Involvement Of Cholecystokinin Research Articles

Involvement of Cholecystokinin (CCK) Receptor in the Regulation of Dexamethasone on Gastric Emptying in Male Rats

Dexamethasone is a potent glucocorticoid, which has been used in the anti-inflammation therapy. It has been well known that the gastrointestinal (GI) motility is affected by stress. However, the role of glucocorticoids in regulating GI motility is unclear. The purpose of this study was to investigate the effect and action mechanism of dexamethasone on the GI motility. In the first study, the male rats were injected intraperitoneally (i.p.) with saline or dexamethasone (15 or 30 μg/ml/kg) 1 h before decapitation. In the second study, dexamethasone (30 μg/ml/kg) and lorglumide (a selective cholecystokinin A receptor, CCKA, antagonist) were injected intraperitoneally 60 min and 30 min prior to decapitation, respectively. All experimental animals were orally ingested with radioactive Na_2^(51)CrO_4 containing 10% charcoal by a PE-205 tubing into the stomach after a 24 h fast and then decapitated 15 min later. The small intestine was divided equally into ten segments. The radioactivity in stomach and each segment of intestine was counted by a gamma-counter. The ratios of gastric emptying and charcoal transit were calculated. Blood samples were collected. The concentrations of CCK and corticosterone in plasma samples were measured by radioimmunoassay, and those of serum adrenocorticotropin (ACTH) were measured by an enzyme immunoassay (EIA) kit. All data were expressed as mean ± s. e. mean, and analyzed by the analysis of variance (ANOVA). The differences between specific means were analyzed by Dunnett's test. The results demonstrate that dexamethasone dose dependently inhibited the level of serum ACTH and the gastric emptying, and the intestinal transit is also inhibited by dexamethasone at the dose of 15 μg/ml/kg. Plasma CCK and corticosterone concentrations were dose-dependently decreased by dexamethasone injection. Furthermore, after injection of lorglumide, the decreased gastric emptying caused by dexamethasone was restored to the control level. These results suggested that dexamethasone-induced inhibition of gastric emptying and intestinal transit is mediated by an action on CCKA receptor.

Involvement of cholecystokinin (CCK) in the daily pattern of gastrointestinal regulation of Senegalese sole (Solea senegalensis) larvae reared under different feeding regimes

Cholecystokinin (CCK) is an important regulator of pancreatic enzyme secretion in adult mammals and teleosteans. Although some studies have focused on the interaction between CCK and trypsin in marine fish larvae, little is known about the circadian patterns of the regulatory mechanism involving these two digestive components. In this study, we took advantage of the characteristic change from a diurnal to a nocturnal feeding habit that occurs in Senegalese sole (Solea senegalensis) post-larvae, to conduct an experiment where larvae and postlarvae were submitted to three different feeding regimes from mouth opening: continuous feeding, diurnal feeding and nocturnal feeding. The aim was to establish different daily feeding scenarios to uncover the operating mechanisms of CCK and tryptic enzyme activity over the 24-hourcycle to better understand the regulation of digestion in developing fish larvae. Results show a prevalence of simultaneous and opposing trends of CCK level and tryptic activity as a function of the postprandial time. This finding supports the existence of a regulatory loop between these two digestive components in pre- and post-metamorphic Senegal sole larvae. In addition, CCK level was also modulated by the gut content, tending to be lower when the gut is full and higher when is being emptied. Furthermore, larvae were able to synchronize digestive functions to very different feeding regimes, although it seems to be important having a diurnal feeding phase during pre-metamorphic stages for a proper development.

Involvement of Cholecystokinin (CCK) Receptor in the Adaptation of Gastric Emptying Induced by Adrenocorticotropin (ACTH) in Male Rats

It has been shown that gastric emptying is delayed in stressed animals. This investigation was to study the effect of adrenocorticotropin (ACTH), a stress hormone, on the gastric emptying and intestinal transit in rats. Fasted male rats were injected intraperitoneally (i.p.) with saline, ACTH (10 or 20 μg/ml/kg), lorglumide (a selective potent cholecystokinin A receptor antagonist, 10 μg/ml/ kg) or ACTH (20 μg/ml/kg) and lorglumide (10 μg/ml/kg) at 30 min before decapitation. All rats were orally ingested with liquid meal containing radioactive Na_2 ^(51)CrO_4 (0.5 μCi/ml) and 10% charcoal at 15 min before decapitation, and blood samples were collected. Administration of ACTH significantly increased the concentrations of plasma corticosterone, but decreased the levels of plasma cholecystokinin (CCK) and gastric emptying as well as intestinal transit in rats. The decreased gastric emptying, but not intestinal transit, was reversed by the treatment of lorglumide. These results suggested that CCKA receptor was involved in the inhibitory effect of ACTH on the gastric emptying in rats.

Hormonal control of tryptic enzyme activity in Atlantic cod larvae (Gadus morhua): Involvement of cholecystokinin during ontogeny and diurnal rhythm

The ontogenetic development of the gut hormone cholecystokinin (CCK) and the key proteolytic enzyme trypsin was described in Atlantic cod larvae (Gadus morhua) from first-feeding until 38days post first-feeding (dpff). CCK is known to play a major role in the endocrine control of digestive processes in mammals and adult fish, but its regulatory role in the larval stages of marine fish is largely unknown. Only small amounts of CCK were found in the body (excluding head) in cod larvae at first-feeding, but CCK levels increased exponentially with development, suggesting a more pronounced role of CCK during ontogeny. Tryptic enzyme activity increased slightly until a standard length of ca. 8mm (approx. 33days dpff) with a significant increase in larvae larger than 8mm standard length, indicating limited digestive capacity in the early stages. To entangle the short-term feedback mechanism between CCK and tryptic enzyme activity, we conducted a 12hour feeding experiment at 21 dpff. Cod larvae receiving only algae revealed a noticeable response in tryptic enzyme activity within two hours in the morning, whereas larvae fed algae and rotifers at the same time showed a slightly delayed response up to four hours. Tryptic enzyme activity remained low in the group receiving only algae as well as the two fed groups in the afternoon. No reaction in tryptic enzyme activity was observed in larvae that received a second meal of rotifers in the afternoon, indicating limited regulatory and digestive capacity to handle several meals in a short period. CCK levels remained relatively constant throughout the day but increased in the afternoon in all three groups when tryptic enzyme activity was low, suggesting that a negative feedback mechanism between CCK and tryptic enzyme activity is present in larval cod at least from 21 dpff.

Proglumide, a cholecystokinin receptor antagonist, exacerbates alloxan-induced diabetes mellitus in Swiss mice.

The effect of proglumide ((+/-)-4-benzamido-N,N-dipropyl-glutaramic acid), a gastrin and cholecystokinin receptor antagonist, has been studied on the fasting plasma glucose (FPG) and insulin levels in normal and alloxan-diabetic mice. In normal mice, proglumide, administered as a single oral dose or twice daily for five consecutive days, did not produce any alteration in those parameters. Injection of alloxan monohydrate (70 mg kg-1 i.v.) produced a significant decrease in plasma insulin and a significant elevation of FPG levels on the 5th day after its administration as evidence of diabetes mellitus. Proglumide sodium, given as a single acute dose on the 5th day of alloxan injection, or as a twice daily dose for 5 days immediately after alloxan injection, significantly exacerbated the hyperglycaemia and further decreased the plasma insulin levels thus worsening the diabetogenic effect of alloxan. These observations point to a possible involvement of cholecystokinin (CCK) in alloxan-induced diabetes and indicate a need for monitoring the levels of FPG in diabetic patients being treated with a high dose of proglumide or other CCK-antagonists.

Involvement of cholecystokinin in baseline and post-prandial whole body insulin sensitivity in rats

The objective of the study was to investigate the role of cholecystokinin (CCK) on the food-induced insulin sensitization phenomenon in healthy Long Evans Tokushima Otsuka (LETO) and Otsuka Long Evans Tokushima Fatty (OLETF) rats. Whole body insulin sensitivity determined by hyperinsulinaemic euglycaemic glucose clamping and the rapid insulin sensitivity test served as endpoints. Determinations were done in both fasted and re-fed animals. The involvement of CCK in post-prandial insulin sensitization was assessed by using proglumide, a CCK receptor blocker, by assessment of hypothalamic CCK-1/CCK-2 receptor expression by rt-PCR technique and by plasma insulin immunoreactivity determinations by means of radioimmunoassay as pharmacological, genetic and analytical approaches, respectively. The body weight of the OLETF rats and the amount of food consumed much exceeded those seen with LETO rats. The post-prandial increase in insulin sensitivity was marked in LETO, but not in OLETF rats. Intravenous proglumide attenuated post-prandial insulin sensitivity in LETO rats, with no effect in OLETF rats. Nevertheless, baseline insulin sensitivity was much lower in OLETF than in LETO rats. Treatment with rosiglitazone increased baseline insulin sensitivity of OLETF rats and evoked an increase in CCK-1 receptor gene expression in LETO rats. The results provide evidence for the involvement of CCK receptors in adjustment of both fasting and post-prandial insulin sensitivity. The data obtained with OLETF rats strongly suggest the predominant role of CCK-1 receptors.

Repeated social defeat-induced depression-like behavioral and biological alterations in rats: involvement of cholecystokinin

Cholecystokinin (CCK) involvement in depression-like disorders is poorly documented. Here, we investigated whether CCKergic neurotransmission is relevant to depressive-like symptoms and antidepressant therapy using a novel preclinical model based on repeated social defeat over 4 weeks in rats. Repeated social defeat triggers changes that could be considered as behavioral and biological correlates of depressive symptoms in humans, such as a hyperactivity of hypothalamic-pituitary-adrenal (HPA) axis (increase of serum corticosterone levels and of adrenal gland weight), increased immobility time in the forced swimming test (FST), decrease of body weight and of sweet water consumption and reduction of hippocampal volume associated with a decreased cell proliferation in the dentate gyrus. In addition, in vivo microdialysis showed that cortical CCK release was tonically increased in defeated rats. Chronic imipramine treatment (16 mg kg(-1) per day for 25 days) prevented both the repeated social defeat-induced alterations of biological and behavioral parameters and the associated increase of cortical CCK release. Chronic blockade of CCK2 receptors by the specific antagonist CI-988 (1 mg kg(-1) per day for 25 days) also normalized immobility time in the FST and prevented HPA axis hyperactivity, reduction of hippocampal volume and cell proliferation and decreased sweet water intake normally evoked by repeated social defeat. These data showed that the repeated social-defeat paradigm can be considered as a suitable model of 'depression' in rats. The causal link between social defeat-evoked (1) increase in cortical CCKergic neurotransmission and (2) depression-like symptoms that we highlighted here strongly suggests that CCKergic systems may be a relevant target for novel antidepressant therapy.

Responses of the gastric vagal afferent activity to interleukin-1 and the involvement of cholecystokinin

Responses of the gastric vagal afferent activity to interleukin-1 and the involvement of cholecystokinin

Gastrin, cholecystokinin and gastrointestinal tract functions in mammals

The aim of the present review is to synthesise and summarise our recent knowledge on the involvement of cholecystokinin (CCK) and gastrin peptides and their receptors in the control of digestive functions and more generally their role in the field of nutrition in mammals. First, we examined the release of these peptides from the gut, focusing on their molecular forms, the factors regulating their release and the signalling pathways mediating their effects. Second, general physiological effects of CCK and gastrin peptides are described with regard to their specific receptors and the role of CCK on vagal mucosal afferent nerve activities. Local effects of CCK and gastrin in the gut are also reported, including gut development, gastrointestinal motility and control of pancreatic functions through vagal afferent pathways, including NO. Third, some examples of the intervention of the CCK and gastrin peptides are exposed in diseases, taking into account intervention of the classical receptor subtypes (CCK1 and CCK2 receptors) and their heterodimerisation as well as CCK-C receptor subtype. Finally, applications and future challenges are suggested in the nutritional field (performances) and in therapy with regards to the molecular forms or in relation with the type of receptor as well as new techniques to be utilised in detection or in therapy of disease. In conclusion, the present review underlines recent developments in this field: CCK and gastrin peptides and their receptors are the key factor of nutritional aspects; a better understanding of the mechanisms involved may increase the efficiency of the nutritional functions and the treatment of abnormalities under pathological conditions.

Involvement of Cholecystokinin 2 Receptor in Food Intake Regulation: Hyperphagia and Increased Fat Deposition in Cholecystokinin 2 Receptor-Deficient Mice

The role of cholecystokinin (CCK) as a satiety factor has been extensively documented. Although most work implies that CCK1 receptor mediates the control of food intake, a contributing role for CCK2 receptor (CCK2R) in the CCK-induced satiety cannot be totally excluded. The hypothesis that CCK2R invalidation disrupts regulatory pathways with impact on feeding behavior was examined in CCK2R(-/-) mice. CCK2R(-/-) mice developed obesity that was associated with hyperphagia. Obesity was related with increased fat deposition resulting from adipocyte hypertrophy. Expression of several adipokines was dysregulated consistently with obesity. Moreover, obesity was associated with disturbed glucose homeostasis as revealed by increased fasting glycemia and insulinemia, impaired glucose tolerance, and hepatic insulin resistance in CCK2R(-/-) mice. In vitro analysis of isolated adipocytes metabolism was consistent with increased storage but preserved insulin sensitivity. Suppression of feeding and concomitant increased expression of hypothalamic proopiomelanocortin after intracerebroventricular injection of gastrin into control mice demonstrates that hypothalamic CCK2 receptors mediate inhibition of food intake. Comparative analysis of hypothalamic mediator gene expression in fed knockout and control mice demonstrated overexpression of ghrelin receptors in CCK2R(-/-) mice, indicating up-regulation of orexigenic pathways. This effect was also observed after body weight normalization, indicating a causative role in the development of hyperphagia and obesity of CCK2R(-/-) mice. Our results give evidence that CCK2 receptor activity plays a contributing regulatory role in the control of food intake.

Involvement of cholecystokinin in peripheral nociceptive sensitization during diabetes in rats as revealed by the formalin response

The possible pronociceptive role of peripheral cholecystokinin (CCK-8) as well as CCK A and CCK B receptors in diabetic rats was assessed. Subcutaneous injection of 0.5% formalin induced a greater nociceptive behavior in diabetic than in non-diabetic rats. Moreover, local peripheral injection of CCK-8 (0.1–100 μg) significantly increased 0.5% formalin-induced nociceptive activity in diabetic, but not in non-diabetic, rats. This effect was restricted to the formalin-injected paw as administration of CCK-8 into the contralateral paw was ineffective. Local peripheral administration of CCK-8, in the absence of formalin injection, produced a low level of, but significant increase in, flinching behavior in diabetic compared to non-diabetic rats. In addition, local peripheral administration of the non-selective CCK receptor antagonist proglumide (1–100 μg), CCK A receptor antagonist lorglumide (0.1–100 μg) or CCK B receptor antagonist CR-2945 (0.1–100 μg), but not vehicle or contralateral administration of CCK receptor antagonists, significantly reduced 0.5% formalin-induced flinching in diabetic rats. CR-2945 was the most effective drug in this condition. These effects were not observed in non-diabetic rats. The local peripheral pronociceptive effect of CCK-8 (100 μg) was significantly reduced by proglumide (100 μg), lorglumide (100 μg), and CR-2945 (100 μg). Results suggest that diabetes-induced peripheral sensitization could be due to a local peripheral release of CCK-8, which in turn would act on CCK B, mainly but also in CCK A, receptors located on the primary afferent neurons.

Involvement of cholecystokinin in the opioid tolerance induced by dipyrone (metamizol) microinjections into the periaqueductal gray matter of rats

The analgesic effect of non-steroidal anti-inflammatory drugs (NSAIDs) is partly due to an action upon the periaqueductal gray matter (PAG), which triggers the descending pain control system and thus inhibits nociceptive transmission. This action of NSAIDs engages endogenous opioids at the PAG, the nucleus raphe magnus and the spinal cord. Repeated administration of NSAIDs such as dipyrone (metamizol) and acetylsalicylate thus induces tolerance to these compounds and cross-tolerance to morphine. Since cholecystokinin plays a key role in opioid tolerance, the present study in rats investigated whether PAG cholecystokinin is also responsible for tolerance to PAG-microinjected dipyrone. Microinjection of cholecystokinin (1 ng/0.5 μl) into PAG blocked the antinociceptive effect of a subsequent microinjection of dipyrone (150 μg/0.5 μl) into the same site, as evaluated by the tail flick and hot plate tests. Microinjection of proglumide (0.4 μg/0.5 μl), a non-selective cholecystokinin antagonist, into PAG prevented the development of tolerance to subsequent microinjections of dipyrone, as well as cross-tolerance to microinjection of morphine (5 μg/0.5 μl) into the same site. In rats tolerant to PAG dipyrone, a PAG microinjection of proglumide restored the antinociceptive effect of a subsequent microinjection of dipyrone or morphine. These results suggest that PAG-microinjected dipyrone triggers and/or potentiates local opioidergic circuits leading to descending inhibition of nociception, on the one hand, and to a local antiopioid action by cholecystokinin, on the other. Reiteration of these events would then result in an enhancement of cholecystokinin's antiopioid action and thus tolerance to opioids and dipyrone in the PAG.

Expression and activities of pancreatic enzymes in developing sea bass larvae ( Dicentrarchus labrax) in relation to intact and hydrolyzed dietary protein; involvement of cholecystokinin

In order to assess the influence of dietary protein on digestive enzyme expression and cholecystokinin (CCK) content in sea bass larvae, four groups of larvae were fed experimental diets from mouth opening until day 42: three isonitrogenous diets with increasing protein hydrolysate levels (0%, 14% and 46% of crude matter) and one diet incorporating starch. The groups fed high starch or high protein hydrolysate level exhibited the lowest growth. The final weight in these groups was 9.5 and 5.6 mg, respectively, whereas it reached approximately 20.0 mg in the groups fed 0% or 14% protein hydrolysate level. The highest levels of trypsin secretion were observed in larvae fed the lowest protein hydrolysate level. Paradoxically, the groups fed diet containing starch also exhibited a high trypsin secretion level. There was a clear allometric relationship between larval CCK content and body mass, but there were also differences between dietary groups. On day 42, the CCK level in the group fed diet incorporating starch (40 fmol/mg dry weight of larvae) was more than twice as high as that found in the other groups. The lowest CCK level (13 fmol/mg) was found in the group fed the highest protein hydrolysate level. Our data suggested that dietary protein level and chain length combined with protein intraluminal proteolytic activity regulate the CCK level in fish larvae as in other vertebrates. The CCK concentration assayed in larvae fed diets with a low protein content or different protein hydrolysate levels is compatible with the existence of an indirect mechanism controlling CCK release and mediating pancreatic enzyme secretion.

Melatonin MT1/2 receptor stimulation reduces cortical overflow of cholecystokinin-like material in a model of anticipation of social defeat in the rat

The involvement of cholecystokinin (CCK) in the potential anxiolytic-like effects of melatonin and of the antitumor MT1/2 receptor agonist, S23478, was assessed by measuring the cortical outflow of CCK-like material (CCKLM) in a rat model of anticipation of social defeat. After repeated social defeats by a male Tryon Maze Dull (TMD) rat, Sprague–Dawley (SD) rats were implanted for microdialysis in the frontal cortex and placed in the same environment as for the defeated sessions, but no confrontation with the TMD rat was allowed. Anticipation of social defeat induced anxiety-like behaviors (immobility, ultrasonic vocalization, defensive postures) associated with a significant increase (~+90%) in cortical CCKLM outflow in SD rats. Acute pretreatment with melatonin (5 or 40 mg/kg i.p.) or S23478, at 5 mg/kg i.p., had no or only minor effects on anxiety-like behaviors and did not affect CCKLM overflow. In contrast, at 40 mg/kg i.p., S23478 significantly reduced the duration of immobility and vocalization as well as the cortical CCKLM overflow (–30%) in defeated SD rats, and both effects were prevented by the MT1/2 receptor antagonist S22153 (40 mg/kg i.p.). These data indicated that MT1/2 receptor stimulation can exert anxiolytic-like effects associated with inhibition of cortical CCKergic neurotransmission in rats anticipating social defeat.

Cholecystokinin expression in the developing and regenerating pancreas and intestine.

In developmental terms, the endocrine system of neither the gut nor the pancreatic islets has been characterized fully. Little is known about the involvement of cholecystokinin (CCK), a gut hormone, involved in regulating the secretion of pancreatic hormones, and pancreatic growth. Here, we tracked CCK-expressing cells in the intestines and pancreata of normal mice (BALB/c), Non Obese Diabetic (NOD) mice and interferon (IFN)-gamma transgenic mice, which exhibit pancreatic regeneration, during embryonic development, the postnatal period and adulthood. We also questioned whether IFN-gamma influences the expression of CCK. The results from embryonic day 16 showed that all three strains had CCK in the acinar region of pancreata, and specifically in alpha cells that also expressed glucagon. However, in adulthood only BALB/c and NOD mice continued this pattern. By contrast, in IFN-gamma transgenic mice, CCK expression was suppressed from birth to 3 months of age in the pancreata but not intestines. However, by 5 months of age, CCK expression appeared in the regenerating pancreatic ductal region of IFN-gamma transgenic mice. In the intestine, CCK expression persisted from fetus to adulthood and was not influenced by IFN-gamma. Intestinal cells expressing CCK did not co-express glucagon, suggesting that these cells are phenotypically distinct from CCK-expressing cells in the pancreatic islets, and the effect of IFN-gamma on CCK varies depending upon the cytokine's specific microenvironment.

Feeding motivation in swine: Relation with insulin, glucose and free fatty acids in portal and jugular blood, and involvement of cholecystokinin

The control of feeding motivation was studied in eight castrated male pigs (92.9 ± 1.5 kg) surgically fitted with jugular and portal vein catheters. The first part of the experiment was set up as a cross-over design. Two weeks after surgery, four pigs were fasted for 24 h (FAST) while the remaining four were fed ad libitum (CTL). Three days later, the same procedure was repeated with the treatments reversed. Blood samples were collected every 4 h during the first 16 h of these two 24-h periods. After each 24-h period, pigs were subjected to a feed motivation test during which blood samples were obtained every 5 min for 60 min for CTL pigs and until 30 min after cessation of eating in FAST pigs. Three days later, the second part of the experiment was conducted. Five of the eight pigs were fasted for another 24 h, injected i.v. with 70 μg kg–1 BW of a cholecystokinin (CCK) receptor antagonist (MK-329), and subsequently subjected to a feed motivation test. Insulin, glucose and FFA concentrations were greater (P < 0.001) in portal than jugular blood. Fasting decreased insulin concentrations in both portal and jugular blood, decreased glucose in portal blood only, and increased FFA in jugular blood only. The number of pushes (P < 0.05), duration of eating (P < 0.001) and amount of feed eaten during the feed motivation test (P < 0.01) were all increased by fasting, and were further increased with MK-329 injection. Results indicate that CCK is involved in the control of satiety in pigs and that concentrations of insulin, glucose and FFA in the jugular vein may not always be representative of concentrations in the portal vein. Key words: Swine, insulin, glucose, cholecystokinin, feeding motivation, fast

Enhanced Cortical Extracellular Levels of Cholecystokinin-Like Material in a Model of Anticipation of Social Defeat in the Rat

The involvement of cholecystokinin (CCK) in the mechanisms of stress and/or anxiety was assessed by in vivo microdialysis in rats subjected to a social stress paradigm. During the initial 30 min period of each conditioning session, a male Sprague Dawley rat (intruder) was placed in a protective cage inside the cage of a male Tryon Maze Dull rat (resident), allowing unrestricted visual, olfactory, and auditory contacts but precluding close physical contact between them. During the following 15 min period, both the protective cage and the resident were removed (nondefeated intruders) or only the protective cage was removed allowing the resident to attack the intruder (defeated rats). This procedure was repeated once daily for 4 d. On the fifth day, a guide cannula was implanted into the prefrontal cortex of intruders. During a single 30 min test session, performed 4 d later, intruders were subjected to only the 30 min protected confrontation to the resident. Anxiety-like behavior (immobility, ultrasonic vocalizations, and defensive postures), associated with an increase (approximately +100% above baseline) in cortical outflow of CCK-like material (CCKLM), were observed in defeated intruders. Pretreatment with diazepam (5 mg/kg, i.p.), but not buspirone (0.5-2 mg/kg, i.p.), prevented both the anxiety-related behavior and CCKLM overflow. The selective CCK-B receptor antagonist CI-988 (2 mg/kg, i.p.) reduced the anxiety-like behavior without affecting the increase in CCKLM outflow. These data indicate that anticipation of social defeat induces a marked activation of cortical CCKergic neurons associated with anxiety-related behaviors in rats.

Cholecystokinin and panic disorder: Past and future clinical research strategies

The involvement of cholecystokinin (CCK) in human anxiety is well documented. Exogenous administration of CCK-2 receptor agonists, such as cholecystokinin-tetrapeptide and pentagastrin, provoke panic attacks in man. Patients with panic disorder (PD) are hypersensitive to CCK-2 receptor stimulation compared to healthy volunteers and patients with other anxiety disorders, and they differ from healthy subjects in CCK metabolism and genetic characteristics of the CCK-2 receptor system. This article reviews the corpus of work supporting the role of CCK in anxiety and suggests three research approaches which can further enhance our understanding of the CCK-2 system in PD. These approaches include: i) searching for a specific anomaly of the CCK-2 receptor system, ii) establishing a relationship between CCK-2 receptor polymorphism and vulnerability to pharmacologically-induced or spontaneous panic attacks, and iii) evaluating the therapeutic efficacy of CCK-2 receptor antagonists which possess adequate pharmacokinetic properties.

Effects of lorglumide and atropine on MgSO4-induced gallbladder emptying in conscious dogs

The aim of the study was to examine the possible involvement of cholecystokinin (by lorglumide) and cholinergic mechanisms (by atropine) in magnesium sulphate (MgSO4)-induced gallbladder contraction of conscious dogs. The gallbladder (GB) volume was determined by ultrasonography. The optimal dose of 80mg kg–1of MgSO4was determined from a MgSO4dose–response curve using doses of 10, 20 ,40, 80, 120mg kg–1. The largest dose of MgSO4was less effective than the optimal dose. Peak gallbladder contraction (32 per cent) was achieved at 30 minutes. Atropine (50μg kg–1s.c.) or lorglumide (1mg kg–1p.o.) fully prevented GB contraction. In conclusion, supraoptimal doses of MgSO4have a diminishing effect. The sustained contraction of the gallbladder in response to the optimal dose of MgSO4can be explained by an additive effect of the cholecystokinin release and a cholinergic trigger mechanism. Ultrasonography and MgSO4stimulation proved to be a valuable technique for examination of gallbladder motility.

Involvement of cholecystokinin A receptors in transient lower esophageal sphincter relaxations triggered by gastric distension

Objective: Transient lower esophageal sphincter relaxations (TLESRs) are the main mechanism underlying gastroesophageal reflux. In the present study we evaluated the effect of loxiglumide, a specific cholecystokinin A (CCK A)-receptor antagonist, on the occurrence of TLESRs evoked by gastric distension. Methods: Eight healthy subjects underwent esophageal manometry using a 10-lumen sleeve assembly during placebo or loxiglumide (10 mg/kg/h) in a randomized double-blind order. Gastric distension was induced by inflation of 400 ml of air. Results: Basal lower esophageal pressure (LESP) and swallow-induced relaxation were not affected by loxiglumide. Loxiglumide significantly reduced the number of TLESRs, from 11.5 (5.8–18.3) to 6.0 (3.3–14.3) during the total recording period of 1 h, and from 5.5 (4.25–7.5) to 2.0 (0.5–6.8) during the first 15 min. The number of common cavities was significantly decreased by loxiglumide, from 8.0 (4.0–20.0) to 5.0 (2.0–7.8). TLESRs represented the main mechanism (60% during placebo, 74% during loxiglumide) underlying common cavities, followed by swallow-induced relaxation. Conclusions: Loxiglumide significantly reduces the number of TLESRs triggered by gastric distension without interfering with swallow-related relaxation of the lower esophageal sphincter, suggesting the involvement of CCK A receptors in the reflex pathway mediat-ing TLESRs.