Multiple cholecystokinin (CCK) receptors and CCK-monoamine interactions are instrumental in the control of feeding

Physiology& Behavior, Vol. 48, pp. 849-857. ©PergamonPress plc, 1990. Printedin the U.S.A.

0031-9384/90$3.00 + .00

Multiple Cholecystokinin (CCK) Receptors and CCK-Monoamine Interactions Are Instrumental in the Control of Feeding S T E V E N J. C O O P E R * A N D C O L I N T. D O U R I S H t

*Laboratory of Psychopharmacology, School of Psychology University of Birmingham, Birmingham, B15 217", UK ~Merck Sharp & Dohme Research Laboratories, Neuroscience Research Centre Terlings Park, Eastwick Road, Harlow, Essex, CM20 2QR, UK COOPER, S. J. AND C. T. DOURISH. Multiple cholecystokinin (CCK) receptors and CCK-monoamine interactions are instrumental in the control of feeding. PHYSIOL BEHAV 48(6) 849-857, 1990.--Almost two decades ago, exogenous cholecystokinin (CCK) was shown to suppress food consumption in rats. Since then, CCK has been detected not only in peripheral tissue but extensively throughout the central nervous system. Furthermore, specific CCK receptors have been described, and a distinction drawn between CCK-A and CCK-B receptors. Recently, potent, orally active CCK antagonists, which show a high degree of selectivity for either CCK-A or CCK-B receptors, have been introduced. The present report reviews recent evidence obtained in studies using devazepide (a selective CCK-A receptor antagonist) and L-365,260 (a selective CCK-B/gastrin receptor antagonist). Both compounds increased food consumption and postponed the onset of satiety in well-satiated rats. L-365,260 was more potent, suggesting that central CCK-B type receptors may mediate the satiety effects of endogenously released CCK. Only devazepide was effective in blocking the feeding-suppressant effect of exogenous CCK, indicating that CCK-A type receptors mediate this effect. In a second series of studies, devazepide but not L-365,260 antagonized the anorectic effect of either d-fenfluramine or systemically administered 5-HT. Hence, CCK-A type receptors appear to be involved in the anorectic effects of these serotonergic drugs. We propose that CCK and 5-HT mechanisms involved in mediating satiety are mutually interdependent. Possible interactions between CCK and catecholaminergic mechanisms are also briefly considered. Cholecystokinin CCK-A and CCK-B receptors Dopamine Noradrenaline

Devazepide

CHOLECYSTOKININ (CCK) reduces the consumption of food when administered to human subjects, primates or other animals (3, 11, 32, 70, 71). An explanation for this effect is that the exogenous CCK enhances satiety, and, in so doing, provides valuable evidence for a physiological role for endogenous CCK in the control of food intake. In brief, food ingestion acts as a stimulus for the release of endogenous CCK (present in the gastrointestinal tract), and circulating levels of CCK may be sufficient to induce a short-term satiety effect (70). This early formulation left many important questions unanswered, as the authors acknowledged (70), but it was also quickly challenged on the grounds that administration of exogenous CCK has aversive effects, which, it was claimed, would be sufficient to account for the satiety-like effect (20,73). While we should remain mindful of aversive and toxic effects of drug treatments affecting food acceptance and ingestion, there are problems with the challenge. For example, there is reliable evidence that kappa opioid receptor agonists produce aversive effects, as measured by conditioned place aversions (54,79), yet they can also be shown to increase the level of food consumption (15). Evidence for aversive effects of drug treatments, therefore, is not necessarily a good predictor of the diree-

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tion of change in feeding behaviour. Moreover, administration of CCK in doses which reduced food consumption did not provoke retching or vomiting in monkeys (32) and did not affect the feeling of well-being in human subjects (71). While the effects of exogenous CCK provide an initial pharmacological signpost, other approaches are also needed to investigate the physiological significance of endogenously released CCK. Clearly, it is important to address the issue of whether circulating levels of endogenous CCK are sufficient to induce a satiety effect (44). Furthermore, the introduction of selective CCK antagonists provides pharmacological tools for analysing the functional effects of endogenously released CCK (31). More than this, the scope of the enquiry will have to be broadened, and account taken of the widespread distribution of CCK (in several molecular forms) not only in peripheral organs but also throughout the central nervous system (58). Central, as well as peripheral, mechanisms need to be considered carefully (and the interrelations between them). The enquiry also has to be broadened to integrate the data on CCK mechanisms with those for monoaminetgic systems known to be involved intimately in the control of food intake (42). It should be a major long-term aim to understand how

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multiple systems interact in determining behavioural responses involved in the procurement and ingestion of food. The fundamental discovery that some monoaminergic neurons also synthesize, store and release peptide neurotransmitters and modulators (39,40) provides the strongest impetus for viewing the actions of monoamines and neuropeptides, like CCK, as components in an integrated, orchestrated system. Our purpose, in the present paper, is to summarize a series of recent experiments which have been designed to address two central issues. The f'irst pertains to the effects of selective cholecystokinin antagonists, and the light which they throw on the means by which endogenous CCK influences food ingestion. The second is concerned with the nature of putative CCK-monoamine interactions in an integrated control of food consumption. MULTIPLECHOLECYSTOKININRECEPTORS

Cholecystokinin in the Brain CCK is located in neural and nonneural tissue of the gastrointestinal tract. In 1975, Vanderhaeghen and his colleagues reported that gastrin-like immunoreactivity is also present in brain (75), and Dockray and his colleagues then showed that much of the immunoreactivity could be attributed to CCK-8, a peptide closely related to gastrin (21,22). Soon afterwards, specific binding sites for CCK in rat, mouse and human brain were identified (34, 35, 61, 62, 78). Hence, in trying to assess "a role" for CCK in the control of feeding behaviour, not only must peripheral physiological events be considered, but account has also to be taken of the possible involvement of centrally located CCK receptors, and of centrally synthesized and released CCK.

CCK-A and CCK-B Type Receptors It was quickly realised that a distinction could be drawn between CCK receptors in the brain and those found in the pancreas (63). This led to the notion of two types of CCK receptor, an Atype found in many peripheral locations (e.g., pancreas, vagus, and pyloric sphincter), and a B-type found in the brain (25, 52, 53). Further study showed that while the CCK-B type receptor is widely distributed in the brain, there are some central locations in which CCK-A type receptors are found (e.g., interpeduncular nu-

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TIME(min) FIG. 2. Effect of devazepide on the frequencyof feeding (left panel) and resting (right panel) in rats deprived of food for 17 h and then given a 40-min prefeeding period. Devazepide significantly increased the frequency of feeding and postponedthe onset of resting. Sixty-minobservation period. [© 1989 AAAS. Reproduced from (27) with permission.]

cleus, area postrema; nucleus of the solitary tract) (25, 37, 38, 52, 53).

Selective CCK Receptor Antagonists The glutaramic acid derivative, proglumide, was recognised as a CCK receptor antagonist (34), and it was, therefore, a particulary interesting finding that proglumide increased food intake in rats (49,68). More potent and selective analogues of proglumide have since been developed, and these include lorglumide (CR-1409) and loxiglumide (CR-1505) (59). Peptidergic CCK analogues have also been developed as selective CCK antagonists (50). In our studies, however, we have made use of two recently developed nonpeptide compounds, both of which show high specificity for CCK receptors and which also exhibit great potency as CCK receptor antagonists (Fig. 1) (31). Devazepide (L-364,718; MK-329) is a substituted benzodiazepine, which has high affinity for CCK-A receptors (ICso = 10" 1o), and shows considerable selectivity for this receptor subtype over the central-type receptor (9, 29, 46). Further development work led to the synthesis of L365,260, which proved to be a potent receptor antagonist, and highly selective for CCK-B and gastfin receptors (7,45). Although peptidal gastdn and CCK-B selective compounds have been reported (10), L-365,260 is the first nonpeptidal (and orally active) substance to be developed which acts as a selective antagonist at

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Time(min) FIG. 3. (upper panel) Comparisons between the behavioural satiety sequence in 17-h food-deprived rats given either a 20-min prefeeding period (thin line) or a 40-rain prefeeding period (thick line). (lower panel) Similar comparisons for 17-h food-deprived rats given a 40-min prefeeding period and then injected with either devazepide at 10 p.g/kg (thin line) or its vehicle (thick line). Sixty-min observation period. [© 1989 AAAS. Reproduced from (27) with permission.]

gastrin and CCK-B receptors. Our strategy has therefore been to employ both devazepide and L-365,260, as CCK receptor antagonists, in attempts to identify the respective contributions of CCK-A and CCK-B type receptors to the control of feeding behaviour.

consumption and support the view that actions of endogenous CCK serve to limit food intake. An increase in food intake does not, however, invariably follow the administration of devazepide

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FIG, 5. Comparative potencies of the CCK-A antagonist devazepide (O) and the CCK-B antagonist L-365,260 (O).in (A) increasing the frequency of feeding and (B) postponing the onset of resting in the satiety sequence. [© 1989 AAAS. Reproduced from (27) with permission.]

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(12), and therefore it is critical to establish the conditions under which reliable increases can be obtained. Not only does exogenous CCK reduce food consumption, but its administration also produces a sequence of behaviour which is characteristic of postprandial satiety (1). It would be expected, therefore, that selective CCK antagonists would increase food intake in satiated animals, and also postpone the development of postprandial satiety. Both predictions have been upheld in recent experiments with devazepide (27). In these studies, rats were first deprived of food for 17 hours and were then permitted to eat food during a 40-min period to induce a state of satiation. As Fig.

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FIG. 6. The CCK-A receptor antagonist devazepide antagonised the suppressant effect of CCK-8 on sucrose consumption in food- and water-deprived rats (upper panel). The selective CCK-B/gastrin receptor antagonist L-365,260 was ineffective against CCK-8 (lower panel). [Reproduced from (26) with permission.]

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FIG. 7. Proposed anatomical pathways for the gut-brain control of food intake. Sensory input is conveyed via gastric vagal afferents to the nucleus of the solitary tract (NTS) and to the parabrachial nucleus (PBN) in the pons. In turn, there are relays to paraventricular (PVN) and ventromedial (VMH) nuclei of the hypothalamus. Cholecystokinin (CCK) may serve as a neurolransmitter or neurohumoural agent at each stage in the projection sequence. The location of relevant CCK receptor subtypes (CCK-A, CCK-B) are indicated. For a comprehensive review of CCK's role in feeding, see Crawley (16).

CCK RECEPTORS AND CCK-MONOAMINE INTERACTIONS

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2 shows, administration of devazepide (10 ng/kg-100 Ixg/kg, SC) after the 40-min prefeeding period led to increases in the frequency of feeding episodes and delays in the onset of resting (a sign of postprandial satiety). The effects produced by devazepide were similar to those obtained by reducing the prefeeding period from 40 min to 20 min (Fig. 3). Hence, devazepide appears to act in a manner analogous to a reduction in the degree of satiation, and, therefore, the results are consistent with a role for endogenous CCK in the development of satiety. Most interesting is the observation that the selective CCK-B/ gastrin receptor antagonist L-365,260 was also effective in enhancing food consumption in satiated animals. Figure 4 compares data for devazepide and L-365,260, and demonstrates that L365,260 was the more potent of the two. Moreover, L-365,260 proved to be more potent in increasing the frequency of feeding and in decreasing resting frequency (Fig. 5). It is remarkable that, in these studies, the threshold dose for L-365,260 to increase food intake was 1.0 ng/kg. The results argue strongly in favour of a role for CCK-B receptors in mediating the satiation induced by endogenous CCK (27). What receptor subtype mediates the effects of exogenous CCK? To answer this question, rats were deprived of food and water overnight before being given access to a 5% sucrose solution in a 30-rain test period. Sucrose ingestion was markedly reduced following injection of CCK-8 (8 I~g/kg, IP), and this effect of CCK was reversed by devazepide but not by L-365,260 (Fig. 6).

Hence, the hypophagic effect of exogenous CCK appears to involve CCK-A receptors, and not to require an action at CCK-B type receptors (26). These results bring us to some interesting preliminary conclusions. We began by noting the difficulty in interpreting early studies with exogenous CCK, and also the resolution, which might come from the use of selective CCK receptor antagonists, to identify the actions of endogenous CCK. Experiments with CCK antagonists have succeeded in providing convincing evidence for a role of endogenous CCK in meal termination and satiety. However, they have also succeeded in establishing a partial dissociation between effects of exogenous and endogenous CCK in terms of the CCK receptors involved. Whereas antagonism of CCK-B receptors appears to be sufficient to increase food intake and to postpone the onset of satiety (presumably by blocking effects of endogenous CCK activity), antagonism of CCK-A receptors is required to block the effects of exogenous CCK. Rather than unifying the actions of endogenous and exogenous CCK, these resuits point to a potentially important distinction between them (see below). PERIPHERALAND CENTRALCCK Some early formulations of the CCK-satiety hypothesis laid particular emphasis on peripheral CCK mechanisms (48,70), but it is now recognised that integrated pathways involving both peripheral and central CCK release and actions probably underlie the changes in feeding (Fig. 7). Several reports have shown that intraventricular infusion of CCK induces satiety (19, 30, 66, 77). Increased CCK release in the hypothalamus has been detected, following a meal, in cats and primates (65,67). Furthermore, in rats, direct injection of CCK-8 into hypothalarnus, medial pontine area, and nucleus of the solitary tract decreases food intake in rats (64). Experiments with the selective CCK-B type receptor antagonist, E-365,260, suggest that actions of endogenous CCK at receptors within the brain are involved in postprandial satiety (27). Moreover, the data linking CCK mechanisms with central monoamines are also con-

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FIG. 11. Schematic model of the proposed cooperativityand interdependence of 5-HT- and CCK-receptor-mediated increases in satiety. The model indicates that, in response to food ingestion, both endogenous 5HT and CCK are released. The cooperativityassumptionis that elevated 5-HT release and action will tend to increase CCK release and action and vice versa. The interdependenceassumptionis that both 5-HT and CCK actions at their respective receptors (interfaced through a logical 'AND' gate) are required for the normaldevelopmentof satiety. Hence, pharmacological interventionswhich block either set of receptors will reduce the satiety-inducingeffect of either transmitter.

sistent with central mediation of CCK's satiety effects. Further research would no doubt benefit from an approach which combined the use of selective receptor agonists and antagonists to identify contributing receptor subtypes, with identification of multiple sites of action. In addition, a conceptual framework has to be developed to accommodate and anticipate interactions between CCK mechanisms and other neurochemically defined systems involved in the controls of feeding and satiety. CHOLECYSTOKININ-MONOAMINEINTERACTIONS

CCK and Noradrenergic Controls of Feeding McCaleb and Myers (47) reported that infusion of noradrenaline (norepinephrine) into preoptic and medical hypothalamic sites elicited feeding in satiated rats. Infusion of CCK, either IP or at the hypothalamic sites, was sufficient to attenuate or block the rats' feeding response to noradrenaline. In additional studies, they found that IP injection of CCK brought about release of radiolabelled noradrenaline at both medial and rostral hypothalamic sites (55). This result led Myers and McCaleb (55) to suggest that CCK may also stimulate noradrenergic neurones that are involved in the mediation of satiety. This may explain findings that CCKinduced anorexia can be attenuated by noradrenergic receptor antagonists (76), and by depletion of hypothalamic catecholamines (74).

CCK and Dopaminergic Controls of Feeding In rats that have been deprived of food for 6 h, dopamine concentrations in the CSF decline and are restored when they have had the opportunity to eat for 1 h (43). Moreover, there is an increase in dopamine release in the nucleus accumbens when food-deprived animals are given the opportunity to eat (57). Dopamine release and effects at dopamine receptors may, therefore, be associated with feeding and also contribute to meal termination and satiety. In support of this suggestion, the dopamine receptor agonist, apomorphine, has been reported to reduce food ingestion (4). Dopamine receptors have been subdivided into two subtypes, D 1 and D E, respectively (41). It is interesting that dopamine ago-

nists which are selective for either the D1 or D2 subtype reduce feeding responses in rats, although the details of the behavioural changes which underlie their anorectic effects may differ (14, 48, 60). A close relationship between dopamine and CCK, in certain brain regions, is indicated by the discovery of colocalization of the two in brain neurones (39,40), and also of corelease (2). In terms of behavioural responses, it should not be surprising, therefore, to find evidence for functional interactions between dopamine and CCK (17,18). Linden (43) has recently obtained direct evidence for a link in terms of feeding behaviour. She found that IP administration of CCK-8 restored levels of dopamine in the CSF of mildly deprived animals. Thus, the satiety effect of CCK may depend, to some degree, on the central release of dopamine. In support of this hypothesis, Linden (43) found that the dopamine antagonist cis-flupentixol blocked not only the anorectic effect of apomorphine but also that of CCK-8. The latter result raises the question of potential interactions between dopamine agonists and selective CCK antagonists. However, we have so far failed to find any effect of either devazepide or L-365,260 on the anorectic effect of the selective dopamine D2 agonist, quinpirole (12,13). Nevertheless, further experiments on potential interactions between drug effects mediated by dopamine and CCK receptors are strongly indicated.

CCK and Serotonergic Controls of Feeding The hypothesis that serotonin (5-HT) is closely involved in processes of satiety (5,6) has generated a considerable amount of experimental investigation. Drugs that act as agonists at 5-HT receptors, release 5-HT, or block 5-HT reputake, are effective in reducing food intake (5,6). On the other hand, 5-HT receptor antagonists have proved effective in increasing food consumption in satiated animals (23). A priori, therefore, there are grounds for asking if there are mechanisms in common between the effects of 5-HT drugs, on the one hand, and those of CCK, on the other. Recent experiments provide the evidence for potential links between serotonergic and CCK mechanisms involved in the control of food intake. Thus, the 5-HT antagonist metergoline proved effective in attenuating the reduction in food intake produced by CCK-8 (4 txg/kg, IP) (72). Metergoline will also block the anorectic effect of d-fenfluramine, which depends on 5-HT activity at 5-HT 1 receptors (56). The peripheral 5-HT antagonist, xylamidine, did not affect the anorectic effect of CCK (72), and, similary, did not block d-fenfluramine's effect on food intake (56). Stallone et al. (72) proposed that exogenous CCK-8 acts at a peripheral site and exerts a satiety effect by subsequent alterations in 5-HT activity in the brain. We have seen above that exogenous CCK appears to act at CCK-A receptors in reducing food intake (26), and this would be consistent with the peripheral site of action for CCK-8 invoked by Stallone and colleagues (72). The relationship between 5-HT and CCK mechanisms can be viewed in an opposite sense, as a recent study of ours demonstrates (12). In this study, the anorectic effect of d-fenfluramine was blocked by devazepide (Fig. 8). This result indicates that the enhanced 5-HT transmission produced by d-fenfinrarninemay lead to an increase in endogenous CCK activity, which in turn produces an increase in satiety. In a subsequent study, dfenfluramine's anorectic effect was not antagonized by L-365,260 (Fig. 9), suggesting that CCK's activity at CCK-A type receptors is required for its effect (13). Systemically administered 5-HT also brings about a reduction in food intake, and the effect is thought to be mediatad by peripherally located receptors since it can be blocked by xylamidine (8). Recent data indicate that there may be a common link between exogenous 5-HT's anorectic effect and that of CCK-8. Like CCK-

CCK RECEPTORS AND CCK-MONOAMINE INTERACTIONS

855

8, the anorectic effect of 5-HT was blocked by devazepide (Fig. 10) but not by L-365,260 (13). Taking all of these recent experiments together, we can identify a number of interesting relationships: 1) The anoreetie effect of exogenous CCK-8 requires the activation of CCK-A type receptors (26) and may depend upon increased "xylamidine-insensitive" 5-HT activity at 5-HT receptors (72). 2) The anorectic effect of d-fenfluramine depends upon "xylamidine-insensitive" stimulation of 5-HT 1 receptors (56), and on CCK activity at CCK-A type receptors (12). 3) The anorectic effect of systemically administered 5-HT depends upon "xylamidine-sensitive" stimulation of 5-HT receptors (8), and on CCK activity at CCKA type receptors (13). 4) The stimulation of CCK-B type receptors may be sufficient for the satiating effect of endogenously released CCK (27). In order to accommodate some of these results, we think it necessary to propose one key assumption, i.e., that both elevated 5-HT activity and elevated CCK activity are required for satiation to be fully expressed as a reduction in feeding and as an induction of postprandial resting. Blocking either component will consequently affect the capacity of the other component to induce a satiety effect. In other words, we envisage the operation of a logical AND gate in determining the onset of satiety. In addition, we also suggest that elevated 5-HT will tend to promote CCK activity, and vice versa, so that there is a form of mutual cooper-

ativity (Fig. 11). With this model, it is clear that receptor antagonists acting at either 5-HT or CCK receptors will also functionally antagonize responses mediated by the partner receptor system. It is worth noting, also, that the model allows two separate effects of CCK's actions at CCK receptors, and these effects could depend upon the two CCK receptor subtypes. SUMMARY Evidence has been reviewed which indicates that the satietyinducing effects of exogenous CCK may depend upon the activation of central monoaminergic systems (5-HT, dopamine, noradrenaline) involved in feeding responses, meal termination and postprandial satiety. We have suggested in the case of 5-HTCCK relationships that there are two linked systems both of which have to be activated in order to achieve an appropriate satiety effect. It is worth noting that this model is neither a serial model nor a model of parallel, independent systems; instead, it suggests interdependent parallel systems. In principle, a substantial number of neurocbemically defined systems could be linked, such that the processes of controlling meal size and satiation depend upon concurrent arousal of functionally interdependent systems. Further experimentation on CCK-monoamine interactions (and interactions involving other peptides) will be required to assess the validity of this scheme.

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