Supplementation by thylakoids to a high carbohydrate meal decreases feelings of hunger, elevates CCK levels and prevents postprandial hypoglycaemia in overweight women.

Thylakoids are chlorophyll-containing membranes in chloroplasts that have been isolated from green leaves. It has been previously shown that thylakoids supplemented with a high-fat meal can affect cholecystokinin (CCK), ghrelin, insulin and blood lipids in humans, and can act to suppress food intake and prevent body weight gain in rodents. This study investigates the addition of thylakoids to a high carbohydrate meal and its effects upon hunger motivation and fullness, and the levels of glucose, insulin, CCK, ghrelin and tumour necrosis factor (TNF)-alpha in overweight women. Twenty moderately overweight female subjects received test meals on three different occasions; two thylakoid enriched and one control, separated by 1 week. The test meals consisted of a high carbohydrate Swedish breakfast, with or without addition of thylakoids. Blood samples and VAS-questionnaires were evaluated over a 4-h period. Addition of thylakoids suppressed hunger motivation and increased secretion of CCK from 180 min, and prevented postprandial hypoglycaemia from 90 min following food intake. These effects indicate that thylakoids may intensify signals of satiety. This study therefore suggests that the dietary addition of thylakoids could aid efforts to reduce food intake and prevent compensational eating later in the day, which may help to reduce body weight over time.

The acute effects of olanzapine on ghrelin secretion, CCK sensitivity, meal size, locomotor activity and body temperature.

OBJECTIVE: Significant weight gain is a problematic side effect of treatment with the antipsychotic drug olanzapine (OLA). Previous studies in rats suggest that one of the contributing factors is an impairment in satiation that results in increased food intake. However, the mechanisms underlying this impairment in satiation remain largely unclear. METHODS AND RESULTS: In this study, we determined the effect of OLA on levels of leptin, insulin, ghrelin, cholecystokinin (CCK), glucagon-like peptide-1, peptide YY and amylin in male rats that had received a fixed amount of food. OLA did not affect the secretion of any of these hormones, except for ghrelin levels, which were increased compared with controls. Furthermore, when ghrelin levels were determined in rats just before they received their meal, OLA caused a significant increase in ghrelin levels compared with controls, whereas OLA failed to affect baseline ghrelin levels. Next, we investigated the effect of OLA on the efficacy of CCK to reduce meal size. With coadministration, OLA pretreatment counteracted the reduction in meal size by CCK, although there was no significant interaction between the treatments. Finally, telemetry measurements revealed that acute OLA treatment causes a temporary decrease in both locomotor activity and body core temperature. CONCLUSION: Taken together, this study shows that acute injection of OLA selectively increases meal-related ghrelin secretion and this may partially underlie the impairment in satiation by OLA.

Acute and chronic effects of dietary fatty acids on cholecystokinin expression, storage and secretion in enteroendocrine STC-1 cells.

Cholecystokinin (CCK) is a peptide hormone secreted from the I-cells of the intestine and it has important physiological actions related to appetite regulation and satiety. In this study we used STC-1 cells to investigate the effects of common dietary-derived fatty acids (FAs) on I-cell secretory function and metabolism. We extend earlier studies by measuring the acute and chronic effects of 11 FAs on CCK secretion, cellular CCK content, CCK mRNA levels, cellular DNA synthesis, cellular viability and cytotoxicity. FAs were selected in order to assess the importance of chain length, degree of saturation, and double bond position and conformation. The results demonstrate that secretory responses elicited by dietary FAs are highly selective. For example, altering the conformation of a double bond from cis to trans (i.e. oleic acid versus elaidic acid) completely abolishes CCK secretion. Lauric acid appears to adversely affect I-cell metabolism and arachidonic acid suppresses DNA synthesis. Our studies reveal for the first time that conjugated linoleic acid isoforms are particularly potent CCK secretagogues, which also boost intracellular stores of CCK. These actions of conjugated linoleic acid may explain satiating actions observed in dietary intervention studies.

The roles of nerve growth factor and cholecystokinin in the enhancement of morphine analgesia in a rodent model of central nervous system inflammation.

Animal models of inflammatory pain are characterized by the release of inflammatory mediators such as cytokines and neurotrophic factors, and enhanced analgesic sensitivity to opioids. In this study, we examine the mechanisms underlying this effect, in particular the roles of cholecystokinin (CCK) and nerve growth factor (NGF), in an animal model of central nervous system (CNS) inflammation induced by spinal administration of lipopolysaccharide (LPS). Although spinal administration of LY-225910 (25 ng), a CCK-B antagonist, enhanced morphine analgesia in naïve rats, it was unable to do so in LPS-treated animals. Conversely, spinal CCK-8S administration (1 ng) decreased morphine analgesia in LPS-treated rats, but not in naïve animals. Further, spinal anti-NGF (3 microg) was able to reduce morphine analgesia in LPS-treated rats, but not in naïve animals, an effect that was reversed by spinal administration of LY-225910. While CCK-8S concentration was increased in spinal cord extracts of LPS animals as compared to controls, morphine-induced spinal CCK release in the extracellular space, as measured by in-vivo spinal cord microdialysis was inhibited in LPS animals as compared to controls, and this was reversed by anti-NGF pretreatment. Finally, chronic spinal administration of beta-NGF (7 microg/day) for 7 days enhanced spinal morphine analgesia, possibly by mimicking a CNS inflammatory state. We suggest that in intrathecally LPS-treated rats, spinal CCK release is altered resulting in enhanced morphine analgesia, and that this mechanism may be regulated to an important extent by NGF.

Role of CCK and potential utility of CCK1 receptor antagonism in the treatment of pancreatitis induced by biliary tract obstruction.

BACKGROUND AND PURPOSE: Cholecystokinin (CCK) stimulates the release of amylase and lipase from the normal pancreas. However, it is not clear to what extent this occurs in the early stages of pancreatitis induced by biliary tract obstruction in the rat and whether CCK initiates an inflammatory cascade in this condition. EXPERIMENTAL APPROACH: Selective CCK1 receptor antagonists, JNJ-17156516 ((S)-(3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionic acid) and dexloxiglumide, were used to assess the response of plasma amylase and lipase to a CCK analogue, CCK8S, in normal rats and in rats with bile duct ligation. KEY RESULTS: Both antagonists suppressed CCK8S-induced elevation of plasma amylase activity in normal rats. JNJ-17156516 was more potent than dexloxiglumide (ED(50)=8.2 vs >30 micromol kg(-1) p.o.) and produced a longer lived inhibition (6 vs 2 h). Plasma amylase and lipase activity were elevated in parallel to CCK plasma concentrations after bile duct ligation and both activities were suppressed in a dose-dependent manner by JNJ-17156516 and dexloxiglumide. JNJ-17156516 was approximately 5- to 10-fold more potent than dexloxiglumide. Infusion of CCK8S to naïve rats to achieve levels similar to those observed after bile duct ligation (20 pM) increased plasma amylase activity and activated nuclear factor-kappaB in the pancreas. These effects were prevented by pretreatment with JNJ-17156516. CONCLUSIONS AND IMPLICATIONS: The elevation of plasma amylase and lipase activity in the early stages of obstruction-induced pancreatitis is largely driven by elevation of plasma CCK concentration and activation of CCK1 receptors. These data show that CCK is an initiating factor in acute pancreatitis in the rat.

Free fatty acids induce cholecystokinin secretion through GPR120.

The ingestion of fat induces secretion of the gut peptide hormone cholecystokinin (CCK); however, the mechanism responsible for lipid-induced CCK release remains unknown. Recently, a group of free fatty acid (FFA) receptors, which includes the long-chain FFA receptors GPR120 and GPR40, has been identified. In this study, we examined whether these FFA receptors mediate lipid-induced CCK release in the mouse. We first observed that intra-gastric administration of long-chain FFAs increased plasma CCK levels. Using mouse enteroendocrine STC-1 cells as a model system, we further studied the mechanism of this FFA-induced CCK secretion. Long-chain FFAs promoted CCK secretion from STC-1 cells, which was abolished either by removal of extracellular Ca2+ or by the L-type Ca2+ channel blocker nicardipine. Furthermore, this FFA-induced CCK secretion was specifically inhibited by transfection of GPR120-specific, but not GPR40-specific, short hairpin RNA. These results indicate that long-chain FFAs induce CCK secretion through GPR120-coupled Ca2+ signaling.

RB101-mediated protection of endogenous opioids: potential therapeutic utility?

The endogenous opioids met- and leu-enkephalin are inactivated by peptidases preventing the activation of opioid receptors. Inhibition of enkephalin-degrading enzymes increases endogenous enkephalin levels and stimulates robust behavioral effects. RB101, an inhibitor of enkephalin-degrading enzymes, produces antinociceptive, antidepressant, and anxiolytic effects in rodents, without typical opioid-related negative side effects. Although enkephalins are not selective endogenous ligands, RB101 induces these behaviors through receptor-selective activity. The antinociceptive effects of RB101 are produced through either the mu-opioid receptor alone or through activation of both mu- and delta-opioid receptors; the antidepressant-like and anxiolytic effects of RB101 are mediated only through the delta-opioid receptor. Although little is known about the effects of RB101 on other physiologically and behaviorally relevant peptides, these findings suggest that RB101 and other inhibitors of enkephalin-degrading enzymes may have potential as novel therapeutic compounds for the treatment of pain, depression, and anxiety.

Effects of combined oleoyl-estrone and rimonabant on overweight rats.

Oleoyl-estrone (OE) decreases appetite, maintains energy expediture, induces lipolysis (sparing protein), and decreases cholesterolemia and insulin resistance. Rimonabant (SR141716) is a cannabinoid-receptor inhibitor that decreases appetite and mobilizes fat. We studied whether their combination improves their slimming effects. Male overweight rats received daily gavages of 5.3 mg/kg OE, 10 mg/kg rimonabant, or both drugs during 10 days. Body weight and composition, energy balance, adipose tissue weight, and serum hormones and metabolites were measured. OE halved food intake and maintained energy expenditure at the expense of body fat. Rimonabant effects on appetite and energy balance were less marked, resulting in lower lipid mobilization. OE and rimonabant followed the OE pattern, with no additive or synergic effects. Glycemia was maintained, but OE decreased insulin, GLP-1, and cholesterol, whilst rimonabant increased cholecystokinin and cholesterol, and decreased NEFA. Both drugs decreased leptin and triacylglycerols; ghrelin was unchanged. The results hint at different mechanisms of action of both drugs: we can assume that OE effects do not involve the cannabinoid pathway. OE does not seem to act, either, after 10 days, through the secretion of ghrelin or the intestinal appetite-controlling peptides tested.

Effects of an antiandrogenic oral contraceptive on appetite and eating behavior in bulimic women.

High androgen levels in women with bulimia nervosa may promote bulimic behavior. The aim of the present study was to investigate the effects of an antiandrogenic oral contraceptive (OC) on appetite and eating behavior in women with bulimia nervosa compared to healthy controls. Twenty-one women with bulimia nervosa and 17 healthy controls matched for age and body mass index participated in the study. Basal and meal-related appetite and secretions of the satiety peptide cholecystokinin (CCK) and the appetite-stimulating peptide ghrelin were studied before and after 3 months of treatment with an antiandrogenic OC (30 microg ethinyl estradiol combined with 3 mg drospirenone). Bulimic behavior was evaluated in relation to changes in hormone levels. Before treatment, bulimic women had higher frequency of menstrual disturbances, acne and hirsutism and higher levels of testosterone but lower meal-related CCK secretion than controls. OC treatment reduced meal-related hunger and gastric distention in bulimics. CCK secretion in response to the meal was unchanged in bulimic women but decreased in the controls. Ghrelin secretion was comparable between groups and did not change in response to OC treatment. The treatment improved bulimic behavior in relation to a decline in testosterone levels in the entire group. Our results support the suggestion that androgens play a role in bulimic behavior. Treatment with an antiandrogenic OC may serve as a new strategy for treatment of bulimia nervosa and particularly in those patients with hyperandrogenic symptoms.

Pork peptone stimulates cholecystokinin secretion from enteroendocrine cells and suppresses appetite in rats.

We found that soybean beta-conglycinin peptone (BconP) suppresses food intake through cholecystokinin (CCK) release from enteroendocrine cells in association with binding of the peptone to rat small intestinal brush border membrane (BBM). The aim of the present study was to find new appetite suppressing peptides. Peptones from chicken, pork, beef, beef liver, and egg white were examined for activities to bind with rat BBM, CCK-release from enteroendocrine cell line STC-1, and induce satiety in rats. Chicken and pork peptone (ChickP and PorkP) bound to BBM with highest ability as evaluated with a surface plasmon biosensor. PorkP and ChickP released CCK in higher amounts than BconP from STC-1 cells dose-dependently, with highest stimulation by PorkP. An orogastric preload of PorkP, but not ChickP, suppressed food intake similarly to BconP, dose-dependently. These results suggest that PorkP interacts directly with the small intestinal CCK cells to release CCK, and that it suppresses appetite in rats.

Involvement of endogenous cholecystokinin in tolerance to morphine antinociception in the nucleus accumbens of rats.

Cholecystokinin (CCK) is an endogenous anti-opioid peptide in the central nervous system. The present study investigated the effects of endogenous CCK on tolerance to morphine antinociception in the nucleus accumbens (NAc) of rats. Chronic administration of morphine to NAc induced marked tolerance to antinociception. Intra-NAc administration of the CCK2 receptor antagonist LY225910 inhibited not only the development but also the expression of chronic morphine-induced antinociceptive tolerance. However, intra-NAc injection of LY225910 did not influence the antinociception induced by intra-NAc administration of morphine in the intact rats. The results indicate that endogenous CCK plays an important role in morphine-induced antinociceptive tolerance in the NAc of rats.

Clinical application of an enzyme immunoassay for cholecystokinin-like immunoreactive substance for determination of the human plasma levels: the effect of metoclopramide on gastrointestinal peptides and stress-related hormones.

Metoclopramide, a prokinetic drug, is widely used to treat vomiting and nausea. Delayed gastric emptying and continual stress are considered important factors, among others, that induce nausea and vomiting. One gastrointestinal motility regulatory factor has been assumed to be the induction of changes in the levels of peptides such as gastrin, somatostatin, motilin, and cholecystokinin (CCK) in plasma. In contrast, adrenocorticotropic hormone (ACTH) and cortisol are used as indicators of stress. Here, we studied the effects of metoclopramide on human plasma gastrin-, somatostatin-, motilin-, and CCK-like immunoreactive substances (ISs) and ACTH-IS and cortisol under stress conditions using repetitive blood sampling in healthy subjects. Metoclopramide hydrochloride at a dose of 30 mg or placebo was orally administered to five healthy male volunteers. Blood samples were taken before and 20, 40, 60, 90, 120, 180, and 240 min after administration, subject to extracting procedures, and submitted to a highly sensitive enzyme immunoassay system. A single administration of metoclopramide caused significant increases in plasma somatostatin-IS levels compared with the placebo. Metoclopramide significantly decreased plasma gastrin- and suppressed ACTH-IS and cortisol levels compared with the placebo. We hypothesize that metoclopramide might have an accelerating gastric-emptying effect and a modulatory effect on the hypothalamo-pituitary-adrenal (HPA) axis and the autonomic nervous function. These effects might be beneficial in stress-related diseases, which suggest that this medicine has clinicopharmacological activities.

Role of free fatty acids in regulating gastric emptying and gallbladder contraction.

The limited effectiveness of orlistat, an inhibitor of gastrointestinal lipases, in inhibiting fat digestion is not completely understood. Therefore we studied the effect of orally and duodenally administered orlistat on gastric emptying, cholecystokinin (CCK) secretion, and gallbladder contraction. In healthy males, gastric emptying of solids and fat were quantified scintigraphically, gallbladder contraction by ultrasound and CCK release by radioimmunoassay. Three studies were performed: (1) oral and (2) duodenal orlistat with a fat-containing meal, and (3) duodenal orlistat with a fat-free meal. Gastric emptying rates of solids and fat (T50% accelerated by 16 and by 22%, p < 0.05, respectively) were significantly faster after duodenal perfusion of orlistat; gallbladder contraction and CCK release were reduced under these conditions (p < 0.005, respectively). With oral orlistat no significant effect was documented on these parameters. We conclude that fat hydrolysis is essential in the regulation of fat-induced gastric emptying and gallbladder contraction.

Proglumide attenuates experimental colitis in rats.

Ulcerative colitis is associated with altered contractile activity and transit time of colon. On the other hand, cholecystokinin (CCK) has been shown to play an important role in regulation of gastrointestinal motor function including colonic contraction and transit. In the present study, an attempt was made to study the effect of proglumide, a CCK receptor antagonist on experimental colitis in rats. Experimental colitis was induced in male Sprague-Dawley rats by instilling 1 ml of 4% acetic acid followed by flushing with 0.5 ml air. The rats were kept in a head-down position for 30s. Finally, each rat received 1.5 ml colonic wash with 1.5 ml saline. Four groups of rats received proglumide orally (0, 250, 500 and 1000mg/kg). The first dose of proglumide was given 1 h before acetic acid challenge, whereas the second dose of proglumide was given 25 h after the first dose. Sham control rats received an equal volume of saline instead of acetic acid. Forty-eight hours after the acetic acid challenge, the colon was removed, weighed and split longitudinally and scored for injury. Part of the colon was used for histopathological study as well as analysis of myeloperoxidase (MPO) activity (as a marker of neutrophil activity). Acetic acid produced severe diarrhea and exfoliation of the colonic epithelium accompanied by extensive destruction of the mucosal interstitium. Proglumide dose dependently protected rats against acetic acid-induced increase in colon weight, diarrhea, MPO activity and colonic injury. Inhibition of CCK exerts a beneficial effect in experimental colitis. Further studies are warranted to determine the mechanism of protection and the therapeutic potential of CCK inhibitors.

Effects of lipopolysaccharide treatment on feeding of goldfish: role of appetite-regulating peptides.

The gram-negative bacteria-derived endotoxin lipopolysaccharide (LPS) is known to play an important role in immune and neurological manifestations during bacterial infections. In mammals, peripheral or brain administration of LPS induces anorexia and is thought to exert its effects through activation of pro-inflammatory cytokines. In this study, we investigated the effects of peripheral (intraperitoneal, IP) and central (intracerebroventricular, ICV) injections of LPS on food intake of goldfish. Fish treated IP with 10, 25, 50, 100 or 250 ng/g LPS or ICV with 1, 10 and 100 ng/g LPS showed a significant dose-dependent decrease in food intake, compared to the saline-treated fish. We also examined the brain mRNA expression of several hypothalamic appetite-related neuropeptides in response to the administration of LPS. IP injections of LPS (100 ng/g) induced a decrease in NPY expression and an increase in CCK, CRF and CART expression. These results indicate that LPS is a potent anorexigenic factor in goldfish and that this endotoxin induces a reduction in appetite, at least in part, by influencing gene expression of appetite-related neuropeptides.

Prostaglandins mediate lipopolysaccharide effects upon cholecystokinin and neurotensin phenotypes in neuroendocrine corticotropin-releasing hormone neurons: in situ hybridization evidence in the rat.

Intraperitoneal injection of the endotoxin lipopolysaccharide produces an inflammation accompanied by immune system activation and secretion of cytokines that stimulate the hypothalamo-pituitary-adrenal (HPA) axis to release the anti-inflammatory corticosterone. Upstream in HPA axis are neuroendocrine corticotropin-releasing hormone neurons in the paraventricular nucleus whose multipeptidergic phenotype changes during inflammation: coexisting corticotropin-releasing hormone and cholecystokinin mRNAs are up-regulated whereas neurotensin mRNA expression is induced de novo. These changes may be mediated by prostaglandins released from perivascular and microglial cells in response to circulating cytokines. We examined by quantitative in situ hybridization histochemistry whether blockade of prostaglandin synthesis by indomethacin alters phenotypic expression in paraventricular nucleus neurons after lipopolysaccharide. Because indomethacin also elevated circulating corticosterone, animals were adrenalectomized and corticosterone replaced. Results showed that i.p. indomethacin administration suppressed lipopolysaccharide effects in a phenotype non-specific manner: one injection was sufficient to prevent both the increase in corticotropin-releasing hormone and cholecystokinin mRNAs expression and the induction of neurotensin mRNA expression. Therefore, neuroendocrine corticotropin-releasing hormone neurons with different peptidergic phenotypes appear to respond as a whole in the acute phase response to systemic infection.

Cholecystokinin secretagogue-induced gastroprotection: role of nitric oxide and blood flow.

This study was done to examine the role of CCK in gastric mucosal defense and to assess the gastroprotective roles of nitric oxide and blood flow. In rats, the CCK secretagogues oleate and soybean trypsin inhibitor augmented gastric mucosal blood flow and prevented gastric injury from luminal irritants. Type A CCK receptor blockade negated CCK secretagogue-induced gastroprotection and exacerbated gastric injury from bile and ethanol but did not block adaptive cytoprotection. CCK secretagogue-induced gastroprotection and hyperemia were negated by nonselective nitric oxide synthase (NOS) inhibition (N(G)-nitro-L-arginine methyl ester) but not by selective inducible NOS inhibition (aminoguanidine). Gastric mucosal calcium-dependent NOS activity, but not calcium-independent NOS activity, was increased following CCK and CCK secretagogues. The release of endogenous CCK plays a role in the intrinsic gastric mucosal defense system against injury from luminal irritants. The protective mechanism appears to involve increased production of nitric oxide from primarily the constitutive isoforms of NOS and a resultant increase in blood flow.

CCK expression in enteroendocrine cell is regulated by soluble factor(s) from underlying fibroblasts.

Studies on the cross-talk between the intestinal epithelium and the underlying connective tissue have concentrated on enterocytes. In contrast, little is known about the interactions between the mesenchymal compartment and the enteroendocrine cells, scattered among the other cell types of the epithelium. To address this question, a panel of coculture systems between the enteroendocrine STC-1 cell line and three intestinal myofibroblastic cell lines (MIC) was used in order to assess different levels of regulation, namely cell-cell and cell-matrix interactions, and the role of diffusible factors. We demonstrate that the expression of cholecystokinin, a typical intestinal hormone produced by STC-1 cells, is up-regulated in the presence of a fibroblastic environment through a paracrine pathway involving FGF2. Concomitantly, STC-1 cell morphology and proliferation were also modulated, but through distinct mechanisms according to the origin of fibroblasts. The results reveal definite epithelio-mesenchymal interactions that may be critical for the maintenance of phenotype and function of enteroendocrine cells.

Eradication of Helicobacter pylori restores the inhibitory effect of cholecystokinin on gastric motility in duodenal ulcer patients.

BACKGROUND: Increased gastric emptying and defective action of endogenous cholecystokinin (CCK), that is known to inhibit this emptying, have been implicated in the pathogenesis of duodenal ulcer (DU). The aim of this double blind study was to assess whether CCK and somatostatin participate in the impairment of gastric motility in active DU patients before and after Helicobacter pylori eradication. METHODS: Tests were undertaken in 10 DU patients without or with elimination of the action of endogenous CCK using loxiglumide, a selective CCK-A receptor antagonist, before and 4 weeks after eradication of H. pylori with 1 week triple therapy that resulted in healing of all DUs tested. The gastric emptying rate after feeding was determined using the 13C-acetate breath test. Before each test, samples of gastric juice were obtained by aspiration using a nasogastric tube for determination of somatostatin using specific radioimmunoassay. RESULTS: Prior to H. pylori eradication gastric emptying half-time was 31 +/- 6 min in placebo-treated DU patients and this emptying rate was not significantly affected in tests after pretreatment with loxiglumide (10 mg/kg i.v.). Following eradication of H. pylori, in tests with placebo gastric emptying half-time was significantly longer (48 +/- 9 min) compared to that prior to H. pylori eradication. Pretreatment with loxiglumide in H. pylori eradicated DU patients significantly enhanced the gastric emptying rate with an emptying half-time of only 33 +/- 4 min. Eradication of H. pylori resulted in a significant increase in somatostatin concentration in gastric juice and loxiglumide significantly reduced this luminal somatostatin in H. pylori-eradicated subjects compared to values before anti-H. pylori therapy. CONCLUSIONS: 1) H. pylori infection in DU patients is accompanied by enhanced gastric emptying and reduction in luminal release of somatostatin; 2) the failure of loxiglumide to affect gastric emptying in H. pylori-infected DU patients might be attributed, at least in part, to the failure of endogenous CCK to control gastric motility due to deficient release of somatostatin; and 3) H. pylori-infected patients appear to exhibit a deficient somatostatin release by endogenous CCK that can be reversed by the eradication of H. pylori indicating that both CCK and somatostatin may contribute to normalization of gastric emptying following H. pylori eradication in DU patients.

Activation of CB1 cannabinoid receptors in rat hippocampal slices inhibits potassium-evoked cholecystokinin release, a possible mechanism contributing to the spatial memory defects produced by cannabinoids.

Cannabinoid use is known to disrupt learning and memory in a number of species. cholecystokinin (CCK) release and CCK receptors have been implicated in spatial memory processes in rodents. Rat hippocampal CCK interneurons express cannabinoid 1 receptors (CB1). The CB1 agonist R(+)WIN 55,212-2 (WIN+), at 1 and 10 micromol, strongly inhibited potassium-evoked CCK release from rat hippocampal slices, while the inactive isomer S(-)WIN,55,212-3 (WIN-) had no effect. CCK release from cerebral cortical slices was not altered by WIN+.