Satiety induced by endogenous and exogenous cholecystokinin is mediated by CCK-A receptors in mice SALLY C. WEATHERFORD, Department
FRANCISCA
Y. CHIRUZZO,
Weatherford, Sally C., Francisca Y. Chiruzzo, and Watson B. Laughton. Satiety induced by endogenousand exogenouscholecystokinin is mediatedby CCK-A receptorsin mice.Am. J. Physiol. 262 (Regulatory Integrative Comp. Physiol. 31): R574-R578, 1992.-To investigate the relative participation of peripheral (CCK-A) and central (CCK-B) cholecystokinin (CCK) receptorsin satiety inducedby endogenousCCK, we examinedthe effect of the CCK-A antagonist MK-329 (lo-315 pg/kg) and the CCK-B antagonist L 365260(0.1-315 pg/kg) on intake of a 20% sucrosesolution in mildly food-deprived mice. Intraperitoneal injection of MK-329 elicited a dose-related increasein sucroseconsumptionwith a minimal effective dose of 31.5 pg/kg. This doseincreasedsucroseintake 23% and the highest dosetested, 315 pg/kg, increasedsucroseintake 63% above baseline.In contrast to MK-329, intraperitoneal administration of L 365260had no effect on sucroseintake at dosesup to 315 pg/kg. To examine the contribution of these two CCK receptor subtypesin satiety inducedby exogenousCCK, CCK-8 (8 pg/kg) wasadministeredaloneand in combination with MK329 and L 365260.MK-329 (10 pg/kg) significantly attenuated the satiety effect of CCK-8, and L 365260 (100 pg/kg) was without effect. These results suggestthat the peripheral CCK receptor subtype mediatessatiety induced by endogenousand exogenousCCK in the mouse. feeding; cholecystokinin-A receptor; cholecystokinin-B receptor; MK-329; L 365260 CHOLECYSTOKININ (CCK) is an endogenous brain-gut peptide that decreases food intake when administered peripherally (1, 14, 15, 18) or centrally (6, 12) in a number of species. In rats, CCK-induced suppression of food intake is accompanied by a sequence of behaviors reminiscent of normal meal termination (2). These findings, along with the fact that CCK is released in response to ingested nutrients (19, 20), were the basis for a hypothesis proposed by Gibbs et al. (15) that endogenous CCK may be a critical component in the physiological control of meal termination or satiety. Essential to the support of this hypothesis would be demonstration of increased meal size after blockade of CCK receptors. However, work with initially available CCK antagonists such as proglumide (33) and CR 1409 (22) failed to support the hypothesis. Recently, Merck has developed a highly selective and potent CCK antagonist, MK-329 (5), that has been a useful tool for investigating the physiological role of CCK in many of its proposed functions (16, 26, 28), including satiety. Several studies have now shown that peripheral administration of MK-329 elicits reliable dose-related increases of food intake in a number of species (10, 11,31), including one study demonstrating increased hunger ratings in humans (37). Although the anatomic and pharmacological nature of the receptors mediating CCK-induced suppression of food intake has not been firmly elucidated, several lines of evidence support the hypothesis that CCK acts through a peripheral or CCK-A receptor subtype (24) at R574
AND WATSON
B. LAUGHTON
of Neurobiology and Obesity Research, Hoffmann-La Roche, Nutley, New Jersey 07110
0363-6119/92
a peripheral site. This notion is based on the finding that MK-329, which is highly selective for CCK-A receptors, blocks CCK-induced suppression of food intake induced by both exogenous (9, 11) and endogenous (10, 17, 31) CCK. Moreover, the satiety effect of CCK is reversed by subdiaphragmatic vagotomy (36) and is attenuated by surgical removal of pyloric CCK receptors through pylorectomy (25). Taken together, this evidence, combined with the fact that peripherally administered CCK does not appear to pass through the blood-brain barrier (27)) supports a peripheral site of action for CCK. One recent report, however, has provided evidence supporting a primary role for the central or CCK-B receptor subtype in the satiety induced by endogenous CCK (10). In that study it was found that the highly selective and potent CCK-B antagonist L 365260 (21) was lOO-fold more potent than MK-329 for stimulating food intake and postponing satiety in partially satiated rats. In a separate report (9), these same antagonists were compared for their effects on satiety induced by exogenous CCK, and it was found that only MK-329, the CCK-A receptor antagonist, blocked the anorectic action of CCK; L 365260 was without effect at doses up to 1 mg/kg. Taken together these results suggest that in the rat exogenous and endogenous CCK may inhibit food intake through different receptor subtypes. In the present experiment, MK-329 and L 365260 were used to examine the relative contribution of CCKA and CCK-B receptors in satiety induced by endogenous and exogenous CCK in another rodent model, the mouse. METHODS
Six maleICR mice (Harlan SpragueDawley, Frederick, MD) weighing30.7 t 0.25 g wereused.Mice werehousedin individual hanging wire-meshcagesin a temperature-controlled environment (21 t l°C) with a 12:12h light/dark cycle (lights off at 1000h) and were maintained on ground Purina Rodent Chow and tap water. Testing procedure. On experimental days mice wereplacedin specializedwire-meshtesting cages(8.75 X 8.75 X 7.25 cm) at the onsetof the dark cycle with free accessto water but not food. Three hourslater they wereinjected intraperitoneally with 30 ~1 of the vehicle solution consisting of 50% dimethyl sulfoxide (Fisher, Fair Lawn, NJ) and 50% saline. Immediately after injection, mice were offered 3 ml of a 20% (wt/vol in distilled water) sucrosesolution in a 3-ml syringe adaptedto fit a sipper tube. Sucroseintake wasmeasuredto the nearestl/32 ml at 10, 20, 30, 60, and 90 min. Baseline intake (intake after vehicle) stabilized after 12 training sessionsat which time drug testing with MK-329 wasinitiated. Four dosesof MK-329 (Ro 41-8035, synthesized at Hoffmann-La Roche, Basel, Switzerland; 10, 31.5, 100, and 315 pg/kg) were tested in ascendingorder in a counterbalanceddesign.A vehicle test day always precededand followed a drug test day, and mice were tested every other day.
$2.00 Copyright 0 1992 the American Physiological Society
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CCK-A RECEPTORS
At the conclusion of the 90-min testing period, mice were returned to their home cagesand allowed ad libitum accessto chow and water until the next deprivation period. After all dosesof MK-329 were tested, testing with L 365260 was initiated. Five dosesof L 365260(Ro 44-0378, synthesized at Hoffmann-La Roche; 0.1, 1.0, 10.0, 100,and 315 pg/kg) were tested using a protocol identical to the one described for MK-329. In a secondexperiment, the samesix mice were tested for their responseto the carboxy-terminal octapeptide of CCK (CCK-8). The effect of intraperitoneally administered CCK-8 (ResearchPlus, Bayonne, NJ; 2, 4, and 8 pg/kg) was evaluated using a similar protocol to that describedabove, the only differences being that the vehicle was 0.9% saline and sucrose intake was measuredfor only 30 min. Once a doseresponseto CCK-8 wasestablished,the effects of MK-329 and L 365260(at dosesthat did not affect sucroseintake when administered alone) on CCK-induced suppression of food intake were examined. On test days mice received an intraperitoneal injection of vehicle (30 pl), MK-329 (10 hg/kg), or L 365260(100 pg/kg). Five minutes later a secondinjection of 0.9% saline (30 ~1)or CCK-8 (8 pg/kg) wasadministered.Sucrosewasavailable immediately after the secondinjection. Drugs and vehicle were administeredin a counterbalanceddesign,and a vehicle-vehicle test day always precededand followed a drug test day. Statistical analyses. The effects of eachantagonist and CCK8 on sucroseintake were analyzed separately. Differences in drug-doseeffects on 90- and 30-min intakes for the two antagonists and CCK-8, respectively, were analyzed with one-way repeatedmeasuresanalysis of variance (ANOVA) with doseof drug the repeated factor. Differences in intakes after vehicle were not found; therefore the pooledvehicle condition wasused as a zero-level dose.Significant differencesin main effects were analyzed with post hoc paired t tests. Each drug dosethat was found to significantly affect sucroseintake wasanalyzed for the latency to the first IO-min interval during which a significant effect on sucroseintake appeared.These data were analyzed with a one-way repeatedmeasures(with drug dosethe repeated measure)ANOVA at each lo-min interval. Post hoc comparisonsusingpaired t testswereusedto determinethe earliesttime point at which intakes were significantly affected relative to vehicle injection. The effects of the two CCK antagonistson CCK-8-induced suppressionof food intake were analyzed separately. In each case,differences in drug effects of intake at the lo-min time point were analyzed with one-way ANOVA, with drug the repeated factor. Significant differences in main effects were analyzed with post hoc paired t tests. RESULTS
MK-329 increased intake of 20% sucrose in a doserelated manner [F(4,29) = 6.53, P < 0.011 with a minimal effective dose of 31.5 fig/kg (P < 0.01; Fig. 1). The earliest time point at which an increase in sucrose intake was evident was 20 min for the 100 (P < 0.01) and 315 pg/kg (P < 0.01) doses and 30 min for the 31.5 pg/kg dose (P c 0.05). In contrast to MK-329, L 365260 did not affect food intake compared with vehicle injection [F(5, 35) = 0.45, P > 0.05; Fig. 21. CCK-8 decreased food intake in a dose-related manner [F(3, 23) = 6.02, P < 0.01; (Fig. 3)]. Post hoc analyses indicated that intakes after all doses of CCK-8 tested were significantly different from control values, with a maximal effect at 8 pg/kg. MK-329 significantly attenuated the inhibitory effect of CCK-8 (P < O.Ol), but the blockade was onlv r>artial because sucrose intake in this
MEDIATE
R575
SATIETY , MK-329 h/kg)
e Q l-
3.0
-z
2.5
lx g m
1.5 1.0
0.04, 0
10
,
,
20
30
,
,
1
1
1
I
60
TIME
90
(min)
Fig. 1. Mean cumulative intake of 20% sucrose after intraperitoneal injection of 50% dimethyl sulfoxide (DMSO)-50% saline vehicle or 1 of 4 doses of MK-329. For visual clarity SE values are shown only at 90-min time point. * P c 0.01 by matched pairs t test after a significant 1 -way ANOVA.
E3.01
+
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1
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100
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315
L 365,260 (/-g/kg) Fig. 2. Mean intake (&SE) of 20% sucrose at 90-min time point after intraperitoneal injection of 50% DMSO-50% saline vehicle or 1 of 5 doses of L 365260.
condition was also reduced compared with control (vehicle-vehicle condition) values (Fig. 4). No antagonism was evident after L 365260 because sucrose intake after this antagonist combined with CCK-8 did not differ from intake after CCK-8 alone (P > 0.1). DISCUSSION
Intraperitoneal administration of the CCK-A antagonist, MK-329, elicited a dose-related increase in sucrose intake in mice. In addition, MK-329 significantly attenuated the satiety effect of peripherally administered CCK-8, whereas the CCK-B antagonist, L 365260, was without effect. These findings are consistent with previous reports in rats and other species (9-11, 13) and provide strong evidence that satiety induced by exogenous CCK is mediated solely by a CCK-A receptor subtype. These results also suggest a role for this receptor subtvpe
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R576
CCK-A RECEPTORS
0
30
20
10
TIME
(min)
Fig. 3. Mean cumulative intake of 20% sucrose after saline vehicle or 1 of 3 doses of CCK-8. CCK-8 vs. 0.9% saline by paired t test after a significant l-way ANOVA: * P c 0.05; ** P 0.01. For visual clarity SE values are shown only at 30-min time point.
7
0, Im
z
I
70
i
60
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i
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8 t.Y
40
if
30
II
I
20 10 I 0-
CCK-8 MK-329
+
CCK-8 + L 365,260
Fig. 4. Inhibition of IO-min sucrose intake after intraperitoneal injections of CCK-8 (8 pg/kg) that had been preceded 5 min earlier by injection of vehicle, CCK-A antagonist MK-329 (10 pg/kg), or CCK-B antagonist L 365260 (100 pg/kg). * P < 0.01 compared with control intake. P < 0.01 compared with intake after CCK-8. Percent inhibition was calculated as (intake after vehicle - intake after drug)/intake after vehicle x 100.
in satiety induced by endogenously released CCK. Our results, however, are not consistent with the report by Dourish et al. (10) in that we did not observe an increase in sucrose intake after administration of L 365260 over a dose range of 0.1-315 pg/kg. Three major differences in the two studies could explain the discrepant results: 1) although chemically identical, the source of the antagonists was different in the two studies; 2) different species were used; and 3) different feeding paradigms were used. The first possibility, the source of the compound, is very unlikely. Before our feeding studies were conducted, we confirmed that our sample inhibited gastrin-stimu-
MEDIATE
SATIETY
lated gastric acid secretion in rats with comparable potency to the L 365260 provided by Merck (data not shown). The second possible explanation for the differing results is the species difference (rats vs. mice). Although this is an obvious possibility, it may not explain the discrepant results. In the present study CCK-8 caused a dose-related suppression of food intake in mice similar to that shown in rats (25) under similar testing conditions. Furthermore, we found that mice responded to MK-329 by increasing their food intake after doses that were similar to those used in studies with rats (9, 31) and other species (11). This suggests that there is not an obvious species difference in CCK-A receptor-mediated responses. Although it is conceivable that mice may have a selective deficiency in CCK-B-mediated responses related to CCK’s anorectic properties, there is no deficit in the response of mice to L 365260 for inhibition of gastrin-stimulated gastric acid secretion (21). In fact, this antagonist appears to be lo-fold more potent in the mouse than in the rat (21). The third possibility for our failure to find an orexigenie effect of L 365260 in mice may be the feeding paradigm and test diet used. We used mildly food-deprived mice and a liquid (20% sucrose) test diet, whereas Dourish et al. (10) used partially satiated rats and pelleted rat chow. Although this might appear the most likely explanation for the discrepant results, several issues remain unresolved. First, our feeding paradigm was sufficiently sensitive to obtain an orexigenic effect of MK-329, although the minimal effective dose in our study was -2.5 orders of magnitude greater than that in the study by Dourish et al. (31.5 vs. 0.1 pg/kg, respectively). However, inasmuch as we tested mice over a fairly wide dose range (0.1-315 pg/kg), and taking into consideration the apparent sensitivity of mice to L 365260 (21), it is unlikely that our dosages were too low. Thus it remains to be determined why in our behavioral paradigm we did not find an effect of L 365260. Our results with mice are consistent with two other studies that were conducted in rats (3, 23). In one study that used food-deprived rats that were sham fed 15% sucrose, the satiating effect of intraintestinal oleate was blocked by MK-329 but not by L 365260 (3). In the other study, MK-329, but not L 365260, stimulated intake of a glucose test solution in non-food-deprived rats (23). The one common component among the three (including the present study) studies in which L 365260 failed to block the satiating effect of endogenous CCK is the use of a liquid test diet. This may be a plausible explanation for the negative results with L 365260. Certainly there is evidence that the orexigenic effects of MK-329 and other CCK antagonists may be dependent on the feeding paradigm that is used (34), and this may be the case for the CCK-B receptor subtype as well. It may be important to note, however, that the potency of MK-329 to antagonize endogenous CCK does not differ significantly when rats are fed a liquid or solid diet (31). Thus, in three diverse feeding paradigms, only the CCK-A receptor antagonist blocked the satiating effect of endogenous CCK. This is evidence that of the two CCK receptor subtypes, the
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CCK-A RECEPTORS
CCK-A receptor is more generally involved in suppression of food intake by endogenous CCK. The results of our study support the hypothesis that the peripheral CCK-A receptor participates in the physiological regulation of meal termination in mice. However, our results do not provide evidence of the anatomic location of the receptors regulating this effect. It may be important to note that ingestion or intraduodenal infusion of saccharides does not release measurable levels of CCK into the peripheral circulation (20, 38). This suggests that the participation of endogenous CCK in satiety after ingestion of sucrose or after intraduodenal infusion of maltose (which is also blocked by a CCK-A antagonist; Ref. 38) may be acting through local release of CCK from enteric neurons (35), vagal neurons (30), and/or gut endocrine cells (4) or from central neurons containing CCK (7, 8, 32). The evidence for CCK acting at a peripheral site has already been discussed; however, there is also evidence to support the hypothesis that endogenous CCK may be acting at central CCK receptors, possibly of the A type (24). First, centrally administered CCK suppresses food intake (6, 12) at doses that are ineffective when given peripherally. Second, there is evidence that CCK is released from hypothalamic neurons postprandially in primates (32). Third, inasmuch as CCK-A receptors are found at central sites (24) and MK-329 readily passes through the blood-brain barrier (29), the drug would have access to these receptors. Additional experiments examining the effect of local administration of CCK-A antagonists will be needed to identify the anatomic location(s) of the CCK-A receptors mediating satiety induced by endogenous and exogenous CCK. In summary, we found that the CCK-A antagonist, MK-329, elicited a dose-related increase in sucrose consumption in mice and significantly attenuated exogenously administered CCK-induced suppression of food intake. Under identical experimental conditions, the CCK-B antagonist, L 365260, was without effect. Our results support the hypothesis that endogenous CCK participates in the physiological control of meal termination and that under our experimental conditions the peripheral CCK-A receptor mediates this effect. Inasmuch as saccharides do not release measurable blood levels of CCK, our results also suggest that the satiety effect of CCK in our experiments is mediated through local release of CCK, which could occur at a peripheral or central location. Additional experiments will be necessary to determine the anatomic site of the receptors that mediate this effect. We thank Drs. Walter Hunkeler and Rene Imhof of Hoffmann-La Roche for synthesizing and supplying samples of MK-329 and L 365260. We also thank Dacie R. Lewis and Dr. Danielle Greenberg of the Bourne Laboratory, New York Hospital, Westchester Division for evaluating and comparing the Roche-synthesized L 365260 vs. a sample from Merck for inhibition of gastrin-stimulated gastric acid secretion. We are also grateful to Drs. Stephen C. Woods and Jerry Sepinwall for their valuable comments on this manuscript. Address for reprint requests: S. Weatherford, Dept. of Psychology, NI-25, Univ. of Washington, Seattle, WA 98195. Received 13 June 1991; accepted in final form 10 October 1991.
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FRANCISCA
Y. CHIRUZZO,
Weatherford, Sally C., Francisca Y. Chiruzzo, and Watson B. Laughton. Satiety induced by endogenousand exogenouscholecystokinin is mediatedby CCK-A receptorsin mice.Am. J. Physiol. 262 (Regulatory Integrative Comp. Physiol. 31): R574-R578, 1992.-To investigate the relative participation of peripheral (CCK-A) and central (CCK-B) cholecystokinin (CCK) receptorsin satiety inducedby endogenousCCK, we examinedthe effect of the CCK-A antagonist MK-329 (lo-315 pg/kg) and the CCK-B antagonist L 365260(0.1-315 pg/kg) on intake of a 20% sucrosesolution in mildly food-deprived mice. Intraperitoneal injection of MK-329 elicited a dose-related increasein sucroseconsumptionwith a minimal effective dose of 31.5 pg/kg. This doseincreasedsucroseintake 23% and the highest dosetested, 315 pg/kg, increasedsucroseintake 63% above baseline.In contrast to MK-329, intraperitoneal administration of L 365260had no effect on sucroseintake at dosesup to 315 pg/kg. To examine the contribution of these two CCK receptor subtypesin satiety inducedby exogenousCCK, CCK-8 (8 pg/kg) wasadministeredaloneand in combination with MK329 and L 365260.MK-329 (10 pg/kg) significantly attenuated the satiety effect of CCK-8, and L 365260 (100 pg/kg) was without effect. These results suggestthat the peripheral CCK receptor subtype mediatessatiety induced by endogenousand exogenousCCK in the mouse. feeding; cholecystokinin-A receptor; cholecystokinin-B receptor; MK-329; L 365260 CHOLECYSTOKININ (CCK) is an endogenous brain-gut peptide that decreases food intake when administered peripherally (1, 14, 15, 18) or centrally (6, 12) in a number of species. In rats, CCK-induced suppression of food intake is accompanied by a sequence of behaviors reminiscent of normal meal termination (2). These findings, along with the fact that CCK is released in response to ingested nutrients (19, 20), were the basis for a hypothesis proposed by Gibbs et al. (15) that endogenous CCK may be a critical component in the physiological control of meal termination or satiety. Essential to the support of this hypothesis would be demonstration of increased meal size after blockade of CCK receptors. However, work with initially available CCK antagonists such as proglumide (33) and CR 1409 (22) failed to support the hypothesis. Recently, Merck has developed a highly selective and potent CCK antagonist, MK-329 (5), that has been a useful tool for investigating the physiological role of CCK in many of its proposed functions (16, 26, 28), including satiety. Several studies have now shown that peripheral administration of MK-329 elicits reliable dose-related increases of food intake in a number of species (10, 11,31), including one study demonstrating increased hunger ratings in humans (37). Although the anatomic and pharmacological nature of the receptors mediating CCK-induced suppression of food intake has not been firmly elucidated, several lines of evidence support the hypothesis that CCK acts through a peripheral or CCK-A receptor subtype (24) at R574
AND WATSON
B. LAUGHTON
of Neurobiology and Obesity Research, Hoffmann-La Roche, Nutley, New Jersey 07110
0363-6119/92
a peripheral site. This notion is based on the finding that MK-329, which is highly selective for CCK-A receptors, blocks CCK-induced suppression of food intake induced by both exogenous (9, 11) and endogenous (10, 17, 31) CCK. Moreover, the satiety effect of CCK is reversed by subdiaphragmatic vagotomy (36) and is attenuated by surgical removal of pyloric CCK receptors through pylorectomy (25). Taken together, this evidence, combined with the fact that peripherally administered CCK does not appear to pass through the blood-brain barrier (27)) supports a peripheral site of action for CCK. One recent report, however, has provided evidence supporting a primary role for the central or CCK-B receptor subtype in the satiety induced by endogenous CCK (10). In that study it was found that the highly selective and potent CCK-B antagonist L 365260 (21) was lOO-fold more potent than MK-329 for stimulating food intake and postponing satiety in partially satiated rats. In a separate report (9), these same antagonists were compared for their effects on satiety induced by exogenous CCK, and it was found that only MK-329, the CCK-A receptor antagonist, blocked the anorectic action of CCK; L 365260 was without effect at doses up to 1 mg/kg. Taken together these results suggest that in the rat exogenous and endogenous CCK may inhibit food intake through different receptor subtypes. In the present experiment, MK-329 and L 365260 were used to examine the relative contribution of CCKA and CCK-B receptors in satiety induced by endogenous and exogenous CCK in another rodent model, the mouse. METHODS
Six maleICR mice (Harlan SpragueDawley, Frederick, MD) weighing30.7 t 0.25 g wereused.Mice werehousedin individual hanging wire-meshcagesin a temperature-controlled environment (21 t l°C) with a 12:12h light/dark cycle (lights off at 1000h) and were maintained on ground Purina Rodent Chow and tap water. Testing procedure. On experimental days mice wereplacedin specializedwire-meshtesting cages(8.75 X 8.75 X 7.25 cm) at the onsetof the dark cycle with free accessto water but not food. Three hourslater they wereinjected intraperitoneally with 30 ~1 of the vehicle solution consisting of 50% dimethyl sulfoxide (Fisher, Fair Lawn, NJ) and 50% saline. Immediately after injection, mice were offered 3 ml of a 20% (wt/vol in distilled water) sucrosesolution in a 3-ml syringe adaptedto fit a sipper tube. Sucroseintake wasmeasuredto the nearestl/32 ml at 10, 20, 30, 60, and 90 min. Baseline intake (intake after vehicle) stabilized after 12 training sessionsat which time drug testing with MK-329 wasinitiated. Four dosesof MK-329 (Ro 41-8035, synthesized at Hoffmann-La Roche, Basel, Switzerland; 10, 31.5, 100, and 315 pg/kg) were tested in ascendingorder in a counterbalanceddesign.A vehicle test day always precededand followed a drug test day, and mice were tested every other day.
$2.00 Copyright 0 1992 the American Physiological Society
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CCK-A RECEPTORS
At the conclusion of the 90-min testing period, mice were returned to their home cagesand allowed ad libitum accessto chow and water until the next deprivation period. After all dosesof MK-329 were tested, testing with L 365260 was initiated. Five dosesof L 365260(Ro 44-0378, synthesized at Hoffmann-La Roche; 0.1, 1.0, 10.0, 100,and 315 pg/kg) were tested using a protocol identical to the one described for MK-329. In a secondexperiment, the samesix mice were tested for their responseto the carboxy-terminal octapeptide of CCK (CCK-8). The effect of intraperitoneally administered CCK-8 (ResearchPlus, Bayonne, NJ; 2, 4, and 8 pg/kg) was evaluated using a similar protocol to that describedabove, the only differences being that the vehicle was 0.9% saline and sucrose intake was measuredfor only 30 min. Once a doseresponseto CCK-8 wasestablished,the effects of MK-329 and L 365260(at dosesthat did not affect sucroseintake when administered alone) on CCK-induced suppression of food intake were examined. On test days mice received an intraperitoneal injection of vehicle (30 pl), MK-329 (10 hg/kg), or L 365260(100 pg/kg). Five minutes later a secondinjection of 0.9% saline (30 ~1)or CCK-8 (8 pg/kg) wasadministered.Sucrosewasavailable immediately after the secondinjection. Drugs and vehicle were administeredin a counterbalanceddesign,and a vehicle-vehicle test day always precededand followed a drug test day. Statistical analyses. The effects of eachantagonist and CCK8 on sucroseintake were analyzed separately. Differences in drug-doseeffects on 90- and 30-min intakes for the two antagonists and CCK-8, respectively, were analyzed with one-way repeatedmeasuresanalysis of variance (ANOVA) with doseof drug the repeated factor. Differences in intakes after vehicle were not found; therefore the pooledvehicle condition wasused as a zero-level dose.Significant differencesin main effects were analyzed with post hoc paired t tests. Each drug dosethat was found to significantly affect sucroseintake wasanalyzed for the latency to the first IO-min interval during which a significant effect on sucroseintake appeared.These data were analyzed with a one-way repeatedmeasures(with drug dosethe repeated measure)ANOVA at each lo-min interval. Post hoc comparisonsusingpaired t testswereusedto determinethe earliesttime point at which intakes were significantly affected relative to vehicle injection. The effects of the two CCK antagonistson CCK-8-induced suppressionof food intake were analyzed separately. In each case,differences in drug effects of intake at the lo-min time point were analyzed with one-way ANOVA, with drug the repeated factor. Significant differences in main effects were analyzed with post hoc paired t tests. RESULTS
MK-329 increased intake of 20% sucrose in a doserelated manner [F(4,29) = 6.53, P < 0.011 with a minimal effective dose of 31.5 fig/kg (P < 0.01; Fig. 1). The earliest time point at which an increase in sucrose intake was evident was 20 min for the 100 (P < 0.01) and 315 pg/kg (P < 0.01) doses and 30 min for the 31.5 pg/kg dose (P c 0.05). In contrast to MK-329, L 365260 did not affect food intake compared with vehicle injection [F(5, 35) = 0.45, P > 0.05; Fig. 21. CCK-8 decreased food intake in a dose-related manner [F(3, 23) = 6.02, P < 0.01; (Fig. 3)]. Post hoc analyses indicated that intakes after all doses of CCK-8 tested were significantly different from control values, with a maximal effect at 8 pg/kg. MK-329 significantly attenuated the inhibitory effect of CCK-8 (P < O.Ol), but the blockade was onlv r>artial because sucrose intake in this
MEDIATE
R575
SATIETY , MK-329 h/kg)
e Q l-
3.0
-z
2.5
lx g m
1.5 1.0
0.04, 0
10
,
,
20
30
,
,
1
1
1
I
60
TIME
90
(min)
Fig. 1. Mean cumulative intake of 20% sucrose after intraperitoneal injection of 50% dimethyl sulfoxide (DMSO)-50% saline vehicle or 1 of 4 doses of MK-329. For visual clarity SE values are shown only at 90-min time point. * P c 0.01 by matched pairs t test after a significant 1 -way ANOVA.
E3.01
+
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1
1
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100
I
315
L 365,260 (/-g/kg) Fig. 2. Mean intake (&SE) of 20% sucrose at 90-min time point after intraperitoneal injection of 50% DMSO-50% saline vehicle or 1 of 5 doses of L 365260.
condition was also reduced compared with control (vehicle-vehicle condition) values (Fig. 4). No antagonism was evident after L 365260 because sucrose intake after this antagonist combined with CCK-8 did not differ from intake after CCK-8 alone (P > 0.1). DISCUSSION
Intraperitoneal administration of the CCK-A antagonist, MK-329, elicited a dose-related increase in sucrose intake in mice. In addition, MK-329 significantly attenuated the satiety effect of peripherally administered CCK-8, whereas the CCK-B antagonist, L 365260, was without effect. These findings are consistent with previous reports in rats and other species (9-11, 13) and provide strong evidence that satiety induced by exogenous CCK is mediated solely by a CCK-A receptor subtype. These results also suggest a role for this receptor subtvpe
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R576
CCK-A RECEPTORS
0
30
20
10
TIME
(min)
Fig. 3. Mean cumulative intake of 20% sucrose after saline vehicle or 1 of 3 doses of CCK-8. CCK-8 vs. 0.9% saline by paired t test after a significant l-way ANOVA: * P c 0.05; ** P 0.01. For visual clarity SE values are shown only at 30-min time point.
7
0, Im
z
I
70
i
60
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i
I- 5o 7
8 t.Y
40
if
30
II
I
20 10 I 0-
CCK-8 MK-329
+
CCK-8 + L 365,260
Fig. 4. Inhibition of IO-min sucrose intake after intraperitoneal injections of CCK-8 (8 pg/kg) that had been preceded 5 min earlier by injection of vehicle, CCK-A antagonist MK-329 (10 pg/kg), or CCK-B antagonist L 365260 (100 pg/kg). * P < 0.01 compared with control intake. P < 0.01 compared with intake after CCK-8. Percent inhibition was calculated as (intake after vehicle - intake after drug)/intake after vehicle x 100.
in satiety induced by endogenously released CCK. Our results, however, are not consistent with the report by Dourish et al. (10) in that we did not observe an increase in sucrose intake after administration of L 365260 over a dose range of 0.1-315 pg/kg. Three major differences in the two studies could explain the discrepant results: 1) although chemically identical, the source of the antagonists was different in the two studies; 2) different species were used; and 3) different feeding paradigms were used. The first possibility, the source of the compound, is very unlikely. Before our feeding studies were conducted, we confirmed that our sample inhibited gastrin-stimu-
MEDIATE
SATIETY
lated gastric acid secretion in rats with comparable potency to the L 365260 provided by Merck (data not shown). The second possible explanation for the differing results is the species difference (rats vs. mice). Although this is an obvious possibility, it may not explain the discrepant results. In the present study CCK-8 caused a dose-related suppression of food intake in mice similar to that shown in rats (25) under similar testing conditions. Furthermore, we found that mice responded to MK-329 by increasing their food intake after doses that were similar to those used in studies with rats (9, 31) and other species (11). This suggests that there is not an obvious species difference in CCK-A receptor-mediated responses. Although it is conceivable that mice may have a selective deficiency in CCK-B-mediated responses related to CCK’s anorectic properties, there is no deficit in the response of mice to L 365260 for inhibition of gastrin-stimulated gastric acid secretion (21). In fact, this antagonist appears to be lo-fold more potent in the mouse than in the rat (21). The third possibility for our failure to find an orexigenie effect of L 365260 in mice may be the feeding paradigm and test diet used. We used mildly food-deprived mice and a liquid (20% sucrose) test diet, whereas Dourish et al. (10) used partially satiated rats and pelleted rat chow. Although this might appear the most likely explanation for the discrepant results, several issues remain unresolved. First, our feeding paradigm was sufficiently sensitive to obtain an orexigenic effect of MK-329, although the minimal effective dose in our study was -2.5 orders of magnitude greater than that in the study by Dourish et al. (31.5 vs. 0.1 pg/kg, respectively). However, inasmuch as we tested mice over a fairly wide dose range (0.1-315 pg/kg), and taking into consideration the apparent sensitivity of mice to L 365260 (21), it is unlikely that our dosages were too low. Thus it remains to be determined why in our behavioral paradigm we did not find an effect of L 365260. Our results with mice are consistent with two other studies that were conducted in rats (3, 23). In one study that used food-deprived rats that were sham fed 15% sucrose, the satiating effect of intraintestinal oleate was blocked by MK-329 but not by L 365260 (3). In the other study, MK-329, but not L 365260, stimulated intake of a glucose test solution in non-food-deprived rats (23). The one common component among the three (including the present study) studies in which L 365260 failed to block the satiating effect of endogenous CCK is the use of a liquid test diet. This may be a plausible explanation for the negative results with L 365260. Certainly there is evidence that the orexigenic effects of MK-329 and other CCK antagonists may be dependent on the feeding paradigm that is used (34), and this may be the case for the CCK-B receptor subtype as well. It may be important to note, however, that the potency of MK-329 to antagonize endogenous CCK does not differ significantly when rats are fed a liquid or solid diet (31). Thus, in three diverse feeding paradigms, only the CCK-A receptor antagonist blocked the satiating effect of endogenous CCK. This is evidence that of the two CCK receptor subtypes, the
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CCK-A RECEPTORS
CCK-A receptor is more generally involved in suppression of food intake by endogenous CCK. The results of our study support the hypothesis that the peripheral CCK-A receptor participates in the physiological regulation of meal termination in mice. However, our results do not provide evidence of the anatomic location of the receptors regulating this effect. It may be important to note that ingestion or intraduodenal infusion of saccharides does not release measurable levels of CCK into the peripheral circulation (20, 38). This suggests that the participation of endogenous CCK in satiety after ingestion of sucrose or after intraduodenal infusion of maltose (which is also blocked by a CCK-A antagonist; Ref. 38) may be acting through local release of CCK from enteric neurons (35), vagal neurons (30), and/or gut endocrine cells (4) or from central neurons containing CCK (7, 8, 32). The evidence for CCK acting at a peripheral site has already been discussed; however, there is also evidence to support the hypothesis that endogenous CCK may be acting at central CCK receptors, possibly of the A type (24). First, centrally administered CCK suppresses food intake (6, 12) at doses that are ineffective when given peripherally. Second, there is evidence that CCK is released from hypothalamic neurons postprandially in primates (32). Third, inasmuch as CCK-A receptors are found at central sites (24) and MK-329 readily passes through the blood-brain barrier (29), the drug would have access to these receptors. Additional experiments examining the effect of local administration of CCK-A antagonists will be needed to identify the anatomic location(s) of the CCK-A receptors mediating satiety induced by endogenous and exogenous CCK. In summary, we found that the CCK-A antagonist, MK-329, elicited a dose-related increase in sucrose consumption in mice and significantly attenuated exogenously administered CCK-induced suppression of food intake. Under identical experimental conditions, the CCK-B antagonist, L 365260, was without effect. Our results support the hypothesis that endogenous CCK participates in the physiological control of meal termination and that under our experimental conditions the peripheral CCK-A receptor mediates this effect. Inasmuch as saccharides do not release measurable blood levels of CCK, our results also suggest that the satiety effect of CCK in our experiments is mediated through local release of CCK, which could occur at a peripheral or central location. Additional experiments will be necessary to determine the anatomic site of the receptors that mediate this effect. We thank Drs. Walter Hunkeler and Rene Imhof of Hoffmann-La Roche for synthesizing and supplying samples of MK-329 and L 365260. We also thank Dacie R. Lewis and Dr. Danielle Greenberg of the Bourne Laboratory, New York Hospital, Westchester Division for evaluating and comparing the Roche-synthesized L 365260 vs. a sample from Merck for inhibition of gastrin-stimulated gastric acid secretion. We are also grateful to Drs. Stephen C. Woods and Jerry Sepinwall for their valuable comments on this manuscript. Address for reprint requests: S. Weatherford, Dept. of Psychology, NI-25, Univ. of Washington, Seattle, WA 98195. Received 13 June 1991; accepted in final form 10 October 1991.
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