CCK enhances response to gastric distension by acting on capsaicin-insensitive vagal afferents

Capsaicin treatment destroys vagal afferent C fibers and markedly attenuates reduction of food intake and induction of hindbrain Fos expression by CCK. However, both anatomical and electrophysiological data indicate that some gastric vagal afferents are not destroyed by capsaicin. Because CCK enhances behavioral and electrophysiological responses to gastric distension in rats and people, we hypothesized that CCK might enhance the vagal afferent response to gastric distension via an action on capsaicin-insensitive vagal afferents. To test this hypothesis, we quantified expression of Fos-like immunoreactivity (Fos) in the dorsal vagal complex (DVC) of capsaicin-treated (Cap) and control rats (Veh), following gastric balloon distension alone and in combination with CCK injection. In Veh rats, intraperitoneal CCK significantly increased DVC Fos, especially in nucleus of the solitary tract (NTS), whereas in Cap rats, CCK did not significantly increase DVC Fos. In contrast to CCK, gastric distension did significantly increase Fos expression in the NTS of both Veh and Cap rats, although distension-induced Fos was attenuated in Cap rats. When CCK was administered during gastric distension, it significantly enhanced NTS Fos expression in response to distension in Cap rats. Furthermore, CCK's enhancement of distension-induced Fos in Cap rats was reversed by the selective CCK-A receptor antagonist lorglumide. We conclude that CCK directly activates capsaicin-sensitive C-type vagal afferents. However, in capsaicin-resistant A-type afferents, CCK's principal action may be facilitation of responses to gastric distension.     

High fat maintenance diet attenuates hindbrain neuronal response to CCK

Rats maintained on a high fat diet reduce their food intake less in response to exogenous cholecystokinin (CCK) than rats maintained on a low fat diet. In addition, inhibition of gastric emptying by CCK is markedly attenuated in rats maintained on a high fat diet. Both inhibition of food intake and gastric emptying by CCK are mediated by sensory fibers in the vagus nerve. These fibers terminate on dorsal hindbrain neurons of the nucleus of the solitary tract and area postrema. To determine whether diet-induced changes in the control of feeding and gastric emptying are accompanied by altered vagal sensory responsiveness, we examined dorsal hindbrain expression of Fos-like immunoreactivity (Fos-li) following intraperitoneal CCK injection of rats maintained on high fat or low fat diets. Following CCK, there were numerous Fos-li nuclei in the area postrema and in the commissural and medial subnuclei of the nucleus of the solitary tract of rats maintained on a low fat diet. However, Fos-li was absent or rare in the brains of rats maintained on a high fat diet. These data suggest that the vagal sensory response to exogenous CCK is reduced in rats maintained on a high fat diet. Our results also are consistent with our previous findings that CCK-induced reduction of food intake and gastric emptying are both attenuated in rats maintained on a high fat diet. In addition our results support the hypothesis that attenuation of CCK-induced inhibition of food intake and gastric emptying may be due to diet-induced diminution of vagal CCK responsiveness.     

Cholecystokinin-induced suppression of locomotion is attenuated in capsaicin pretreated rats

Cholecystokinin (CCK), a peptide found in both gastrointestinal endocrine cells and neurons, suppresses food intake and reduces locomotor behavior when injected systemically. Both the locomotor and ingestive effects of CCK are abolished by subdiaphragmatic vagotomy. Pretreatment of adult rats with capsaicin attenuates the reduced locomotor activity and reduced food intake which normally occurs following injection of exogenous cholecystokinin. Since capsaicin damages or destroys small-diameter, unmyelinated, sensory neurons, including vagal sensory fibers, these data support the interpretation that both CCK-induced suppression of food intake and CCK-induced reduction of locomotion are mediated by fine, unmyelinated sensory neurons.     

An increase in the synthesis and release of calcitonin gene-related peptide in two-kidney,one-clip hypertensive rats

Previous investigations have indicated that capsaicin-sensitive sensory nerves play an important role in modulation of the peripheral resistance of the circulation system. In the present study, we examined the role of capsaicin-sensitive sensory nerves in two-kidney, one-clip (2K1C) renovascular hypertension rats. Systolic blood pressure (BP) was monitored by the tail-cuff method throughout the experiment. Concentrations of calcitonin gene-related peptide (CGRP) in the plasma, the level of CGRP mRNA in dorsal root ganglia (DRG) and the density of CGRP immunoreactive (CGRP-ir) fibers in mesenteric artery were measured. Blood pressure was significantly elevated at day 10 postoperation (BP was 143+/-10 and 114+/-7 mm Hg for 2K1C and Sham groups, respectively, p<0.05). Treatment with capsaicin, which selectively depletes neurotransmitters in sensory nerves, enhanced hypertensive responses to clipping (BP was 168+/-7 and 143+/-10 mm Hg at day 10 postoperation for Cap1+2K1C and 2K1C groups, respectively, p<0.05), and BP in the rats treated with a second injection of capsaicin was greater than that in the rats treated with a single injection of capsaicin (At day 30 postoperation, BP was 199+/-7 and 166+/-9 mm Hg for Cap2+2K1C and 2K1C groups, respectively, p<0.01; mean arterial pressure was 185.2+/-6.6 and 150.5+/-4.1 mm Hg for Cap2+2K1C and 2K1C groups, respectively, p<0.01). The expression of alpha-CGRP mRNA in DRG (122.87+/-3.67 arbitrary units, p<0.05), the level of CGRP in the plasma (75.40+/-4.99 pg/ml, p<0.01) and the density of CGRP-ir fibers in mesenteric artery (525.67+/-31.42 intersections, p<0.05) were significantly increased in 2K1C rats. Treatment with capsaicin, a single injection or a second injection, prevented the increased in the expression of CGRP mRNA in DRG. However, the decreased level of CGRP was only observed in the rats treated with a second capsaicin. These results suggest that in 2K1C hypertensive rats, the activity of capsaicin-sensitive sensory nerves is increased, which is playing a compensatory depressor role to partially counteract the increase in blood pressure, and that the cardiovascular actions of CGRP is mediated by the alpha-CGRP isoform.     

Capsaicin application to central or peripheral vagal fibers attenuates CCK satiety

Capsaicin treatment destroys small primary sensory neurons including a subpopulation of vagal afferents. Intraperitoneal, fourth ventricular or perivagal application of capsaicin attenuated or abolished cholecystokinin (CCK)-induced suppression of food intake. Capsaicin applied to the thoracolumbar spinal cord or to the pyloric region of the stomach did not alter CCK-induced reductions of food intake. Intraperitoneal capsaicin treatment reduced substance P-like immunoreactivity (SPLI) in the spinal dorsal horn and parts of the dorsal hindbrain. SPLI depletion, therefore, served as a histochemical indicator of the spread of capsaicin from its site of application. Capsaicin applied directly to the vagal trunks did not reduce SPLI in the spinal cord or hindbrain. Intraventricular capsaicin reduced SPLI in the hindbrain but not in the spinal cord. These data indicate that localized capsaicin application attenuates CCK-induced suppression of food intake by impairing the function of either central or peripheral portions of vagal afferent neurons. The data also support the conclusion that intraperitoneal capsaicin attenuates CCK-induced suppression of feeding by impairing vagal sensory function.     

Capsaicin does not attenuate bombesin-induced suppression of operant responding for food reward.

Systemic treatment with capsaicin, a neurotoxin which damages unmyelinated peptide-containing sensory neurons, has been shown to attenuate bombesin (BBS)-induced suppression of food intake. To determine whether capsaicin-sensitive fibers mediate the effect of BBS on appetitive motivation, we examined BBS-induced suppression of operant responding in rats pretreated neonatally with capsaicin (50 mg/kg; SC) or control vehicle. At 8-10 weeks of age, rats were trained to bar press for food. After achieving a stable level of performance, the animals were injected with BBS (10 micrograms/kg), normal saline, or prefed with 20 Noyes 45-mg pellets. Animals were then tested in an operant chamber on an FR 5 schedule of reinforcement for one hour. The results indicated that BBS suppressed bar pressing, regardless of whether animals were pretreated with capsaicin or control vehicle. These findings are inconsistent with the hypothesis that BBS induces satiety via capsaicin-sensitive neurons. The results suggest the possibility that more than one mechanism may mediate the effects of BBS: a neural mechanism involved in consummatory responses and a humoral mechanism involved in the operant response.     

NMDA receptor blockade attenuates CCK-induced reduction of real feeding but not sham feeding

Systemic injection of MK-801, a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptor ion channels, increases meal size and delays satiation. We examined whether MK-801 increases food intake by directly interfering with actions of cholecystokinin (CCK). Prior administration of MK-801 (100 microg/kg ip) reversed the inhibitory effects of CCK-8 (2 and 4 microg/kg ip) on real feeding of both liquid and solid foods. MK-801 alone did not alter 30-min sham intake of 15% sucrose compared with intake after saline. Furthermore, while CCK-8 (2 or 4 microg/kg ip) reduced sham intake, this reduction was not attenuated by MK-801 pretreatment. To ascertain whether MK-801 attenuation of CCK-induced reduction of real feeding was associated with attenuated inhibition of gastric emptying, we tested the effect of MK-801 pretreatment on CCK-induced inhibition of gastric emptying of 5-ml saline loads. Ten-minute gastric emptying was accelerated after MK-801 (3.9 +/- 0.2 ml) compared with saline vehicle (2.72 +/- 0.2 ml). CCK-8 (0.5 microg/kg ip) reduced 10-min emptying to 1.36 +/- 0.3 ml. Pretreatment with MK-801 did not significantly attenuate CCK-8-induced reduction of gastric emptying (0.9 +/- 0.4 ml). This series of experiments demonstrates that blockade of NMDA ion channels reverses inhibition of real feeding by CCK. However, neither inhibition of sham feeding nor inhibition of gastric emptying by CCK is attenuated by MK-801. Therefore, increased food intake after NMDA receptor blockade is not caused by a direct interference with CCK-induced satiation. Rather, increased real feeding, either in the presence or absence of CCK, depends on blockade of NMDA receptor participation in other post-oral feedback signals such as gastric sensation or gastric tone.     

Acute hypoxia prolongs the apnea induced by right atrial injection of capsaicin.

Inspiratory central drive is augmented by acute hypoxia that leads to a hyperventilation, but it is inhibited by capsaicin (Cap)-induced stimulation of pulmonary C fibers (PCFs) that produces an expiratory apnea. We hypothesized that acute hypoxia should shorten or eliminate the Cap-induced apnea. The ventilatory responses to bolus injection of Cap (0.2-0.5 microg) into the right atrium before and during acute hypoxia (10% O(2) for approximately 1 min; Hypoxia+Cap) were compared in anesthetized and spontaneously breathing rats. We found that Cap injection during acute hypoxia produced an extremely long-lasting apnea (69.67 +/- 11.97 s) that was 16-fold longer than the apnea induced by Cap alone (expiratory duration = 4.37 +/- 0.53 s; P < 0.01). A similar prolonged apnea was also observed during hypoxia in anesthetized guinea pigs. Bilateral vagotomy abolished apneic responses to Cap both before and during hypoxia. Subsequent recording of single-fiber activity of PCFs (PCF(A)) showed that acute hypoxia did not significantly affect baseline PCF(A) but that it doubled PCF(A) responses to Cap via increasing both the firing rate (3.34 +/- 0.76 to 7.65 +/- 1.32 impulses/s; P < 0.05) and burst duration (1.12 +/- 0.18 to 2.32 +/- 0.31 s; P < 0.05). These results suggest that acute hypoxia augments PCF-mediated inspiratory inhibition and thereby leads to an extremely long-lasting apnea. This interaction is partially due to hypoxic sensitization of PCF response to Cap.     

CCK inhibits the orexigenic effect of peripheral ghrelin

CCK and ghrelin exert antagonistic effects on ingestive behavior. The aim of the present study was to investigate the interaction between ghrelin and CCK administered peripherally on food intake and neuronal activity in specific hypothalamic and brain stem nuclei, as assessed by c-Fos-like immunoreactivity (c-FLI) in nonfasted rats. Ghrelin (13 microg/kg body wt) injected intraperitoneally significantly increased the cumulative food intake when measured at 30 min and 1 h after injection, compared with the vehicle group (2.9 +/- 1.0 g/kg body wt vs. 1.2 +/- 0.5 g/kg body wt, P < 0.028). Sulfated CCK octapeptide (CCK-8S) (2 or 25 microg/kg body wt) injected simultaneously blocked the orexigenic effect of ghrelin (0.22 +/- 0.13 g/kg body wt, P < 0.001 and 0.33 +/- 0.23 g/kg body wt, P < 0.0008), while injected alone, both doses of CCK-8S exerted a nonsignificant trend to reduce food intake. Ghrelin (13 microg/kg body wt ip) markedly increased the number of c-FLI-positive neurons per section in the arcuate nucleus (ARC) compared with vehicle (median: 31.35 vs. 9.86, P < 0.0001). CCK-8S (2 or 25 microg/kg body wt ip) had no effect on neuronal activity in the ARC, as assessed by c-FLI (median: 5.33 and 11.21 cells per section), but blocked the ghrelin-induced increase of c-fos expression in this area when both peptides were administered simultaneously (median: 13.33 and 12.86 cells per section, respectively). Ghrelin at this dose had no effect on CCK-induced stimulation of c-fos expression in the paraventricular nucleus of the hypothalamus and the nucleus of the solitary tract. These results suggest that CCK abolishes ghrelin-induced food intake through dampening increased ARC neuronal activity.     

Role of thromboxane receptors in the dipsogenic response to central angiotensin II

Central angiotensin II (ANG II) regulates thirst. Because thromboxane A2-prostaglandin H2 (TP) receptors are expressed in the brain and mediate some of the effects of ANG II in the vasculature, we investigated the hypothesis that TP receptors mediate the drinking response to intracerebroventricular (icv) injections of ANG II. Pretreatment with the specific TP-receptor antagonist ifetroban (Ifet) decreased water intake with 50 ng/kg icv ANG II (ANG II + Veh, 7.2 +/- 0.7 ml vs. ANG II + Ifet, 2.8 +/- 0.8 ml; n = 5 rats; P < 0.001) but had no effect on water intake induced by hypertonic saline (NaCl + Veh, 8.4 +/- 1.1 ml vs. NaCl + Ifet, 8.9 +/- 1.8 ml; n = 5 rats; P = not significant). Administration of 0.6 microg/kg icv of the TP-receptor agonist U-46,619 did not induce drinking when given alone but did increase the dipsogenic response to a near-threshold dose of 15 ng/kg icv ANG II (ANG II + Veh, 1.1 +/- 0.7 vs. ANG II + U-46,619, 4.5 +/- 0.9 ml; n = 5 rats; P < 0.01). We conclude that central TP receptors contribute to the dipsogenic response to ANG II.     

Neonatal capsaicin treatment alters basal pulmonary mechanics and response to methacholine in F344 rats.

Full methacholine dose-response curves were performed on anesthetized tracheostomized Fischer 344 adult rats treated neonatally with capsaicin (50 mg/kg) or with vehicle alone. Capsaicin, the hot extract of pepper, releases substance P (SP) from nonmyelinated sensory nerve endings and causes acute bronchoconstriction and airway microvascular leakiness. Chronic treatment with capsaicin leads to depletion of SP and other tachykinins from afferent C-fibers and can therefore be used as a tool to investigate the contribution of SP innervation to airway responses. The rats (9 controls and 6 treated with capsaicin) were paralyzed with succinylcholine and mechanically ventilated at a constant tidal volume and frequency. Airway resistance (RL) and dynamic compliance (Cdyn) were determined at each dose of methacholine from measurements of volume, flow, and transpulmonary pressure. Capsaicin-treated rats were found to have a significantly reduced baseline RL [0.150 +/- 0.039 (SD) vs. 0.225 +/- 0.050 cmH2O.ml-1.s, P = 0.009] and a correspondingly significantly elevated Cdyn (0.371 +/- 0.084 vs. 0.268 +/- 0.053 ml/cmH2O, P = 0.012). There was no significant difference in sensitivity to methacholine, but the maximal response to methacholine was significantly greater in the capsaicin-treated rats. In terms of RL, the maximal response for capsaicin-treated rats was 6.03 x baseline +/- 0.98 vs. 4.30 x baseline +/- 1.80 (P = 0.05) for controls, and for Cdyn changes the maximal decrease was 5.75 x baseline +/- 1.22 vs. 3.83 +/- 0.69 (P = 0.002). The observed differences in RL and Cdyn coupled with the differences in maximal responses can be attributed to the selective destruction of a subpopulation of pulmonary afferent C-fibers.(ABSTRACT TRUNCATED AT 250 WORDS)     

Endogenous amylin contributes to the anorectic effects of cholecystokinin and bombesin

Previous studies indicated that amylin contributes to the anorectic effects of cholecystokinin (CCK) and bombesin (BBS), possibly by enhancing the release of pancreatic amylin or by modulating their anorectic actions within the central nervous system (CNS). To elucidate the interaction between amylin and CCK or BBS, respectively, we investigated the influence of an IP injection of CCK or BBS on feeding in amylin-deficient mice (IAPP(-/-)). The anorectic effects of CCK and BBS were nearly abolished in IAPP(-/-) mice compared to wildtype (WT) mice (e.g. 20 microg/kg CCK, 1-h food intake: WT/NaCl 0.53 +/- 0.03 g; WT/CCK 0.16 +/- 0.03 g (P < 0.001); IAPP(-/-)/NaCl 0.49 +/- 0.05 g; IAPP(-/-)/CCK 0.39 +/- 0.04 g). Acute amylin replacement restored the anorectic effect of CCK in IAPP(-/-) mice.To find out whether CCK or BBS enhance the feeding-induced release of pancreatic amylin, we injected rats with CCK-8 (0.5-50 microg/kg) or BBS (5 microg/kg) and measured plasma amylin levels after injections. Neither CCK nor BBS increased the plasma amylin level in rats. We suggest that the mediation of the anorectic effects of CCK and BBS by amylin is not dependent on a CCK- or BBS-induced release of pancreatic amylin, but may rather be due to a modulation of their effects by amylin within the CNS.     

Dietary resistant starch increases hypothalamic POMC expression in rats

Resistant starch (RS) is fermentable dietary fiber. Inclusion of RS in the diet causes decreased body fat accumulation and altered gut hormone profile. This study investigates the effect of feeding RS on the neuropeptide messenger RNA (mRNA) expressions in the arcuate nucleus (ARC) of the hypothalamus and whether vagal afferent nerves are involved. The rats were injected intraperitoneally with capsaicin to destroy unmyelinated small vagal afferent nerve fibers. The cholecystokinin (CCK) food suppression test was performed to validate the effectiveness of the capsaicin treatment. Then, capsaicin-treated rats and vehicle-treated rats were subdivided into a control diet or a RS diet group, and fed the corresponding diet for 65 days. At the end of study, body fat, food intake, plasma peptide YY (PYY) and glucagon-like peptide 1 (GLP-1), and hypothalamic pro-opiomelanocortin (POMC), neuropeptide Y (NPY), agouti-related peptide (AgRP) gene expressions were measured. RS-fed rats had decreased body fat, increased POMC expression in the hypothalamic ARC, and elevated plasma PYY and GLP-1 in both the capsaicin and vehicle-treated rats. Hypothalamic NPY and AgRP gene expressions were not changed by RS or capsaicin. Therefore, destruction of the capsaicin-sensitive afferent nerves did not alter the response to RS in rats. These findings suggest that dietary RS might reduce body fat through increasing the hypothalamic POMC expression and vagal afferent nerves are not involved in this process. This is the first study to show that dietary RS can alter hypothalamic POMC expression.     

The daidzein- and estradiol- induced anorectic action in CCK or leptin receptor deficiency rats

We investigated the effect of daidzein feeding and estradiol treatment on food intake in cholecystokinin-1 receptor (CCK1R) deficiency, leptin receptor (ObRb) deficiency rats and their wild-type rats. These rats underwent an ovariectomy or a sham operation. For the 5 week experiment, each rat was divided in three groups: control, daidzein (150 mg/kg diet), and estradiol (4.2 μg/rat/day) groups. In both CCK1R+ and CCK1R? rats, daidzein feeding and estradiol treatment significantly decreased food intake. Daidzein feeding significantly reduced food intake in ovariectomized ObRb? rats, although not in ObRb+ rats. Estradiol treatment significantly lowered food intake in ovariectomized ObRb+ and ObRb? rats. In the ovariectomized rats, estradiol treatment significantly increases uterine weight, while daidzein feeding did not change it, suggesting that daidzein might have no or weak estrogenic effect in our experiment. These results suggest that CCK1R and ObRb signalings were not essential for the daidzein- and estradiol-induced anorectic action.     

Abdominal vagal mediation of the satiety effects of CCK in rats

CCK type 1 (CCK1) receptor antagonists differing in blood-brain barrier permeability were used to test the hypothesis that satiety is mediated in part by CCK action at CCK1 receptors on vagal sensory nerves innervating the small intestine. Devazepide penetrates the blood-brain barrier; A-70104, the dicyclohexylammonium salt of N alpha-3-quinolinoyl-D-Glu-N,N-dipentylamide, does not. At dark onset, non-food-deprived control rats and rats with subdiaphragmatic vagotomies received a bolus injection of devazepide (2.5 micromol/kg i.v.) or a 3-h infusion of A-70104 (3 micromol.kg(-1).h(-1) i.v.) either alone or coadministered with a 2-h intragastric infusion of peptone (0.75 or 1 g/h). Food intake was determined from continuous computer recordings of changes in food bowl weight. In control rats both antagonists stimulated food intake and attenuated the anorexic response to intragastric infusion of peptone. In contrast, only devazepide was effective in stimulating food intake in vagotomized rats. Thus endogenous CCK appears to act both at CCK1 receptors beyond the blood-brain barrier and by a CCK1 receptor-mediated mechanism involving abdominal vagal nerves to inhibit food intake.     

Paraventricular nucleus lesions abolish the inhibition of feeding induced by systemic cholecystokinin

Peripherally administered cholecystokinin (CCK) initiates a behavioral syndrome which includes reduced food consumption and reduced exploratory behaviors. Previous studies suggest that CCK stimulates receptors in the gut, activating the vagus nerve, which relays sensory information to the nucleus tractus solitarius (NTS) and its ascending pathways. Terminal regions of ascending NTS projections include the paraventricular nucleus of the hypothalamus (PVN), the central nucleus of the amygdala (CNA), and the bed nucleus of the stria terminalis (BNST). Lesions of these three target sites were performed in rats to test the hypothesis that structures postsynaptic to the NTS mediate the behavioral syndrome induced by CCK. Knife cut lesions of the PVN abolished the reductions in feeding induced by CCK (5 and 10 micrograms/kg IP), as compared to sham lesioned control rats. PVN lesions only partially attenuated the reductions in exploration induced by CCK (2.5, 5, and 10 micrograms/kg IP), as compared to sham lesioned control rats. Electrolytic lesions of the CNA partially attenuated the reductions in exploratory behavior induced by CCK (2.5, 5, and 10 micrograms/kg IP), and had no effect on the reductions in feeding induced by CCK (5 and 10 micrograms/kg IP). Electrolytic lesions of the BNST had no effect on either the reductions in feeding or the reductions in exploration induced by CCK. The PVN appears to be one critical forebrain target site for mediating the actions of CCK on feeding. The CNA appears to facilitate the actions of CCK on exploration. Individual components of the behavioral syndrome induced by CCK may be mediated by anatomically distinct forebrain loci.     

Neuromedin U has a physiological role in the regulation of food intake and partially mediates the effects of leptin

Intracerebroventricular (ICV) administration of Neuromedin U (NMU), a hypothalamic neuropeptide, or leptin, an adipostat hormone released from adipose tissue, reduces food intake and increases energy expenditure. Leptin stimulates the release of NMU in vitro, and NMU expression is reduced in models of low or absent leptin. We investigated the role of NMU in mediating leptin-induced satiety. ICV administration of anti-NMU immunoglobulin G (IgG) (5 nmol) to satiated rats significantly increased food intake 4 h after injection, an effect seen for 相似文献   

Endogenous cholecystokinin reduces food intake and increases Fos-like immunoreactivity in the dorsal vagal complex but not in the myenteric plexus by CCK1 receptor in the adult rat

We hypothesized that endogenous CCK reduces food intake by activating the dorsal vagal complex (DVC) and the myenteric neurons of the gut. To test this hypothesis, adult rats were given camostat mesilate; a nonnutrient releaser of endogenous CCK, by orogastric gavage, and Fos-like immunoreactivity (Fos-LI) was quantified in the DVC and the myenteric plexus. The results for endogenous CCK were compared with those for exogenous CCK-8. Exogenous CCK-8 reduced food intake and stimulated Fos-LI in the DVC and in myenteric neurons of the duodenum and jejunum. In comparison, endogenous CCK reduced food intake and increased DVC Fos-LI but did not increase Fos-LI in the myenteric plexus. Similar to CCK-8, devazepide, a specific CCK(1) receptor antagonist, and not L365,260, a specific CCK(2) receptor antagonist, attenuated the reduction of food intake by camostat. In addition, Fos-LI in the DVC in response to both exogenous CCK-8 and camostat administration was significantly attenuated by vagotomy, as well as by blocking CCK(1) receptors. These results demonstrate for the first time that reduction of food intake in adult rats by endogenous CCK released by a nonnutrient mechanism requires CCK(1) receptors, the vagus nerve, and activation of the DVC, but not the myenteric plexus.     

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.     

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.