MK-329 blocks the inhibition of alcohol intake by CCK-8

Peripheral administration of sulfated cholecystokinin octapeptide (CCK-8) potently reduces alcohol intake, preference, and blood levels in rats. MK-329 (L-364,718 or Devazepide) acts at peripheral cholecystokinin (CCK_A) receptors to antagonize CCK-8's physiological and behavioral effects, such as pancreatic stimulation and inhibition of feeding. We determined whether CCK_A receptor blockade would also prevent CCK-8's alcohol satiety effect. Water-deprived female and male rats (n = 7 for each) received randomized combinations of intraperitoneal injections of MK-329 (0, 100, 200, or 400 μg/kg) followed by CCK-8 (0 or 4 μg/kg). Rats were then given access to 5% w/v ethanol for 30 min, followed by 30-min access to water, with food ad lib. MK-329 at all doses significantly (p < 0.05) reduced the suppression of alcohol intake and food intake by CCK-8. MK-329 alone increased alcohol intake at 400 μg/kg, and increased food intake, in females and males at 100 and 200 μg/kg, respectively. We concluded that CCK-8's alcohol and food satiation effects depend on specific, peripheral CCK_A receptors, and satiation of alcohol consumption and drinking-associated feeding reflect an endogenous functional interaction of CCK-8 with CCK_A receptors.     

Desacyl ghrelin inhibits the orexigenic effect of peripherally injected ghrelin in rats

Studies showed that the metabolic unlike the neuroendocrine effects of ghrelin could be abrogated by co-administered unacylated ghrelin. The aim was to investigate the interaction between ghrelin and desacyl ghrelin administered intraperitoneally on food intake and neuronal activity (c-Fos) in the arcuate nucleus in non-fasted rats. Ghrelin (13 μg/kg) significantly increased food intake within the first 30 min post-injection. Desacyl ghrelin at 64 and 127 μg/kg injected simultaneously with ghrelin abolished the stimulatory effect of ghrelin on food intake. Desacyl ghrelin alone at both doses did not alter food intake. Both doses of desacyl ghrelin injected separately in the light phase had no effects on food intake when rats were fasted for 12 h. Ghrelin and desacyl ghrelin (64 μg/kg) injected alone increased the number of Fos positive neurons in the arcuate nucleus compared to vehicle. The effect on neuronal activity induced by ghrelin was significantly reduced when injected simultaneously with desacyl ghrelin. Double labeling revealed that nesfatin-1 immunoreactive neurons in the arcuate nucleus are activated by simultaneous injection of ghrelin and desacyl ghrelin. These results suggest that desacyl ghrelin suppresses ghrelin-induced food intake by curbing ghrelin-induced increased neuronal activity in the arcuate nucleus and recruiting nesfatin-1 immunopositive neurons.     

Endogenous CCK is not involved in the regulation of interdigestive gastrointestinal and gallbladder motility in conscious dogs.

In this study, we assessed whether endogenous CCK is involved in the regulation of interdigestive gastrointestinal and gallbladder motility in conscious dogs with force transducers chronically implanted in the gastric antrum, duodenum, jejunum and gallbladder. L364718 at a dose of 1.0 mg/kg was used as a specific and potent CCK receptor blocker, and its effect on spontaneous interdigestive motility and plasma motilin release were examined. Additionally, the contractile activity of exogenous synthetic canine motilin (20-100 ng/kg) with or without pretreatment with L364718 at a dose of 1.0 mg/kg was assessed. Whether the blocking effect of L364718 on CCK receptors was sufficient or not was verified by giving CCK-OP at a bolus dose of 10 ng/kg. As a result, cyclic changes in interdigestive motor activity and the plasma motilin concentration were not affected by pretreatment with L364718. L364718 also did not affect motilin-induced interdigestive contractile activity in the gastrointestinal tract and gallbladder. On the other hand, the effect of CCK-OP was completely abolished by pretreatment with L364718. It is concluded that endogenous CCK is not involved in the regulation of spontaneous and motilin-induced interdigestive contractions in the canine gastrointestinal tract and gallbladder.     

Food Intake in Prader-Willi Syndrome and Controls with Obesity After Administration of a Benzodiazepine Receptor Agonist

Benzodiazepine receptor (BZR) agonists, used extensively for their anxiolytic effects, have been shown to increase food intake in many mammalian species. Little information, however, is available on the effects of BZR agonists on feeding behaviors of humans. Food intake was evaluated in a 60-minute free-feeding standardized test after the acute administration of the BZR agonist chlordiazepoxide (CDP, Librium; 5 mg or 20 mg) or placebo. Subjects were 12 individuals with the Prader Willi syndrome (PWS), a disorder characterized by extreme hyperphagia and morbid obesity, and 11 controls with obesity. PWS subjects showed the characteristic hyperphagia associated with the appetite disorder, consuming more than six times as many sandwiches as controls with obesity. Results revealed no significant effect of either dose of CDP on the food intake of either group. Serum assays revealed that dose-dependent, clinically effective levels of CDP and active metabolites were achieved. These results suggest that acute administration of the BZR agonist CDP, at the therapeutic levels used, may not increase food intake in populations with obesity. However, the chronic effects of CDP on appetite in human populations still need to be explored.     

Potency of L-364,718 as an antagonist of the behavioral effects of peripherally administered cholecystokinin

A new antagonist of the peripheral cholecystokinin receptor, L-364,718, was found to block the reductions in food intake and exploratory activity induced by intraperitoneal administration of cholecystokinin octapeptide sulfate. L-364,718 significantly reversed the cholecystokinin-induced reduction in feeding at doses of 10 micrograms/kg - 10 mg/kg i.p. L-364,718 significantly reversed the cholecystokinin-induced reduction in exploratory activity at doses of 500 ng/kg - 10 mg/kg i.p. The time course of antagonist activity of L-364,718 was immediate to 90 minutes after intraperitoneal administration. L-364,718 had no significant effect on food intake or exploratory activity when administered alone, over the dose range of 100 ng/kg-10 mg/kg i.p. This compound appears to be at least one hundred times more potent than proglumide or benzotript as an antagonist of the behavioral effects of peripherally administered cholecystokinin.     

The effects of centrally administered apelin-13 on food intake, water intake and pituitary hormone release in rats

Apelin is the recently identified endogenous ligand for the G-protein-coupled receptor, APJ. Preproapelin and APJ mRNA are found in hypothalamic regions known to be important in the regulation of food and water intake, and pituitary hormone release. The effects of intracerebroventricular (ICV) administration of pyroglutamylated apelin-13 on food and water intake and pituitary hormone release in rats were investigated. Apelin-13 had little effect on food intake, but dose-dependently increased drinking behaviour and water intake at 1 h. Apelin-13 (10 nmol) increased water intake by up to sixfold compared to saline. Compared to saline control, apelin-13 (10 nmol) significantly increased plasma ACTH and corticosterone and decreased plasma prolactin, LH and FSH at 30 min. In vitro, apelin-13 stimulated the release of CRH and AVP from hypothalamic explants, but had no effect on NPY release. These results suggest that apelin may play an important role in the hypothalamic regulation of water intake and endocrine axes.     

Anxiolytic-like effect of succinic acid in mice

The putative anxiolytic activity of succinic acid was examined in male mice by using a number of experimental paradigms of anxiety and compared with that of the known anxiolytic compound diazepam. Use of the elevated plus-maze test revealed that diazepam (1.0, 2.0 and 4.0 mg/kg, PO) or succinic acid (3.0 or 6.0 mg/kg, PO) increased the percentage of entries into open arms and of time spent on open arms. In novel food consumption test, succinic acid (3.0, 6.0, and 12.0 mg/kg, IP) caused significant increases in food intake during 5 min when compared with the vehicle. In the stress-induced hyperthermia test, 40 min after drug administration rectal temperature was measured, succinic acid at dose of 1.5 mg/kg, inhibited stress-induced hyperthermia. Thus, these findings indicated that, in contrast with diazepam, succinic acid exhibits anxiolytic-like effect.     

Corticotrophin-releasing factor mediates hypophagia after adrenalectomy, increasing meal-related satiety responses

Adrenalectomy-induced hypophagia is associated with increased satiety-related responses, which involve neuronal activation of the nucleus of the solitary tract (NTS). Besides its effects on the pituitary–adrenal axis, corticotrophin-releasing factor (CRF) has been shown to play an important role in feeding behaviour, as it possesses anorexigenic effects. We evaluated feeding-induced CRF mRNA expression in the paraventricular nucleus (PVN) and the effects of pretreatment with CRF₂ receptor antagonist (Antisauvagine-30, AS30) on food intake and activation of NTS neurons in response to feeding in adrenalectomised (ADX) rats. Compared to the sham group, ADX increased CRF mRNA levels in the PVN of fasted animals, which was further augmented by refeeding. AS30 treatment did not affect food intake in the sham and ADX + corticosterone (B) groups; however, it reversed hypophagia in the ADX group. In vehicle-pretreated animals, refeeding increased the number of Fos and Fos/TH-immunoreactive neurons in the NTS in the sham, ADX and ADX + B groups, with the highest number of neurons in the ADX animals. Similarly to its effect on food intake, pretreatment with AS30 in the ADX group also reversed the increased activation of NTS neurons induced by refeeding while having no effect in the sham and ADX + B animals. The present results show that adrenalectomy induces an increase in CRF mRNA expression in the PVN potentiated by feeding and that CRF₂ receptor antagonist abolishes the anorexigenic effect and the increased activation of NTS induced by feeding in the ADX animals. These data indicate that increased activity of PVN CRF neurons modulates brainstem satiety-related responses, contributing to hypophagia after adrenalectomy.     

The Stimulatory Effect of Cerebral Intraventricular Injection of cNPY on Precocial Feeding Behavior in Neonatal Chicks (Gallus domesticus)

Neuropeptide Y (NPY) is one of the most potent stimulants of food intake in many animals. Most of the supporting evidence for the effects of NPY has been gathered in mammalian species using porcine NPY. To investigate the effects of NPY on precocial feeding initiation in chicks, we firstly used chicken NPY (cNPY) to study its role in food intake and spontaneous activities in 3-day-old male chicks. Food intake was monitored at different times after intracerebroventricular (ICV) injection of cNPY (2.5, 5.0 or 10.0 μg/10 μL) and anti-cNPY antibody (anti-cNPY) (1:9000, 1:3000 or 1:1000 in dilution). cNPY given at different doses significantly increased food intake at 30 min, 60 min, 90 min and 120 min after injection. Chicks treated with 5.0 μg/10 μL of cNPY showed a maximal 4.48 fold increase in food intake comparing to the control at 30 min. There is still more than 2 fold increase in food intake at 120 min after injection of cNPY. Food intake was significantly inhibited by a single ICV injection of anti-cNPY diluted to 1:9000 (60% inhibition), 1:3000 (92% inhibition), and 1:1000 (95% inhibition) at 30 min with 1:1000 being the maximally effective concentration. The inhibitory effects of anti-cNPY (diluted to1:9000, 1:3000, 1:1000) at 120 min post ICV injection were 22%, 42% and 46%, respectively. But ICV of anti-cNPY (1:3000 in dilution) did not block the orexigenic effect of 2.5 μg/10 μL of cNPY. ICV injection of different concentrations of cNPY increases locomotor activity in a dose-dependent manner while ICV anti-cNPY greatly decreased the distance moved by each chick compared to control groups. Taken together, our results demonstrated that cNPY has a promoting effect on chick food intake and locomotor activity, and that endogenous cNPY might play a positive role in regulating precocial feeding behavior in newly hatched chicks.     

Hypothalamic gonadotropin-inhibitory hormone precursor mRNA is increased during depressed food intake in heat-exposed chicks

The regulation of food intake in chickens (Gallus gallus domesticus) represents a complex homeostatic mechanism involving multiple levels of control, and regulation during high ambient temperatures (HT) is poorly understood. In this study, we examined hypothalamic mRNA expression of gonadotropin-inhibitory hormone (GnIH) to understand the effect of HT on an orexigenic neuropeptide. We examined the effects of HT (35 °C ambient temperature for 1, 24 or 48 h) on 14-day old chicks. HT significantly increased rectal temperature and suppressed food intake, and also influenced plasma metabolites. The expression of GnIH precursor mRNA in the diencephalon was significantly increased in chicks at 24-and 48 h of HT when food intake was suppressed significantly, whilst no change was observed for GnIH precursor mRNA and food intake at 1h of HT. In situ hybridization and immunocytochemistry further revealed the cellular localization of chicken GnIH precursor mRNA and its peptide in the paraventricular nucleus (PVN) in the chick hypothalamus. We examined plasma metabolites in chicks exposed to HT for 1 or 48 h and found that triacylglycerol concentration was significantly higher in HT than control chicks at 1h. Total protein, uric acid and calcium were significantly lower in HT chicks than control chicks at 48h. These results indicate that not only a reduction in food intake and alteration in plasma metabolites but also the PVN-specific expression of GnIH, an orexigenic agent, may be induced by HT. The reduced food intake at the same time as GnIH expression was increased during HT suggests that HT-induced GnIH expression may oppose HT-induced feeding suppression, rather than promote it. We suggest that the increased GnIH expression could be a consequence of the reduced food intake, and would not be a direct response to HT.     

A sex difference in the effect of CCK-8 on food and water intake in obese (ob/ob) and lean (+/+) mice

Male and female ob/ob and +/+ mice were tested with CCK-8 (1, 2, 4 and 8 micrograms/kg) administered 15 min prior to 30-min access to solid food after 17.5 hr food deprivation and 15 min prior to 30-min access to water after 17.5 hr water deprivation. The threshold dose for suppressing 30-min food intake was 2 micrograms/kg for all mice. Larger doses of CCK-8 inhibited food intake in male obese and lean mice in a linear fashion. The dose-response relationship for female mice, however, was not linear: lean females failed to suppress food intake following 4 or 8 micrograms/kg and obese females did not suppress food intake at 4 micrograms/kg. There was also a sex difference in the effect on water intake. No dose of CCK-8 changed water intake in lean males and only the 8 micrograms/kg dose decreased water intake in obese males. In contrast CCK-8 (1, 4 and 8 micrograms/kg) increased water intake in obese females, CCK-8 (1 and 8 micrograms/kg) increased water intake in lean females and no dose of CCK-8 decreased water intake in females. These data demonstrate significant sex differences in the effect of CCK-8 on food and water intake in mice.     

Feeding-suppressive mechanism of sulfated cholecystokinin (26-33) in chicks

The anorexigenic effect of cholecystokinin (CCK) is well documented in mammals, but documentation in neonatal chicks is limited. Thus, the present study investigated the mechanism underlying the anorexigenic effect of CCK in neonatal chicks. Intraperitoneal (IP) injection of sulfated CCK(26-33) (CCK8S) significantly decreased food intake in chicks at 60 and 300 nmol/kg. Non-sulfated CCK(26-33) (CCK8) also significantly decreased food intake, but its anorexigenic effect was observed only at the highest dose (300 nmol/kg) and short-lived. However, CCK(30-33) (CCK4) had no effect on food intake. Also, the intracerebroventricular (ICV) injection of CCK8S (0.2 and 1 nmol) significantly decreased food intake in chicks. Similar to IP administration, the anorexigenic effect of CCK8 was weak and CCK4 did not affect food intake. IP and ICV injections of CCK8S caused conditioned aversion and increased plasma corticosterone concentrations, suggesting that their anorexigenic effects might be related to stress and/or malaise. This might be true in ICV-injected CCK8S because co-injection of astressin, a corticotropin-releasing hormone receptor antagonist, tended to attenuate the effect of CCK8S. The present study revealed that N-terminal amino acids and the sulfation of Tyr are important for the anorexigenic effect of CCK8S after IP and ICV administered in chicks. Additionally, the effect of central CCK8S might be related to stress and/or malaise.     

Nicotine increases sucrose self-administration and seeking in rats

Associations between nicotine in cigarettes and food consumption may alter the incentive value of food such that food cue-reactivity is exaggerated during abstinence from smoking. This effect may contribute to the weight gain associated with cessation of smoking. We examined the effects of nicotine (0.4 mg/kg base subcutaneous) paired (NPD) or unpaired (NUP) with 10% sucrose self-administration (SA; 0.2 ml/delivery, 1 h/day for 10 days) on SA response rate and intake as well as sucrose cue-reactivity following either 1 or 30 days of forced abstinence. Rats were administered the training dose of nicotine prior to a second, consecutive cue-reactivity session. NPD rats responded at over three times the rate for sucrose and earned nearly twice the number of sucrose deliveries as NUP rats or saline controls. Sucrose cue-reactivity was greater after 30 days versus 1 day of forced abstinence for all groups. History of nicotine exposure had no effect on sucrose cue-reactivity. However, the subsequent injection of nicotine increased sucrose cue-reactivity only in the NPD groups. There were no abstinent-dependent effects of nicotine challenge on sucrose cue-reactivity. A study conducted in parallel with water as the reinforcer revealed a less dramatic effect of nicotine on intake. There was no history or abstinence-dependent effects of nicotine on water cue-reactivity. Nicotine increases the reinforcing effects of sucrose and sucrose-paired cues when nicotine is present. An implication of these findings is that relapse to nicotine (cigarettes) could substantially elevate food cue-reactivity.     

Increased circulating cholecystokinin contributes to anorexia and anxiety behavior in mice overexpressing pancreatic polypeptide

We have previously reported that pancreatic polypeptide (PP) overexpressing mice display thin phenotype with delayed gastric emptying and decreased food intake. In the present study, we further examined if CCK contributes to anorexia and anxiety behavior in PP overexpressing mice. Plasma CCK levels in PP overexpressing mice and their littermates were determined by radioimmunoassay using antisera specific to sulfated CCK-8 and CCK-33. To elucidate the role of CCK in PP overexpressing mice, CCK-1 receptor antagonist (L-364,718) or saline was administered intraperitoneally and food intake was measured for 2 h. CCK-2 antagonist (L-365,260) or saline was injected intraperitoneally and the elevated plus-maze test was performed to assess anxiety. Plasma CCK levels were significantly increased in PP overexpressing mice. Administration of L-364,718 increased food intake in PP overexpressing mice compared to the saline-injected PP overexpressing group, while L-364,718 did not increase food intake in non-transgenic littermates. PP overexpressing mice exhibited anxiety in the plus-maze test. Administration of CCK-2 receptor antagonist (L-365,260) reversed the decreased percentage of entry into the open arms in PP overexpressing mice. These results indicated that elevated CCK may contribute to anorexic and anxious phenotype of PP overexpressing mice.     

Effects of chlordiazepoxide and beta-carboline 3-carboxylic acid ethyl ester on non-suppressed and minimally-suppressed responding in the squirrel monkey.

Lever-pressing of squirrel monkeys was maintained under a multiple fixed-interval (FI) 5-min schedule of food presentation. In one component, responding was suppressed to various degrees by the presentation of electric shock following each 30th response. When responding was either substantially or minimally suppressed, intermediate doses of chlordiazepoxide (CDAP, 1-30 mg/kg) increased both suppressed and non-suppressed responding. Beta-carboline 3-carboxylic acid ethyl ester (beta-CCE, 0.1-3 mg/kg) had little effect at low to intermediate doses (0.1-0.3 mg/kg) and decreased both minimally-suppressed and non-suppressed responding to a comparable extent at higher doses. Repeated daily dosing with beta-CCE (up to 10 mg/kg) resulted in rapid tolerance to its rate-decreasing effects. As agonists do not typically exhibit rapid tolerance for anxiolytic efficacy, the current results suggest that some behavioral effects of inverse agonists may not be strictly opposite those of benzodiazepines.     

Stimulation and inhibition of food intake in sheep by centrally-administered hypothalamic releasing factors

Short-term effects of hypothalamic releasing factors on feeding behavior and digestive motility patterns were assessed in hay-fed sheep trained to eat more than half the total amount eaten over 8 h within the first 3 h after food presentation. Thyrotropin-releasing hormone (TRH) given intracerebroventricularly (ICV, 30 ng/kg) or intravenously at higher doses (IV, 3 micrograms/kg) reduced food consumption by 20 p. cent. The ICV or IV TRH-induced reduction was associated with behavioral excitation and stimulation of antroduodenal motor activity without changes in water intake. The ovine corticotropin releasing factor (oCRF 41) decreased food and water intake by 30-50% when administered ICV (60 ng/kg) but was not active when given systemically at doses up to 6 micrograms/kg. The synthetic human growth hormone releasing factor (hGRF 44) administered centrally (60 ng/kg) increased the amount of food intake and the antral motor activity without behavioral excitation. The results indicate a centrally-mediated facilitation of food intake by GRF and its inhibition by CRF which also affect water consumption. The presence of digestive motor effects suggests that extrapituitary pathways may be involved, as for TRH, in the action of both GRF and CRF.     

γ-氨基丁酸对鳜摄食和食欲的影响

为阐明γ-氨基丁酸(GABA)对鳜(Siniperca chuatsi)摄食和食欲的影响, 对鳜脑室注射生理盐水和不同剂量的GABA(50、125、500和2000 μg)。结果显示, 注射125 μg GABA组的鳜在2h内摄食量显著升高。实时荧光定量PCR (RT-qPCR)结果显示, 注射125 μg GABA 0.5h后, 鳜鱼脑中AgRP和NPY mRNA表达量上调, CART和POMC mRNA表达量下调, 都和鳜摄食量增加相一致。相比于对照组, 注射GABA后Leptin-R的mRNA表达量在0.5h和2h都有显著下降。这些结果表明GABA可能通过leptin的信号通路来影响食欲, 进而影响摄食量。研究结果可以为GABA在水产饲料中的应用提供理论依据。     

Diltiazem enhances food intake and gastrointestinal function in rats

The present study was to investigate the effects of diltiazem, a ghrelin receptor agonist, on food intake and gastrointestinal functions in rats. Rats were intragastrically administered with diltiazem solution (daily 16 mg/kg, 30 mg/kg or 80 mg/kg, 30 d), and the rats with saline as control. To detect the effects of diltiazem on food intake and body weight, the average daily food intake and body weight were recorded, and the serum metabolic hormones of plasma growth hormone (GH) and neuropeptide Y (NPY) were tested by radioimmunoassay. By means of the spectrophotometer and the modified Mett's method, the effects of diltiazem on rat's gastrointestinal function and pepsin activity were tested, respectively. In addition, the gastric juice's acidity of rats was detected by titration and the secretion amount was calculated. The results showed that the food intake and body weight were maximally promoted by diltiazem at the dose of 30 mg/kg daily (30 d). The average daily food intake and body weight were significantly increased, and the serum concentrations of GH and NPY were also remarkably increased in diltiazem-treated groups compared with those in control group. The results also showed that the gastric emptying rate, gastric acid secretion and the activity of pepsin were significantly increased in diltiazem-treated group compared with those in control group. These results suggest that diltiazem induces enhancement of eating, in the same time, it can also stimulate the gastrointestinal function and regulate growth of rat.     

Effects of chronic oral rimonabant administration on energy budgets of diet-induced obese C57BL/6 mice

The endocannabinoids have been recognized as an important system involved in the regulation of energy balance. Rimonabant (SR141716), a selective inverse agonist of cannabinoid receptor 1 (CB1), has been shown to cause weight loss. However, its suppressive impact on food intake is transient, indicating a likely additional effect on energy expenditure. To examine the effects of rimonabant on components of energy balance, we administered rimonabant or its vehicle to diet-induced obese (DIO) C57BL/6 mice once daily for 30 days, by oral gavage. Rimonabant induced a persistent weight reduction and a significant decrease in body fatness across all depots. In addition to transiently reduced food intake, rimonabant-treated mice exhibited decreased apparent energy absorption efficiency (AEAE), reduced metabolizable energy intake (MEI), and increased daily energy expenditure (DEE) on days 4-6 of treatment. However, these effects on the energy budget had disappeared by days 22-24 of treatment. No chronic group differences in resting metabolic rate (RMR) or respiratory quotient (RQ) (P > 0.05) were detected. Rimonabant treatment significantly increased daily physical activity (PA) levels both acutely and chronically. The increase in PA was attributed to elevated activity during the light phase but not during the dark phase. Taken together, these data suggested that rimonabant caused a negative energy balance by acting on both energy intake and expenditure. In the short term, the effect included both reduced intake and elevated PA but the chronic effect was only on increased PA expenditure.