastric emptying was prolonged and food intake was decreased, although the differences were not statistically significant, hence Shaw et al. (1985) concluded that it remained unclear whether the effect of CCK on food intake was dependent on the vagus. Also, in patients who have undergone surgical removal of the duodenum where CCK is supposed to be primarily produced, there is a higher (not lower) release of CCK postprandially (Mossner et al., 1989). More work is needed to help clear up many of these apparent inconsistencies. Bulimia nervosa is a disorder where patients demonstrate an uncontrolled pattern of recurrent binge eating (DSM-III, 1987). A satiety impairment is suggested as patients often complain of a decreased sensation of fullness (Pyle et al., 1981). This impairment may be due to decrease in circulating CCK in patients with this disorder (Geraciotti and Liddle, 1988). Although CCK administration has failed to limit the size of binging in bulimics (Mitchell et al., 1986), CCK levels have been found to return to normal postprandial levels after treatment with antidepressants (Geraciotti and Liddle, 1988). In the elderly, there is an increase in CCK release under fasting and fat-stimulating conditions (Khalil et al., 1985). This can potentially place the malnourished elderly at further risk because with continued decrease in food intake, more CCK is released which causes more satiety and further decreases in food intake (Silver et al., 1988). In summary, an in animals, CCK causes decreases in food intake in humans. Although attractive as a therapeutic modality in eating disorders such as obesity or bulimia, CCK to date has had limited success.

4. WHY STUDY RESULTS DIFFER The effect of CCK appears to be very paradigm dependent. Much of the controversy surrounding CCK is due to skepticism by various researchers because of the inability to recreate findings previously reported. Differences in results may be related to whether the animal is in the fasting or nonfasting state as levels of circulating CCK are different in these two states (Pasley et al., 1987). Circadian fluctuations of circulating CCK, particularly light-dark cycle levels (Kraly, 1981), may play a role. Mori et al. 0986) found that CCK has more of an effect during

29

the dark period in rats as compared to the light period. Differences in studies may be related to the species (Section 2). Responses may also be dependent on the sex of the animal. The dose-response curve of CCK's effect on food intake was linear in males but not in females (Strohmayer and Smith, 1987). Also, the effect of CCK appears to be dependent upon the presence of progesterone as Wager-Srdar et al. (1987) found lack of sensitivity to CCK during periods of the menstrual cycle in rats when progesterone levels were low. The type of diet may alter the response of CCK. In pigs, CCK inhibits the intake of monoglycerides but not a fatty acid or barley-based diet (Gregory et al., 1989). Another difference in studies may be secondary to which CCK compound is used. In dogs, potency is dependent on the COOH-terminal amide group and the sulfated tyrosine moiety (Inui et al., 1989) while in cats, there is no difference in activity between the sulfated and unsulfated compound (Bado et al., 1988). Site of administration plays a role as intracerebroventricular injections are more potent than intraperitoneal (ip) (Section 2.2) and ip injections are more potent than hepato-portal injections (Grcenberg and Smith, 1988). Timing and length of injection is important as well. In humans, if a bolus of CCK is given just before a meal, there is a decrease in food intake, whereas if CCK is infused for 20 min before and 20 min during a meal, there is an increase in food intake (Sturdevant and Goetz, 1976). Also, after several days of administration, overall food intake is no longer affected (West et aL, 1984) as the decrease in meal size is offset by the increase in meal frequency. Finally, the actual measurement of circulating CCK can be affected by the site of collection, method of processing the sample, and antibody and tracer used (as applicable) (Baile et aL, 1986).

5. EVIDENCE FOR A PHYSIOLOGICAL ROLE 5.1. INTRODUCTION There is increasing evidence that CCK acts physiologically to decrease food intake, although this remains a controversial subject. Pharmacological doses that decrease food intake have been shown to produce the same circulating level of CCK, seen after a meal (Smith et al., 1985). Within physiological range in humans (5-10 picomolar), exogenous CCK has been shown to decrease gastric emptying (Liddle et al., 1986). Similar findings have been shown in monkeys (McHugh and Moran, 1986). 5.2. USE OF ANTAGONISTS Another way to attempt to demonstrate a physiological role is through the use of antagonists. (Reviews of CCK antagonists--Gardner and Jensen, 1984; Silverman et al., 1987.) The possible role for CCK antagonists in food regulation was realised after studies showed that antibodies to CCK (Della-Fera et aL, 1981) or animals autoimmunized against CCK

30

A.J. SILVERand J. E. MORLEY

(McLaughlin et al., 1985) increased food intake compared to controls. In general, the antagonists studied have been effective in blocking exogenously-administered CCK. When examined alone, however, the proposed effect (to increase food intake compared to control) has been more difficult to demonstrate. In rats, Shillabeer and Davison (1984) found that the antagonist progtumide acted on endogenous CCK (released by a preload) to increase food intake, however Schneider et al, (1986) could not replicate these findings. They concluded that perhaps the preload did not release sufficient endogenous CCK. Conflicting findings have been noted with other antagonists such as L-364,718 where either no effect (Lotti et al., 1987; Khosla and Crawley, 1988) or enhancement (Silver et al., 1989) of food intake when administered alone, has been shown. In the latter study, L-364,718 enhanced feeding when the mouse was satiated, suggesting that endogenous CCK plays a physiological role only as the animal nears complete satiation and that other factors are more important in the modulation of food ingestion in hungry animals. Dourish et al. (1989) found that antagonists to both CCK-A receptors (peripheral type) and CCK-B receptors (brain type) increased food intake in partially satiated rats. Because the CCK-B antagonist was 100 times as potent in postponing satiety, the study suggests that endogenous CCK causes satiety by acting on CCK-8 receptors in the brain. Thus, as with CCK itself, the effect of the antagonist is dependent upon the paradigm (dose, strain, age, type of food, time of day, fasted versus nonfasted, prefed versus no prefeeding) (Silver et al., 1989). To conclude, although CCK antagonists decrease the effects of exogenous CCK on food intake, their role in affecting endogenous CCK and when administered alone needs further clarification.

6. FUTURE STUDIES Work in the future will most probably explore different paradigms to see if optimal administration of CCK can be used in the treatment of obesity. Further work is also needed to explore the interrelationship between CCK and the opioid system in modulating food intake. Finally, exciting work remains in the role of CCK antagonists in treating malnourished individuals such as those with cancer or elderly patients with anorexia.

BAILE, C. A. and DELLA-FERA,M. A. (1984) Peptidergic control of food intake in food-producing animals. Fedn Proc. 43, 2898-2902. BAILE, C. A., MCLAUGHLIN, C. L. and DELLA-FERA, M. A.

(I986) Role of eholecystokinin and opioid peptides in control of food intake. Physiol. Rev. 66, 172-234. BECKER, H. D., WERNER, M. and SCHAFMAYER,A. (1984) Release of radioimmunologic cholecystokinin in human subjects. Am. J. Surg. 147, 124-129. BEINFELD, M. C. (1983) Cholecystokinin in the central nervous system: A minireview. Neuropeptides 3, 411-427. 8ILLINGTON, C. J., LEVINE, A. S. and MORLEY, J. E. (1983) Are peptides truly satiety agents? A method of testing for neurohumoral satiety effects. Am. J. Physiol. 245, R920--R926. BROBECK, J. R., TEPPERMAN,J. and LONG, C. N. H. (1943) Experimental hypothalamic hyperphagia in the albino rat. Yale J. Biol. Med. 15, 831-853. BYRNES, D. J., HENDERSON, L., BORODY, T. and REHFELD,

J. F. (1981) Radioimmunoassay of cholecystokinin in human plasma. Clin. chim. Acta l l l , 81-89. CALAM, J., ELLIS,A. and DOCKRAY,G. J. (1982) Identification and measurement of molecular variants of cholecystokinin in duodenal mucosa and plasma. J. clin. Invest. 69, 218-225. CANNON,W. B. and WASHBURN,A. L. (1912) An explanation of hunger. Am. J. Physiol. 29, 441-454. CONOVER, K. L., COLLINS, S. M. and WEINGARTEN, H. P. (1989) Pyloroplasty does not disturb liquid satiety. Physiol. Behav. 45, 523-528. CRAWLEY,J. N. and SCHWABER,J. S. (1984) Abolition of the behavioral effects of cholecystokinin following bilateral radiofrequency lesions of the parvocellular subdivision of the nucleus tractus solitarius. Brain Res. 295, 289-299. DAVISON,J. S. (1987) Vagal inhibition of gastric acid secretion: evidence for cholecystokinin as the inhibitory transmitter in the mouse stomach. Can. J. Physiol. Pharm. 65, 1937-1941. DEBAS, H. T., FAROOQ,O. and GROSSMAN,M. I. (1975) Inhibition of gastric emptying is a physiologicalaction of cholecystokinin. Gastroenterology 68, 1211-1217. DELLA-FERA, M. A., BAILE, C. A., SCHNEIDER, B. S. and GRINKER,J. (1981) Cholecystokinin antibody injected in cerebral ventricles stimulates feeding in sheep. Science 212, 687~89. DEUTSCH,J. A. and HARDY,W. T. (1977) Cholecystokinin produces bait shyness in rats. Nature 266, 196. DEUTSCH,J. A., MOKINA, F. and PUERTO,A. (1976) Conditioned taste aversion caused by palatable nontoxic nutrients. Behav. Biol. 16, 161-174. DIAGNOSTIC AND STATISTICAL MANUAL OF MENTAL DIS-

ORDERS:DSM-III-R (1987) American Psychiatric Association Washington, D.C. DOCKRAY,G. J. (1976) Immunochemical evidence of cholecystokinin-like peptides in brain. Nature, Lond. 264, 568-570. DOURISH, C. T., HAWLEY, D. and IVERSEN, S. D. (1988)

REFERENCES

Enhancement of morphine analgesia and prevention of morphine tolerance in the rat by the cholecystokinin antagonist L-364,718. Eur. J. Pharm. 147, 469-472. DOURISH, C. T., RYCROFT, W. and IVERSEN, S. D. (1989)

ANAND, B. K. and BROBECK, J. R. (1951) Hypothalamic control of food intake in rats and cats. Yale J. Biol. Med.

24, 123-140. ANTIN,J., GIBBS,J., HOLT,J., YOUNG,R. C. and SMITH,G. P. (1975) Cholecystokinin elicits the complete behavioral sequence of satiety in rats. J. comp. physiol. Psychol. 89, 784-790. BADO,A., RODRIQUEZ,M., LEWlN,M. J., MART1NEZ,J. and DUBRASQUET,M. (1988) Cholecystokinin suppresses food intake in cats: structure-activity characterization. Pharm. Biochem. Behav. 31, 297-303.

Postponement of satiety by blockade of brain cholecystokinin (CCK-8) receptor. Science 245, 1509-1511. EVERS, B. M., GOMEZ,G., TOWNSEND,C. M., RAJARAMAN,S. and THOMPSON,J. C. (1989) Endogenous cholecystokinin regulates growth of human cholangiocarcinoma. Ann. Surg. 210, 317-322. EWART, W. R. and WINGATE, D. L. (1983) Cholecystokinin

octapeptide and gastric mechanoreceptor activity in rat brain. Am. J. Physiol. 244, G613~G617. FARIS,P. L., MCLAUGHLIN,C. L., BAILE,C. A. and OLNEY, J. W. (1984a) Morphine analgesia potentiated but

ROLE OF CCK IN REGULATIONOF FOOD INTAKE

tolerance not affected by active immunization against cholecystokinin. Science 226, 11215-1217. FARIS, P. L., SCALLET,A. C., OLNEY, J. W., DELLA-FERA, M. A. and BAILE,C. A. (1984b) Behavioral and immunohistochemical analysis of cholecystokinin in the hypothalamic paraventricular nucleus. Soc. Neurosci. Abstr. 6, 784. FIGLEWICZ,D. P., SIPULS,A. J., PORTE,D., WOODS,S. C. and LIDDLE, R. A. (1989) Intraventricular CCK inhibits food intake and gastric emptying in baboons. Am. J. Physiol. 256, RI313-RI317. FISHER, R. S., LIPSHUTZ,W. and COHEN, S. (1973) Cholecystokinin decreases food intake in rats. J. comp. physiol. Psychol. 84, 488~,95. FLOOD,J. F., SMITH,G. E. and MORLEY,J. E. (1987) Modulation of memory processing by cholecystokinin: dependence on the vagus nerve. Science 236, 832-834. FLOOD, J. F., SILVER,A. J. and MORLEY,J. E. (in press) Do peptide-induced changes in feeding occur because of changes in motivation to eat? Peptides. FORGACS,I. C., ISAACS,P. E. T., LADAS,S., MURPHY, G. M. and DOWLING,R. H. (1983) Meal composition influences plasma immuno-relative cholecystokinin (5R-CCK) levels and gallbladder (GB) contraction. Gastroenterology 84, 1157. GARDNER,J. D. and JENSEN,R. T. (1984) Cholecystokinin receptor antagonists. Am. J. Physiol. 246, G471~G476. GERACIOTI, T. O. and LIDDLE, R. A (1988) Impaired cholecystokinin secretion in bulimia nervosa. N. Engl. J. Med. 319, 683-688. Glans, J. and SMITH, G. P. (1985) Satiety: the roles of peptides from the stomach and the intestine. Fedn Proc. 45, 1391-1395. Glans, J., YOUNG,R. C. and SMITH,G. P. (1973) Cholecystokinin decreases food intake in rats. J. comp. physiol. Psychol. 84, 488--495. GLICK, Z., THOMAS,D. W. and MAYER,J. (1971) Absence of effect of injections of the intestinal hormones secretin and cholecystokinin pancreozymin upon feeding behavior. PhysioL Behav. 6, 5-I I. GREENBERG, D. and SMITH, G. P. (1988) Hepatic-portal infusion reduces the satiating potency of CCK-8. Physiol. Behav. 44, 535-538. GREENWAY, F. L. and BRAY, G. A. (1977) Cholecystokinin and satiety. Life Sci. 21, 769-772. GREGORY, P. C., MCFADYEN, M. and RAYNER, D. V. (1989) Duodenal infusion of fat, cholecystokinin secretion and satiety in the pig. Physiol. Behav. 45, 1021-1024. HARPER, A. A. and RAPER, H. S. (1943) Pancreozymin, a stimulant of the secretion of pancreatic enzymes in extracts of the small intestine. J. Physiol., Lond. 102, 115-125. HAYS, S. E., GOODMAN, F. K. and PAUL, S. M. (1981) Cholecystokinin receptors in brain: effects of obesity, drug treatment, and lesions. Peptides 2, 21-26. HILL, P., GARBACZEWSKI,L., KOPPESCHAAR, H., THIJSSEN, J. H., DE WAARD, E. and WYNDER, E. L. (1988) Peptide and steroid hormones in subjects at different risk for diet-related diseases. Am. J. clin. Nutr. 48, 782-786. HINTON, V., ROSOFSKY, M., GRANGER, J. and GEARY, N. (1986) Combined injection potentiates the satiety effects of pancreatic glucagon, cholecystokinin and bombesin. Brain Res. Bull. 17, 615-619. HOUPT, T. R., ANIKA, S. M. and WOLFF, N. C. (1978) Satiety effects of cholecystokinin and caerulein in rabbits. Am. J. Physiol. 235, R23-R28. HOWLS, K. A., NEWTON, B. W. and MALEY, B. E. (1989) Cholecystokinin octapeptide immunoreactivity in the nucleus tractus solitarius of the cat. Peptides 10, 73 78. HUNT, J. N. and SPURRELL, W. R. (1951) The pattern of emptying of the human stomach. J. Physiol., Lond. 113, 157-168.

JPN 361~"

31

IADAROLA, M. J., NARANGO, J. R., DUCHEMIN, A. M. and QUACH, T. T. (1989) Expression of cholecystokinin and enkephalin mRNA in discrete brain regions. Peptides 10, 687-692. INUI, A., OKITA, M., INOUE, T., SAKATANI,N., OYA, N., MORIOKA,H., OIMOm, M. and BABA,S. (1989) Effect of cholecystokinin octapeptide analogues on food intake in the dog. Am. J. Physiol. 257, R946-R951. IvY, A. C. and OLDBERG,E. (1928) A hormone mechanism for gall-bladder contraction and evacuation. Am. J. Physiol. 86, 599-613. JAMIF,SON, J. E. (1973) Secretin, Cholecystokinin, Pancreozymin, and Gastrin, pp. 195-217. Eds. J. E. JORPESand V. MUTT. Springer-Verlag: New York. KAPAS, L., OBAL,F., ALFOLDI,P., RUBICSEK,G. and PENKE, B. (1988) Effects of nocturnal intraperitoneal administration of cholecystokinin in rats: simultaneous increase in sleep, increase in EEG slow-wave activity, reduction of motor activity, suppression of eating, and decrease in brain temperature. Brain Res. 438, 155-164. KHALIL, T., WALKER, J. P., WIENER, I., FAGAN, C. J., TOWNSEND,C. M., GREELEY,G. H. and THOMPSON,J. C. (1985) Effect of aging on gallbladder contraction and release of cholecystokinin-33 in humans. Surgery 98, 423-429. KHOSLA,S. and CRAWLEY,J. N. (1988) Potency of L-364,718 as an antagonist of the behavioral effects of peripherally administered cholecystokinin. Life Sci. 42, 153-159. KISSILErr,H. R., PbSuNreR, F. X., THORNTON,J. and SMITH, G. P. (1981) C-Terminal octapeptide of cholecystokinin decreases food intake in man. Am. J. clin. Nutr. 34, 154-160. KRALY, F. S. (1981) A diurnal variation in the satiating potency of cholecystokinin in the rat. Appetite 2, 177-191. KULKOSKY, P. J., BRECKENRIDGE, C., KRINSKY, R. and WOODS, S. C. (1976) Satiety elicited by the C-terminal octapeptide of cholecystokinin-pancreozymin in normal and VMH-lesioned rats. Behav. Biol. 18, 227-234. LARSSON,L. I. and REm~LD, J. F. (1979) Localization and molecular heterogeneity of cholecystokinin in the central and peripheral nervous system. Brain Res. 165, 201-218. LEIaOWITZ, S. F. (1986) Brain monoamines and peptides: role in the control of eating behavior. Fedn Proc. 45, 1396-1403. LESAUrER, J., GOLDBERG,B. and GEARV, N. (1998) CCK inhibits real and sham feeding in gastric vagotomized rats. PhysioL Behav. 44, 527-534. LEVINE,A. S. and MORLEY,J. E. (1982) Peripherally administered somatostatin reduces feeding by a vagal mediated mechanism. Pharmac. Biochem. Behav. 16, 897-902. LEV1NE,A. S., HUGHES,J. J., MORLEY,J. E., GOSNELL,B. A. and SILVIS, S. E. (1984a) Calcitonin as a regulator of gastric acid secretion. Psychopharmac. Bull. 20, 459-461. LEVINE,A. S., SIEVERT,C. E., MORLEY,J. E., GOSNELL, B. A. and SILVlS,S. E. (1984b) Peptidergic regulation of feeding in the dog (Canis familiaris). Peptides 5, 675-679. LIDDLE, R. A., GOLDFINE,I. D. and WILLIAMS,J. A. (1984) Bioassay of plasma cholecystokinin in rat: effect of food, trypsin inhibitor, and alcohol. Gastroenterology 87, 542-549. LIDDLE,R. A., RUSHAKOFF,R. J., MORITA,E. T., BECCARIA, L., CARTER,J. D. and GOLDFINE,I. D. (1988) Physiological role for cholecystokinin in reducing postprandial hyperglycemia in humans. J. din. Invest. 81, 1675-1681. LILJA, P., FRIED, G. M., WIENER, I., INOUE, K. and THOMPSON,J. C. (1982) Comparison of concentrations of plasma cholecystokinin in pig, dog, and man after food or intraduodenal fat. Gastroenterology 82, l ll8. LINDEN,A. and UVNAS-MOBERG,K. (1987) Plasma levels of cholecystokinin (CCK-8 and CCK-33-39) in response to feeding and during pregnancy in dogs. Scand. J. Gastroenterol. 22, 859-864.

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A.J. SILVER and J. E. MORLEY

LOTTI, V. J., PENDLETON, R. G., GOULD, R. J., HANSON, H. M., CHANG R. S. L. and CLINESCHMIDT,B. V. (1987) In vivo pharmacology of L-364,718, a new potent nonpeptide peripheral cholecystokinin antagonist. J. Pharmac. exp. Ther. 241, 103 109. MAKHLOUF, G. M. (1974) The neuroendocrine design of the gut. Gastroenterology 67, 159-184. MARTIN, R., GEIS, R., HOLL, R., SCHAFTER,M. and VOIGHT, K. H. (1983) Co-existence of unrelated peptides in oxytocin and vasopressin terminals of rat neurohypophyses: immunoreactive methionine-enkephalin, leucine-enkephalin- and CCK-like substances. Neuroscience 8, 213-227. McHUGH, P. R. and MORAN, T. H. (1986) The stomach, cholecystokinin, and satiety. Fedn Proc. 45, 1384-1390. MCLAUGHL1N, C. t . and BAILE,C. A. (1981) Obese mice and the satiety effects of cholecystokinin, bombesin, and pancreatic polypeptide. Physiol. Behav. 26, 433-437. MCLAUGHLIN, C. L., PEIKIN, S. R. and BAILE,C. A. (1983) Trypsin inhibitor effects on food intake and weight gain in Zucker rats. Physiol. Behav. 31, 487-491. McLAUGHLIN, C. L., BAILE, C. A. and BUONOMO, F. C. (1985) Effect of CCK antibodies on food intake and weight gain in Zucker rats. Physiol. Behav. 34, 277-282. MIASK1EWlCZ, S. L., STRICKER, E. M. and VERBALIS,J. G. (1989) Neurohypophyseal secretion in response to cholecystokinin but not meal-induced gastric distention in humans. J. clin. Endocr. Metab. 68, 837-843. MICELI, M. O. and MALSBURY,C. W. (1983) Feeding and drinking responses in the golden hamster following treatment with cholecystokinin and angiotensin II. Peptides 4, 103 106. MITCHELL. J. E., LAINE, D. E., MORLEY, J. E. and LEVINE, A. S. (1986) Natoxone but not CCK-8 may attenuate binge-eating behavior in patients with the bulimia syndrome. Biol. Psychiatr. 21, 1399-1406. MORAN, T. H. and McHUGH, P. R. (1982) Cholecystokinin suppresses food intake by inhibiting gastric emptying. Am. J. Physiol. 242, R491 R497. MORAN, T. H. and McHUGH, P. R. (1988) Gastric and nongastric mechanisms for satiety action of cholecystokinin. Am. J. Physiol. 254, R628-R632. MORAN, T. H.. SHNAYDER, L., HOSTETLER, A. M. and McHUGH, P. R. (1988) Pylorectomy reduces the satiety action of cholecystokinin. Am. J. Physiol. 255, R1059 R1063. MORLEY, J. E. (1980) The neuroendocrine control of appetite: the role of the endogenous opiates, cholecystokinin, TRH, gamma-amino-butyric-acid and the diazepam receptor. Life Sci. 27, 355 368. MORLEY, J. E. (1987) Neuropeptide regulation of appetite and weight. Endocr. Rev. 8, 256587. MORLEY, J. E. (1989) Apetite regulation: the role of peptides and hormones. J. Endocr. Invest 12, 135-147. MORLEY, J. E. and LEWNE, A. S. (1985) The pharmacology of eating behavior. A. Rev. Pharmac. Toxicol. 25, 127-146. MORLEY, J. E. and SILVER, A. J. (1988) Anorexia in the elderly. Neurobiol. Aging 9, 9-16. MORLEY, J. E., VARNER, A. A., MODLIN, I. M., CARLSON, H. E., BRAUNSTEIN,G. D., WALSH, J. H. and HERSHMAN, J. M. (1980) Failure of bombesin to alter anterior pituitary hormone secretion in man. Clin. Endocr. 13, 369-373. MORLEY, J. E., LEVINE, A. S., MURRAY, S. S. and KNEIP, J. (1982a) Peptidergic regulation of norepinephrine induced feeding. Pharmac. Biochem. Behav. 16, 225-228. MORLEY, J. E., LEWNE, A. S., KNEIP, J. and GRACE, M. (1982b) The effect of vagotomy on the satiety effects of neuropeptides and naloxone. Life Sci. 30, 1943-1947. MORLEY, J. E., LEVINE,A. S., PLOTKA, E. D. and SEAL, U. S. (1983a) The effect of naloxone on feeding and spontaneous locomotion in the wolf. Physiol. Behav. 30, 331--334.

MORLEY, J. E., LEVINE, A. S., KNEIP, J., GRACE, M. and BILLINGTON, C. J. (1983b) The effect of peripherally administered satiety substances on feeding induced by butorphanol tartrate. Pharmae. Bioehem. Behav. 19, 577-582. MORLEY, J. E., LEVINE, A. S., GOSNELL, B. A., MITCHELL, J. E., KRAHN, D. D. and NIZIELSKI,S. E. (1985a) Peptides and feeding. Peptides 6, 181-192. MORLEY, J. E., LEVINE, A. S., BARTNESS, T. J., NIZlELSKL S. E., SHAW, M. J. and HUGHES, J. J. (1985b) Species differences in the response to cholecystokinin. Ann. N.Y. Acad. Sci. 488, 413-416. MOSSNER, J., REGNER, U. F., ZEEH, J. M., BRUCH, H. P. and EBERLEIN, G. (1989) Influence of food on plasma cholecystokinin and gastrin in patients with partial gastric resections and Roux-en-Y anastomosis. 27, 94-98. MURPHY, R. B., SMITH, G. P. and GIBBS,J. (1987) Pharmacological examination of cholecystokinin (CCK-8)induced contractile activity in the rat isolated pylorus. Peptides 8, 127-134. MUTT, V. and JORPES, E. (1971) Hormonal polypeptides of the upper intestine. Biochem. J. 125, 57 58. MYERS, R. D., SWARTZWELDER,H. S., PEINADO,J. M., LEE, T. F., HEPLER, J. R., DENBOW, D. M. and FERRER, J. M. (1986) CCK and other peptides modulate hypothalamic norepinephrine release in the rat: dependence on hunger or satiety. Brain Res. Bull. 17, 583-597. NIEDERAU,C., LIDDLE, R. A., FERRELL,L. D. and GRENDELL, J. H. (1986) Beneficial effects of cholecystokinin-receptor blockade and inhibition of proteolytic enzyme activity in experimental acute hemorrhagic pancreatitis in mice. Evidence for cholecystokinin as a major factor in the development of acute pancreatitis. J. din. Invest. 78, 1056 1063. PARROTT, R. F. and BALDWIN,B. A. (1981) Operant feeding and drinking in pigs following intracerebroventricular injection of synthetic cholecystokinin octapeptide. Physiol. Behav. 26, 419-422. PASLEY, J. N., BARNES, C. L. and RAYFORD, P. L. (1987) Circadian rhythms of serum gastrin and plasma cholecystokinin in rodents. Prog. clin. biol. Res. 227, 371-378. PASSARO, E., DEBAS, H., OLDENDORF, W. and YAMADA, T. (1982) Rapid appearance of intraventricularly administered neuropeptides in the peripheral circulation. Brain Res. 241, 335 340. PI-SUNYER, F. X., KISSILEFF,H. R., THORNTON, J. and SMITH, G. P. (1982) C-terminal octapeptide of cholecystokinin decreases food intake in obese men. Physiol. Behav. 29, 627-630. PYLE, R. L., MITCHELL, J. E. and ECKERT, E. D. (1981) Bulimia: a report of 34 cases. J. clin. Psychiatr. 42, 60-64. QUIGLEY, J. P. (1955) The role of the digestive tract in regulating the ingestion of food. Ann N.Y. Acad. Sci. 63, 6-14. QUIGLEY, J. P. and HALLARAN,W. R. (1932) The independence of spontaneous gastrointestinal motility. Am. J. Physiol. 100, 102-110. QUIGLEY, J. P. and PHELPS, K. R. (1934) The mechanism of gastric motor inhibition from ingested carbohydrates. Am. J. Physiol. 109, 133-138. REAGAN,J. E., ROBINSON,J. L., LOTTI,V. J. and GOLDMAN, M. E. (1987) Fasting and L-364,718 prevent cholecystokinin-induced elevations of plasma insulin levels. Eur. J. Pharm. 144, 241-243. REHFELD, J. F. (1978) Immunochemical studies on cholecystokinin. II. Distribution and molecular heterogeneity in the central nervous system in man and hog. J. biol. Chem. 253, 4022-4030. REIDELBERGER, R. D. and SOLOMON,T. E. (1986) Comparative effects of CCK-8 on feeding, sham feeding and exocrine pancreatic secretion in rats. Am. J. Physiol. 251, R97-RI05.

ROLE OF CCK IN REGULATIONOF FOOD INTAKE REIDELBERGER, R. D., KALOGERIS,T. J. and SOLOMON,T. E. (1989) Plasma CCK levels after food intake and infusion of CCK analogues that inhibit feeding in dogs. Am. J. Physiol. 256, R1148-R1154. ROLLS, B. J., ROLLS, E. T., ROWE, E. A. and SWEENEY, K. (1981) Sensory specific satiety in man. Physiol. Behav. 27, 137-142. RUSHAKOFF, R. J., GOLDFINE, I. D., CARTER, J. D. and LIDDLE, R. A. (1987) Physiological concentrations of cholecystokinin stimulate amino acid-induced insulin release in humans. J. clin. Endocr. Metab. 65, 395-401. SAITO, A., WILLIAMS, J. A. and GOLDFINE, I. D. (1981) Alterations in brain cholecystokinin receptors after fasting. Nature, Lond. 289, 599~500. SAKSTANI,N., ]NUI, A., INOUE, T., OYA, M., MORIOKA, H. and BABA,S. (1987) The role of cholecystokinin octapeptide in the central control of food intake in the dog. Peptides 8, 651~56. SAVORY, C. J. and GENTLE, M. J. (1980) Intravenous injections of cholecystokinin and caerulein suppresses food intake in domestic fowls. Experimentia 36, 1191-1192. SCHEURER, U., VARGA,L., DRACT, E., BURKI, H. R. and HALTER, F. (1983) Measurement of cholecystokinin octapeptide induced motility of rat antrum, pylorus, and duodenum in vivo. Am. J. Physiol. 244, G261-G265. SCHNEEMAN, B. O. and LYMAN,R. L. (1975) Factors involved in the intestinal feedback regulation of pancreatic enzyme secretion in the rat. Proc. Soc. exp. Biol. Med. 148, 897-903. SCHNEEMAN,B. O. and LYMAN,R. L. (1977) Distribution of cholecystokinin activity in the rat small intestine. Digestion 15, 28-33. SCHNEIDER, B. S., MONAHAN, J. W. and HmSCH, J. (1979) Brain cholecystokinin and nutritional status in rats and mice. J. clin. Invest. 64, 1348-1356. SCHNEIDER,L. H., GIBBS,J. and SMITH,G. P. (1986) Proglumide fails to increase food intake after an ingested preload. Peptides 7, 135-140. SHAW, M. J., HUGHES, J. J., MORLEY, J. E., LEVINE, A. S., SILVlS, S. E. and SHAFER,R. B. (1985) Cholecystokinin octapeptide action on gastric emptying and food intake in normal and vagotomized man. Ann. N.Y. Acad. Sci. 448, 640~541. SHILLAaEER, G. and DAVlSON,J. S. (1984) The cholecystokinin antagonist, proglumide, increases food intake in the rat. Regul. Pept. 8, 171-176. SHILLAnEER, G. and DAVISON, J. S. (1987) Endogenous and exogenous cholecystokinin may reduce food intake by different mechanisms. Am. J. Physiol. 253, R379-R382. SHINYA, H. and FUJIMURA, M. (1989) Possible role of cholecystokinin in the development of acute pancreatitis in rats. Arch. jap. Chir. 58, 3-17. SILVER, A. J., FLooD, J. F. and MORLEY, J. E. (1988) Effect of gastrointestinal peptides on ingestion in old and young mice. Peptides 9, 221 225. SILVER, A. J., FLooD, J. F., SONG, A. M. and MORLEY, J. E. (1989) Evidence for a physiological role for CCK in the regulation of food intake in mice. Am. J. Physiol. 256, R646 R652. SILVERMAN, M. A., GREENBERG, R. E. and BANK, S. (1987) Cholecystokinin receptor antagonists: a review. Am. J. Gastroentero/. 8, 703-708. SJODIN, L. (1972) Influence of secretin and cholecystokinin on canine gastric secretion elicited by food and exogenous gastrin. Acta physiol, scand. 85, 110-117. SMITH,G. P. and GIBBS,J. (1979) Postprandial satiety. Prog. Psychobiol. Physiol. Psychol. 8, 179-242. SMITH, G. P., JEROME, C., CUSHIN, B. J., ETERNO, R. and SIMANSKY, K. J. (1981) Abdominal vagotomy blocks the satiety effect of cholecystokinin in the rat. Science 213, 1036-1037.

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SMITH, G. P., JEROME, C. and NORGREN, R. (1983) Vagal afferent axons mediate the satiety effect of CCK-8. Soc. Neurosci. Abstr. 9, 902. SMITH, G. P., GREENBERG, D., FALUSCO, J. D., GIBBS, J., LIDDLE, R. A. and WILLIAMS,J. A. (1985) Plasma levels of cholecystokinin produced by satiating doses of exogenous CCK-8. Proc. Soc. Neurosci. Abstr. 11, 557. SPIEGEL, T. g., SHRAGER, E. E. and STELLAR, E. (1989) Responses of lean and obese subjects to preloads, deprivation, and palatability. Appetite 13, 45~59. STACHER, G., STEINRINGER, H., SCHNIERER, G., SCHNEIDER, C. and WINKELHNER, S. (1982) Cholecystokinin octapeptide decreases intake of solid food in man. Peptides 3, 133-136. STERN, J. J., CUDILLO, C. A. and KRUPER, J. (1976) Ventromedial hypothalamus and short-term feeding suppression by caerulein in male rats. J. comp. physiol. Psychol. 90, 484-490. STRAUS, E. and YALOW, R. S. 0979) Cholecystokinin in the brains of obese and nonobese mice. Science 203, 68~9. STROHMAYER,A. J. and SMITH,G. P. (1987) A sex difference in the effect of CCK-8 on food and water intake in obese (ob/ob) and lean ( + / + ) mice. Peptides 8, 845-848. STULER, J. M., SIMON, H., CESSELIN, F., LEGRAND, J. C., GLOWINSKI, J. and TASS1N,J. P. (1981 ) Biochemical investigation on the localization of the cholecystokinin octapeptide in dopaminergic neurons originating from the ventral tegmental area of the rat. Neuropeptides 2, 131-139. STURDEVANT,R. A. L. and GOETZ, H. Cholecystokinin both stimulates and inbibits human food intake. Nature, Lond. 261, 714-716. VANDERHAEGHEN,J. J., SIGNEAU,J. C. and GEPTS, W. (1975) New peptide in the vertebrate CNS reacting with gastrin antibodies. Nature, Lond. 221, 557 559. VANDERHAEGHEN,J. J., LOTSTRA,F., DE MEY, J. and GILLES, C. (1980) Immunohistochemical localization of cholecystokinin- and gastrin-like peptides in the brain and hypophysis of the rat. Proc. natn. Acad. Sci. U.S.A. 77,

1190-1194. VANDERHAEGHEN, J. J., LOTSTRA, F., VIERENDEELS, G., GILLES, C., DESCHEPPER, C. and VERBANCK, P. (1981) Cholecystokinins in the central nervous system and neurohypophysis. Peptides 2, 81-88. VAN DER WEELE, D. A., HARACZKIEWICZ,E. and DICONTI, M. (1980) Pancreatic glucagon administration, feeding, glycemia, and liver glycogen in rats. Brain Res. Bull. 4, 17-21. VERBALIS, J. G., MCCANN, M. J., MCHALE, C. M. and STRICKER, E. M. (1986) Oxytocin secretion in response to cholecystokinin and food intake: differentiation of nausea from satiety. Science 232, 1417-1419. WAGER-SRDAR, S. A., GANNON, M. and LEVINE,A. S. (1987) The effect of cholecystokinin on food intake in gonadectomized and intact rats: the influence of sex hormones. Physiol. Behav. 40, 25-28. WATKINS, L. R., KINSCHECK, I. B., KAUFMAN, E. F. S., MILLER, J., FRENK, H. and MAYER, D. J. (1985) Cholecystokinin antagonists selectively potentiate analgesia induced by endogenous opiates. Brain Res. 327, 181-190. WEST, D. B., FLY, D. and WOODS, S. C. (1984) Cholecystokinin persistently suppresses meal size but not food intake in free-feeding rats. Am. J. Physiol. 246, R776-R787. WEST, D. B., GREENWOOD, M. R., MARSHALL, K. A. and WooDs, S. C. (1987) Lithium chloride, cholecystokinin and meal patterns: evidence that cholecystokinin suppresses meal size in rats without causing malaise. Appetite 8, 221-227. WILSON, M. C., DENSON, D., BEDFORD, A. and HUNSlNGER, R. N. (1983) Pharmacological manipulation of sincalide (CCK-8)-induced suppression of feeding. Peptides 4, 351-357.

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A. J. SILVER and J. E. MORLEY

YAMAGISHI, T. and DEBAS, H. T. (1978) Cholecystokinin inhibits gastric emptying by acting on both proximal stomach and pylorus. Am. J. Physiol. 234, E375-E378. YOUNES, M., WANK, S. A., VINAYEK, R., JENSEN, R. J. and GARNDNER, J. n . (1989) Regulation of bombesin receptors on pancreatic acini by cholecystokinin. Am. J. Physiol. 256, G9291-G9298.

ZHU, X. O., OREELEY, G. H., LEWIS, B. G., LILJA, P. and THOMPSON, J. C. (1986) BIood-CSF barrier to CCK and effect of centrally administered bombesin on release of brain CCK. J. Neurosci. Res. 15, 393-403. ZORBIN, M. A., WAMSKY,J. K., INNIS,R. B. and KUHAR, M. J. (1981) Cholecystokinin receptors: presence and axonal flow in the rat vagus nerve. Life Sci. 29, 697-705.