Effects of three feeding schedules on tumor and host of Lewis lung carcinoma-bearing mice

The effect of three feeding schedules on tumor and host were examined in Lewis Lung bearing (TB) and nontumor bearing (NTB) C57/B1 mice. Both NTB and TB animals were divided into three groups: the control groups which were fed ad libitum; the intermittent fed (IMF) groups were fed for 32 hr and fasted for 16 hr in each 48-hr cycle, and the alternate day fed (ADF) groups were fed for a 24-hr interval in each 48-hr cycle. The animals were killed at the end of the fifteenth day, following a fed day for all groups. In the NTB groups, only the ADF group showed decreased food intake and lower body weight gain as compared to their control group. In the TB mice, as compared to their control group, the IMF group showed a significant reduction in the mean tumor weight with no change in the mean host weight, even though the daily food intakes of these two groups were the same over the experimental interval. In contrast, the ADF group showed reductions in both host and tumor weights as compared to their control group. The tumor to host weight ratios were significantly reduced for both the IMF and ADF groups as compared to the ratios found for the control groups, which suggests a differential effect on the tumor and on the host due to the feeding schedule. As assessed by the protein, RNA, and DNA concentrations, no compositional differences were noted for the tumors obtained from the animals that were maintained on each of the three different feeding schedules. In the NTB mice, no differences in tissue leucine (Leu) oxidation occurred between the groups for liver and skeletal muscle, whereas in the TB animals in vitro Leu oxidation capability by skeletal muscle specimens was markedly enhanced in the ADF group, but no difference was noted for the IMF group of the TB mice when compared to the control group. Taken together, these results suggest that the 32-hr fed:16-hr fast schedule (IMF) was beneficial and the 24-hr fed:24-hr fast schedule was detrimental compared to the ad libitum feeding schedule with respect to tumor and host relationships.     

Facilitation of cancer-associated anorexia by cholecystokinin

Cholecystokinin octapeptide (CCK-8, 5 micrograms/kg) was injected i.p. into male Sprague-Dawley rats bearing the Walker 256-carcinosarcoma, or into non-tumour bearing controls, on a 20-h food deprivation schedule. Food and water intake and body weight maintenance were monitored for 15 days after tumour implantation and compared to that of tumour-bearing animals not injected with CCK-8. Food intake was significantly reduced for the duration of the two 4-day periods of CCK-8 injection, indicating that behavioural tolerance to this peptide did not occur. The severity of anorexia and body weight loss in tumour-bearing animals was significantly greater than that observed in non-tumour bearing controls, for the first 13 days of observation. These results indicate that endogenous peptides, such as CCK, may function in tumour-bearing animals to enhance the anorexia and wasting which typifies the anorexia cachexia syndrome.     

Effects of naloxone and cholecystokinin on food and water intake in vasopressin-deficient rats (Brattleboro strain)

Opioid peptides and cholecystokinin (CCK) have been shown to play a role in regulation of feeding behavior. Another neuropeptide that has recently been suggested to be involved in feeding is vasopressin. We explored possible interactions between opiates, CCK and vasopressin in feeding regulation by studying feeding suppression produced by naloxone and CCK in Brattleboro (DI) rats, which are homozygous for diabetes insipidus and lack the ability to synthesize vasopressin. Ten DI and 15 age-matched Long Evans (LE) rats were food deprived for 14 hours on two different days and then injected with naloxone (2.5 mg/kg) on one day or saline on the other. Thirty minutes later the food was returned and food and water consumption were measured after 1, 3 and 4 hr. Naloxone suppressed the food consumption of both DI and LE rats but the suppression was greater for the DI rats. This result was specific to feeding as water consumption was suppressed in LE more than in DI rats. Two weeks later, the same rats were food deprived for 6 hours on two different days and then injected with CCK-8 (2.5 micrograms/kg) on one day and with saline on the other. Food was returned one minute after the injection and food and water consumption were measured 30 and 60 minutes later. Food intake was reduced equally for both DI and LE rats. Water intake was not reduced. The results suggest that the suppression of feeding by CCK does not require an intact vasopressinergic system. The greater feeding suppression by naloxone in DI rats may suggest that opiates are interacting with vasopressin in producing their effects on food intake.     

Tumor anorexia: effects on neuropeptide Y and monoamines in paraventricular nucleus

Paraventricular (PVN) concentrations of neuropeptide Y (NPY), serotonin (5-HT) and dopamine (DA) in anorectic tumor-bearing (TB) rats were measured before and after tumor resection. At onset of anorexia in TB versus non-tumor bearing (NTB) Controls 5-HT increased from 12.19+/-0.49 pg/microg to 14.89+/-0.81 pg/microg ( P<0.05 ) while DA and NPY decreased from 7.34+/-0.42 pg/microg to 4.97+/-0.56 pg/microg and 23.47+/-4.27 pg/microg to 13.64+/-1.44 pg/microg, respectively ( P<0.05 ). After tumor resection, these neuromediators normalized when compared to sham-operated NTB rats. NTB pair-fed Controls were also studied. We conclude that the increased 5-HT and the decreased DA and NPY concentrations in PVN are associated with cancer anorexia and that the NPY food stimulatory effect is linked to serotoninergic and dopaminergic systems in hypothalamus.     

Continuous intraventricular infusion of neuropeptide Y evokes episodic food intake in satiated female rats: effects of adrenalectomy and cholecystokinin

In these studies the pattern of feeding behavior during continuous intraventricular (IVT) infusion of NPY for 4 hr in the satiated female rat was monitored. Whereas saline infusion was ineffective, each of the three doses of NPY (117, 470 or 1175 pmol/hr) increased feeding during the entire 4 hr infusion and 2 hr postinfusion period. The cumulative food intake at the end of 4 hr of NPY infusion was enhanced in a dose-related fashion between 0, 117 and 470 pmol/hr; at 1175 pmol/hr food intake plateaued. In addition, the latency to initiate feeding response decreased in a dose-related fashion and feeding occurred in discrete (35-45) episodes during the 4 hr infusion period. Further, the total time feeding and local eating rate (g/min) increased significantly in response to the higher rates of NPY infusion. Concurrent infusion of cholecystokinin (CCK) at either equimolar or 2.5 x NPY dose, affected neither the NPY-induced cumulative food intake nor any other parameter of feeding behavior. On the other hand, cumulative food intake was significantly decreased in adrenalectomized rats in response to NPY infusion (470 pmol/hr); a response due primarily to a marked suppression in some, and almost complete cessation of food consumption in other rats during the second 2 hr period of NPY infusion. These studies show that continuous central infusion of NPY can produce sustained, intermittent feeding behavior and adrenalectomy significantly curtailed the duration of NPY effectiveness.(ABSTRACT TRUNCATED AT 250 WORDS)     

CCK-resistance in Zucker obese versus lean rats

Obese Zucker rats are less sensitive to the satiety effect of CCK than lean litter mates. The present studies further characterised this CCK resistance. Subcutaneous injection of the CCK agonist caerulein dose-dependently decreased food intake in Zucker obese and lean rats whereas the CCK-B agonist gastrin-17 did not. Caerulein at 4 μg/kg, which resulted in CCK plasma bioactivity slightly above postprandial levels, decreased food intake in lean rats but not in obese rats. The decrease in food intake was also more marked at higher caerulein doses (20–100 μg/kg) in lean versus obese rats. In lean animals the satiety effects of the “near physiological” 4 μg/kg caerulein dose was abolished after blockade of vagal afferents with capsaicin, whereas the effects of higher caerulein doses were not. CCK-stimulated amylase secretion from pancreatic acini and binding capacity of ¹²⁵I- labelled CCK-8 were decreased in obese versus lean rats. The CCK-A antagonist loxiglumide at 20 mg/kg, a dose which abolished the action of all caerulein doses on food intake, failed to alter the food intake either in obese or in lean rats when given without an agonist. The results suggest that the satiety effects of “near physiological” doses of caerulein in lean rats are mediated by vagal afferents whereas pharmacological doses act via non-vagal mechanisms. The differences in CCK's satiety effect between lean and obese rats may be due to differences in CCK-receptor binding and action at peripheral vagal sites. However, the failure of the CCK-A antagonist to increase food intake questions whether any of the effects of exogenous CCK are of physiological relevance.     

Eating, drinking and temperature responses to intracerebroventricular cholecystokinin in the chick

The central effect of cholecystokinin-octapeptide (CCK), SQ 19,844 or sincalide, on the intake of food and water and on colonic temperature (Tc) was investigated using the broiler cockerel. Four-week old chicks were maintained in a thermoneutral environment of 23-24 degrees C. After food was removed for a 24 hr interval, CCK was infused in a volume of 10.0 microliters into the lateral cerebral ventricle (ICV) in doses ranging from 10-150 ng. Although lower doses of CCK had no effect on food intake, 100 or 150 ng of CCK significantly reduced consumption of food in a dose-dependent manner; water drinking was significantly decreased by 100 ng of CCK. In addition, CCK at doses of 100 and 150 ng prevented the slow rise in Tc observed following infusions of control CSF. This latter effect appeared to be a result of feeding activity associated with caloric intake and the heat increment in the control birds rather than a specific thermoregulatory effect. Overall, our results suggest that CCK may comprise a part of the central mechanism underlying the neural control of short term satiety in an avian species similar to that proposed for the mammal.     

Effects of cholecystokinin octapeptide (CCK-8) on food intake in adult and aged rats under different feeding conditions

The effects of CCK on food intake were investigated under fixed feeding conditions in comparison to a test meal taken after 16 h of food deprivation. The experiments were performed on young adult rats (8 weeks old) as well on aged rats (23 months old). Intraperitoneal CCK-8 (8 and 40 μg/kg) significantly reduced the size of a test meal following 16-h food deprivation. This effect was independent of the age of the rats. However, under fixed feeding conditions neither of the doses used in this study reduced food intake in the young adult rats, whereas the highest dose of 40 μg/kg did so in the aged rats. These results suggest that the hypophagic effect of exogenous CCK-8 depends on experimental conditions, food intake being reduced after a period of food deprivation but not under a fixed feeding regimen in adult animals. Furthermore, the data suggest that age is a factor contributing to the complex behavioral actions of CCK, because only old animals were more susceptible to an anorectic action of CCK under the fixed feeding schedule. An explanation may lie in an interaction of other known behavioral effects of CCK (e.g., anxiogenic, mnemonic action) with its effects under the different feeding schedules.     

LY226936 Administered Orally and Centrally to Obese Zucker Rats Suppresses Food Intake and Body Weight Gain

LY226936, methylcarbamothoic acid-S-(4,5-dihydro-2-thiazolyl) ester, is a new compound that, when administered to obese Zucker rats, caused reduced food intake. LY226936 reduced the food consumption after a single oral dose of 50 and 100 mg/kg. On chronic oral administration to meal-fed obese (5 to 35 mg/kg. once daily) and to fed obese and lean (15 mg/kg. twice daily) Zucker rats, LY226936 reduced food intake and body weight gain for periods ranging from 40 to 48 days. The effect on both parameters was statistically significant. There is no evidence in our studies that tolerance to the actions of LY226936 developed. LY226936 decreased the consumption of both high carbohydrate and high fat diets. Food consumption of meal-fed obese Zucker rats was reduced significantly each time a single dose of 10 ugm LY226936 per rat was infused intracerebroventricularly. None of the receptors studied (mu and kappa opioid, CCK, serotonin, neuropeptide Y, galinin, N-methyl-D-aspartic acid) appeared to bind LY226936 and therefore, appear not to be involved in the depression of food intake by the obese Zucker rat.     

Alteration of ingestive behaviours by nucleus accumbens in normal and streptozotocin-induced diabetic rats

Twenty-four hour basal food and water intakes were recorded in Wistar rats. Diabetes was produced in a group of rats by injecting streptozotocin (STZ, 75 mg/kg, b.w., IP) and their post-diabetic basal food and water intakes were recorded. Noradrenaline (2 microg) and dopamine (2 microg) were injected separately into the nucleus accumbens through the implanted cannula in non-diabetic and diabetic animals and their 24 hr food and water intakes were recorded. Food and water intakes were also recorded following bilateral electrolytic lesions of nucleus accumbens in both the groups of rats. In diabetic rats, basal food and water intakes were significantly increased in comparison to basal intakes of non-diabetic rats. Following injection of noradrenaline, a significant increase in water intake but not food intake was seen in non-diabetic rats, whereas food and water intakes remained unchanged in diabetic rats. Following injection of dopamine, a significant increase in food and water intakes was observed in non-diabetic rats, whereas dopamine-induced increase in food intake was absent in diabetic rats. The bilateral lesions of nucleus accumbens resulted in a significant inhibition of food and water intakes in non-diabetic rats, whereas inhibition of water intake without change in food intake observed in diabetic rats. However, no difference was observed in the pattern of change in water intake following lesions or dopamine injections between non-diabetic and diabetic rats, whereas difference was observed for food intake. The results suggest that nucleus accumbens activity changes for food intake, but not for water intake in diabetes.     

Disruption of seasonality in growth hormone-transgenic coho salmon (Oncorhynchus kisutch) and the role of cholecystokinin in seasonal feeding behavior

Seasonal variation in daily food intake is a well-documented phenomenon in many organisms including wild-type coho salmon where the appetite is noticeably reduced during periods of decreased day length and low water temperature. This reduction may in part be explained by altered production of cholecystokinin (CCK) and growth hormone (GH). CCK is a hormone produced in the brain and gut that mediates a feeling of satiety and thus has an inhibitory effect on food intake and foraging behaviour. Growth hormone (GH) enhances feeding behaviour and consequently growth, but its production is reduced during winter. The objectives of this study were: first, to compare the seasonal feeding behaviour of wild and GH-transgenic coho salmon; second, to determine the behavioural effect of blocking the action of CCK (by using devazepide) on the seasonal food intake; and third, to measure CCK expression in brain and gut tissues between the two genotypes across seasons. We found that, in contrast to wild salmon, food intake in transgenic salmon was not reduced during winter indicating that seasonal control of appetite regulation has been disrupted by constitutive production of GH in transgenic animals. Blocking of CCK increased food intake in both genotypes in all seasons. The increase was stronger in wild genotypes than transgenic fish; however blocking CCK in wild-type fish in winter did not elevate appetites to levels observed in the summer. The response to devazepide was generally faster in transgenic than in wild salmon with more rapid effects observed during summer than during winter, possibly due to a higher temperature in summer. Overall, a seasonal effect on CCK mRNA levels was observed in telencephalon with levels during winter being higher compared to the summer in wild fish, but with no seasonal effect in transgenic fish. No differences in seasonal CCK expression were found in hypothalamus. Higher levels of CCK were detected in the gut of both genotypes in winter compared to summer. Thus, CCK appears to mediate food intake among seasons in both wild-type and GH-transgenic salmon, and an altered CCK regulation may be responsible at least in part for the seasonal regulation of food intake.     

Continuous infusion of cholecystokinin and meal pattern in the rat

Purified natural cholecystokinin (CCK-33) was infused continuously for two days at a rate of 5.9 μg/hr in two rats trained to bar-press for food (Noyes pellet 45 mg) on a fixed ratio of five bar presses to obtain one pellet. The animals also received control surgery and were tested in the operant chamber for two days, one prior to and the other following the CCK-33 treatment. CCK-33 suppressed the number of meals, the total amount of food eaten, and the total duration of time spent eating. However, the size of each meal and the rate of intake were not affected. The CCK effect did not interact with the light-dark phases of diurnal cycle. It appears that a major effect of continuous systemic elevation of CCK-33 is to reduce food intake by prolonging the satiety period rather than by decreasing the individual meal size.     

Exogeneous and endogenous CCK inhibit ethanol ingestion in Sardinian alcohol-preferring rats

Ethanol ingestion, like food ingestion, stimulates release of the signaling molecule cholecystokinin (CCK) from the small intestine. Here, we investigated the possibility that ethanol-induced CCK release might be a negative-feedback control of ethanol ingestion, similar to its function as part of the mechanism by which ingested food produces meal-ending satiation. We used Sardinian alcohol-preferring (sP) and Marchesian Sardinian (msP) alcohol-preferring rats, two apparently identical substrains that spontaneously ingest pharmacologically relevant amounts of ethanol, as well as their background strain, Wistar (W) rats. We demonstrated that: (1) intraperitoneal (IP), but not intracerebroventricular, injections of 0.5-4 microg/kg CCK-8 produced transient, dose-related reductions in 10% ethanol ingestion; (2) this inhibitory effect of CCK-8 on ethanol intake appeared behaviorally similar to its inhibitory action on ingestion of sucrose solutions; (3) the inhibitory effect of IP CCK-8 on ethanol ingestion occurred without evidence of tolerance when tests were repeated on consecutive days; (4) IP CCK-8 reduced ethanol intake despite simultaneously reducing blood ethanol levels (BALs); and (5) antagonism of CCK1 receptors with devazepide increased ethanol intake, indicating that endogenous CCK normally limits the size of bouts of ethanol ingestion. These results implicate peripheral CCK in the control of ethanol ingestion in sP and msP alcohol-preferring rats.     

Drinking,but not feeding,is opiate-sensitive in hamsters

The long-lasting opiate antagonist, naltrexone (NTX), was examined for its effects on various types of consummatory behavior in male golden hamsters and rats. Rat, but not hamster, 24 hr food and water intakes were significantly decreased by four daily NTX (10.0 mg/kg) injections. Hamsters displayed a minimal night to day feeding ratio compared to rats. hamsters increased food intake following insulin (50 U/kg) administration, but not after 24 hr food deprivation (FD) or 2-deoxy-D-glucose (2-DG; 800 mg/kg) injections. NTX (1.0 and 10 mg/kg) had no effect on feeding, but markedly attenuated hamster drinking induced by 48 hr water deprivation or hypertonic saline injection. Dexamethasone (DEX), a glucocorticoid which depletes pituitary β-endorphin and produces anorexia in rats, had no effect on daily hamster intake. Since the normal feeding profile of the hamster is similar to that of naloxone and DEX-treated rats, hamsters appear to lack an opiate-sensitive feeding system. In contrast, stimulated drinking behavior of hamsters operates through an opiate-sensitive mechanism. Thus, there are marked species differences concerning the involvement of endogenous opioids is consummatory behavior.     

Effect of intraperitoneal CCK-8 on food intake and brain orexin-A after 48 h of fasting in the rat

We investigated the interactions of the peripheral satiety peptide cholecystokinin and the brain orexin-A system in the control of food intake. The effect of an intraperitoneal (i.p.) injection of sulfated cholecystokinin octapeptide (in this article called CCK) (5 microg/kg, 4.4 nmol/kg) or of phosphate-buffered saline (PBS, vehicle control) on 48 h fasting-induced feeding and on orexin-A peptide content was analyzed in diverse brain regions innervated by orexin neurons and involved in the control of food intake. Administration of CCK after a 48 h fast reduced fasting-induced hyperphagia (P<0.05). I.p. CCK increased the orexin-A content in the posterior brainstem of 48 h fasted rats by 35% (P<0.05). Fed animals receiving CCK had 48% higher orexin-A levels in the posterior brainstem than fasted rats (P<0.05). In the lateral hypothalamus, fasting decreased orexin-A levels by 50% as compared to fed rats (P<0.05). In the septal nuclei, the combination of fasting and CCK administration reduced orexin-A contents compared to fed PBS and CCK animals by 13% and 17%, respectively (P<0.05). These results suggest a convergence of pathways activated by peripheral CCK and by fasting on the level of orexin-A released in the posterior brainstem and provide evidence for a novel interaction between peripheral satiety signaling and a brain orexigen in the control of food intake.     

Effects of Insulin Administration in Diabetic Rats on Food and Drink Rhythmic Schedules

In normal rats food and water intakes are associated in terms of time and quantity and their diurnal rhythms are synchronized. Intake behavior in streptozotocin-induced diabetic rats (ID) with marked polyphagia and polydipsia and in diabetic rats with continuous insulin administration (IT) has been studied. The daily percentages of food and water intakes during the dark phase were lower in IT than in control rats (C), being even lower in ID rats. However, all three groups showed circadian rhythmicity in food intake, although with less amplitude in the ID and IT animals compared to the C ones. A loss of the normal circadian rhythm of water intake was observed in the ID rats and although the insulin administration recovered circadian rhythmicity, it did not restore the temporal relations between food and water intakes. These results may indicate that the circadian pattern of water intake is more influenced by insulin than food intake. The daily pattern of this hormone may play an important role in the circadian modulation of the homeostatic mechanisms integrating both intake behaviors.     

Cholecystokinin Decreases Food Intake in Rats1

Partially purified cholecystokinin (CCK) was injected intraperitoneally into fasted rats prior to food presentation. The hormone produced a large doserelated suppression of intake of solid and liquid diets. Identical doses of the synthetic terminal octapeptide of cholecystokinin produced identical results. An effective dose of CCK did not suppress drinking after water deprivation. Treated animals did not appear ill and were not hyperthermic; neither CCK nor the octapeptide produced learning of a taste aversion in bait-shyness tests. The effect of CCK is not a property of all gut hormones, since injections of secretin did not affect feeding. These studies raise the possibility that CCK plays an inhibitory role in the short-term control of feeding behavior.     

Daily CCK injection enhances reduction of body weight by chronic intracerebroventricular leptin infusion

In the present study, we tested the hypothesis that a single daily injection of the gut peptide CCK, together with continuous leptin infusion, would produce significantly greater loss of body weight than leptin alone. We found that a single daily intraperitoneal injection of CCK-8 (0.5 microg/kg) significantly enhanced the weight-reducing effects of 0.5 microg/day leptin infused continuously into the lateral ventricle of male Sprague-Dawley rats by osmotic minipump. However, CCK and leptin together did not enhance reduction of daily chow intake. Furthermore, there was no synergistic reduction of 30-min sucrose intake, although a significant main effect of both leptin and CCK was observed on sucrose intake. These results 1) confirm our previous reports of synergy between leptin and CCK on body weight, 2) demonstrate that enhancement of leptin-induced weight loss does not require bolus administration of leptin, and 3) suggest that enhanced body weight loss following leptin and CCK does not require synergistic reduction of food intake by leptin and CCK.     

Increased short-term food satiation and sensitivity to cholecystokinin in neurotrophin-4 knock-in mice

Neurotrophin-4 (NT-4) knockout mice exhibited decreased innervation of the small intestine by vagal intraganglionic laminar endings (IGLEs) and reduced food satiation. Recent findings suggested this innervation was increased in NT-4 knock-in (NT-4KI) mice. Therefore, to further investigate the relationship between intestinal IGLEs and satiation, meal patterns were characterized using solid and liquid diets, and cholecystokinin (CCK) effects on 30-min solid diet intake were examined in NT-4KI and wild-type mice. NT-4KI mice consuming the solid diet exhibited reduced meal size, suggesting increased satiation. However, compensation occurred through increased meal frequency, maintaining daily food intake and body weight gain similar to controls. Mutants fed the liquid diet displayed a decrease in intake rate, again implying increased satiation, but meal duration increased, which led to an increase in meal size. This was compensated for by decreased meal frequency, resulting in similar daily food intake and weight gain as controls. Importantly, these alterations in NT-4KI mice were opposite, or different, from those of NT-4 knockout mice, further supporting the hypothesis that they are specific to vagal afferent signaling. CCK suppressed short-term intake in mutants and controls, but the mutants exhibited larger suppressions at lower doses, implying they were more sensitive to CCK. Moreover, devazepide prevented this suppression, indicating this increased sensitivity was mediated by CCK-1 receptors. These results suggest that the NT-4 gene knock-in, probably involving increased intestinal IGLE innervation, altered short-term feeding, in particular by enhancing satiation and sensitivity to CCK, whereas long-term control of daily intake and body weight was unaffected.     

Abrogation of peripheral cholecystokinin-satiety in the capsaicin treated rat

Cholecystokinin (CCK) is a peripheral and central mediator of short-term satiety. When given i.p., CCK decreases food intake in previously fasted rats for a period of 30 min. The effect has been previously shown to be abolished by vagotomy and more specifically by severing of vagal sensory rootlets. These studies were designed to determine the effects on rat feeding behavior, and in particular CCK-satiety, of the sensory neurotoxin capsaicin. In neonates, capsaicin selectively and permanently destroys unmyelinated sensory fibers including those in the vagus nerve. Rat neonates were treated with capsaicin, 50 mg/kg or vehicle, and surviving females studied at 8-10 weeks of age. The weights, 24-h food intake, and feeding responses to insulin were the same in adult capsaicin treated (Cap Rx) and vehicle treated (Veh Rx) rats. CCK (8 micrograms/kg i.p.) reduced 30 min food intake 61 +/- 18% in Veh Rx animals (mean +/- S.D., P less than 0.01). In capsaicin denervated animals, CCK also significantly reduced 30 min food intake from 5.09 +/- 1.10 to 3.92 +/- 0.84 g (P less than 0.01), but the mean reduction, 23 +/- 6%, was significantly less than in Veh Rx rats (P less than 10(-4]. A separate group of females, similarly treated as neonates with capsaicin or vehicle, were subjected to bilateral lesioning of the ventromedial hypothalamus. Both Cap Rx and Veh Rx animals gained significantly and equally more than non-lesioned controls. 24 h vagal transport of substance P was reduced 70% in age matched capsaicin treated animals compared to controls. These studies demonstrate that peripheral CCK-satiety is partly mediated by capsaicin sensitive fibers, presumably in the vagus nerve. Substance P is one possible transmitter mediating this reflex. Further conclusions are that active inhibition of an intact peripheral CCK-stimulated reflex arc is not necessary for full expression of central inducers of feeding, e.g., insulin or lesioning of the ventromedial hypothalamus, and that destruction of these fibers does not alter long-term weight regulation in rats receiving a normal diet.