Camostate- and caerulein-induced delay of gastric emptying in the rat: effect of CCK receptor antagonists

The effect of camostate, a potent releaser of endogenous cholecystokinin (CCK), and of caerulein, an amphibian peptide mimicking the biological actions of CCK, as well as of selective CCK receptor antagonists on gastric emptying of liquids was studied in the rat. Oral administration of camostate (200 mg/kg with the liquid test meal preceded by the same dose 10 min before the meal) significantly delayed gastric emptying of saline, an effect which was completely blocked by previous administration of the CCKA receptor antagonist, devazepide, at a dose (1 mg/kg i.v.) unable to modify the emptying rate when administered alone. Caerulein (0.03-30 nmol/kg i.v.) also delayed the emptying rate in a dose-dependent manner, with an ID50 of 3.94 nmol/kg. The effect of the peptide was also inhibited by devazepide. The CCKB receptor antagonist, L365,260 (3R-(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1, 4-benzodiazepine-3-yl)-N'-(3-methylphenyl)-urea; 3 mg/kg i.v.), was completely unable to modify the CCK (both endogenous and exogenous)-induced delay in gastric emptying. Repeated (7 days) camostate administration did not modify the gastric motor response to endogenous CCK, thus, suggesting that adaptation did not take place. These results demonstrate that endogenous and exogenous CCK delays gastric emptying of liquids through stimulation of CCKA receptors and suggest that adaptation of the gastric motor response to CCK does not occur.     

Vasopressin dilates the rat carotid artery by stimulating V1 receptors

1. The effect of the intraperitoneal administration of cholecystokinin sulphated octapeptide (CCK-8S) (10 nmol/kg i.p.) on endogenous levels of several amino acids in five areas of the rat brain was analyzed. The olfactory bulb, hypothalamus, hippocampus, cerebral frontal cortex, and corpus striatum were evaluated. In addition, the effects of CCK-8S and PD 135,158 (1 mg/kg), a selective CCK(B) antagonist, on the performance of rats submitted to a dark/light transition test were also studied. 2. Upon administration of CCK-8S, the concentration of glutamate was reduced (27%) in the olfactory bulb. The same was observed when the levels of glycine (31%) or alanine (43%) were determined. No significant effects were produced by CCK-8S on cortical and hypothalamic levels. In the hippocampus, the concentration of both glutamate (27%) and taurine (29%) were reduced, whereas the levels of GABA in the striatum (29%) were increased. 3. After a single injection of CCK-8S, the time spent by the rats in the illuminated site of the dark/light transition test box, was not changed. On the contrary, the administration of PD 135,158 increased the time spent in the lighted compartment. 4. These results show that systemic administration of CCK-8S produced regional specific changes in brain amino acids, without producing any significant behavioral modification in the rat exposed to a dark/light box. In contrast, the selective CCKB receptor antagonist, PD 135,158, induces anxiolytic-like action in an animal model of anxiety.     

CCK receptor antagonists in animal models of anxiety: comparison between exploration tests, conflict procedures and a model based on defensive behaviours

The present experiments compared the behavioural effects of one cholecystokininA (CCKA; lorglumide) and two CCKB (PD 135,158 and LY 288513) receptor antagonists in classical animal models of anxiety, including conflict tests (punished lever pressing and Vogel drinking tests in rats) and exploratory models (elevated plus-maze test in rats and light/dark choice test in mice), and a recently developed mouse defence test battery (MDTB) which has been validated for the screening of both anti-panic and classical anxiolytic (i.e. benzodiazepines) drugs. Diazepam was used as a positive control. Results showed that all three CCK receptor antagonists were inactive in both conflict tests. Furthermore, despite the incorporation of more ethologically-derived measures (i.e. risk assessment activities or directed exploration, or both) no effects were observed in the elevated plus-maze and in the light/dark tests. These profiles contrast with that of diazepam which displayed clear anxiolytic-like effects in these models. In the MDTB, the CCK receptor antagonists failed to modify parameters (i.e. risk assessment, defensive threat/attack and escape attempts), which have been shown to be particularly sensitive to drugs effective in the treatment of generalized anxiety. By contrast, the CCKB receptor antagnoists PD 135,158 (0.001-0.01, 1 mg/kg, i.p.) and LY 288513 (1 and 3 mg/kg, i.p.) significantly decreased avoidance distance when the rat was first placed in the test apparatus, an effect which is consistent with an anti-panic-like action. Overall, these findings support the idea that classical animal models of anxiety may not be suitable for evaluation of the behavioural effects of CCK receptor antagonists, whereas tests which may model certain aspects of human panic such as the MDTB appear to be more reliable tools when screening such compounds.     

PEDB: the Prostate Expression Database

Naloxone is generally considered to be a pure antagonist, but it may produce several behavioral effects, such as hyperalgesia or stimulation of respiration. We studied the effect of naloxone on gastric emptying and gastrointestinal transit in rats. Six to eight Wistar rats (200-250 g) were used for each experiment. Either saline or naloxone (0.01-10 mg/kg) was injected intraperitoneally at 0 min. At 30 min, radiolabeled saline or milk 1 mL was infused into the stomach. At 60 min, gastric emptying and gastrointestinal transit were calculated by measuring the radioactivity in the gastrointestinal tract. Naloxone significantly inhibited gastric emptying of saline (P = 0.002) and of milk (P < 0.05), but not the gastrointestinal transit of either (P > 0.05). Gastric emptying of saline showed a significant peak (P < 0.05) in the dose-response curve at 0.7 mg/kg. Therefore, naloxone significantly inhibits gastric emptying of saline and milk, but not the gastrointestinal transit of either. IMPLICATIONS: Although naloxone is generally considered to be a pure opioid receptor antagonist, it delays gastric emptying of saline or milk, as does morphine in the rat. However, it is uncertain from our results whether naloxone inhibited gastric emptying by antagonizing the effects of endogenous opioids.     

The effect of centrally administered CCK-receptor antagonists on food intake in rats

Cholecystokinin (CCK) receptors are classified as two subtypes, designated CCK(A) and CCK(B), and both subtypes are found in brain and peripheral tissues of rats. CCK-8 has been shown to act peripherally to reduce meal size, and this satiating action can be blocked by CCK(A)-receptor antagonists. Recent evidence suggests that, in addition to the peripheral action of CCK, central CCK mechanisms may also be involved in satiety. Central administration of proglumide, a mixed CCK-receptor antagonist (CCK(A) > CCK(B)) has been shown to increase food intake and block the satiating effect of peripherally administered CCK-8 (15). In an attempt to replicate and extend these results, rats were given injections of proglumide or selective CCK-receptor antagonists into the lateral ventricle prior to a peripheral injection of CCK-8 or saline. Only proglumide stimulated an increase in 30-min test meal intake and attenuated the satiating effect of CCK-8. Two selective CCK(A)-receptor antagonists, lorglumide and devazepide, did not increase intake significantly when given alone, and they did not attenuate the effect of peripherally administered CCK-8. The selective CCK(B)-receptor antagonist, L365,260, reduced intake at all doses tested except the lowest. The lowest dose did not increase intake when given alone and did not attenuate the inhibitory effect of CCK on test-meal intake. Finally, a combination of devazepide and L365,260 did not increase intake or block the effect of peripherally administered CCK-8. These results suggest that CCK released by neurons in the brain and acting on central CCK(A)- and CCK(B)-receptors is not necessary for the control of meal size or for the satiating effect of peripherally administered CCK-8 in rats under our experimental conditions.     

Glucagon-like peptide-1 retards gastric emptying and small bowel transit in the rat: effect mediated through central or enteric nervous mechanisms

This study investigated effects of glucagon-like peptide-1(7-36)amide (GLP-1) on gastric emptying, small intestinal transit, and contractility of smooth muscle strips in rats. GLP-1 at doses of 10 and 20 pmol/kg/min administered intravenously dose-dependently retarded transit of the small intestine (P < 0.001), while only the higher dose of 20 pmol/kg/min retarded gastric emptying (P < 0.01). GLP-1 at concentrations up to 10(-4) M did not affect the basal tone or contractility of the gastrointestinal muscle strips that were stimulated with electric field stimulation or acetylcholine. Our results demonstrate that small intestinal transit seems more sensitive than gastric emptying to inhibition by GLP-1 at physiologic levels in plasma. Furthermore, this inhibition appears to be mediated through central mechanisms rather than through peripheral actions. Thus, GLP-1 is suggested to inhibit gastric emptying and small intestinal transit through an indirect effect via central or enteric nervous mechanisms.     

The effect of octreotide on gastric emptying at a dosage used to prevent complications after pancreatic surgery: a randomised, placebo controlled study in volunteers

BACKGROUND: Octreotide is used in many centres to prevent complications after pancreatic surgery. Delayed gastric emptying is a another complication occurring in around 30% of patients after pancreatoduodenectomy (PD) and causes prolonged hospital stay. The influence of octreotide on this complication is doubtful. AIMS: To assess the effect of octreotide, at the clinical dosage used after pancreatic surgery, on gastric emptying in healthy volunteers. SUBJECTS AND METHODS: Eight healthy male volunteers (mean age 22.5 years) participated in this double blind, placebo controlled study. On day 1 subjects received 100 micrograms of octreotide or placebo subcutaneously, three times daily and on day 2, one hour after the fourth injection, gastric emptying, postprandial cholecystokinin (CCK) release, and mouth to caecum transit time (MCTT) were measured. This protocol was repeated after one week, in a crossover design. On the test day subjects received a liquid test meal (1.57 MJ/300 ml) and gastric emptying measurements were performed with applied potential tomography, an non-invasive, validated technique which measures gastric emptying through impedance differences. From the gastric emptying curves, lag time, t50, and postlag emptying rate were measured. MCTT was measured using the hydrogen breath test. RESULTS: Lag time decreased from 29.6 (6.3) (mean (SEM)) to 12.2 (4.6) minutes (p < 0.05) during octretide treatment; t50 decreased from 87.8 (12.0) to 47.5 (8.2) minutes (p < 0.02) and there was a trend towards an increased postlag emptying rate (0.8 to 1.6% per minute; p = 0.07). MCTT increased from 150 (12.7) to 229 (17.9) minutes during octreotide treatment (p < 0.01). Octreotide suppressed postprandial CCK release (p < 0.05). CONCLUSIONS: MCTT was delayed by octreotide, suggesting impairment of small bowl treatment. Octreotide administered at the clinical dosage for pancreatic surgery accelerates gastric emptying, mainly by shortening the lag time. Suppression of postprandial CCK release may be involved in this process. Octreotide administration is therefore not a contributing factor in the pathogenesis of delayed postoperative gastric emptying after PD and might even play a role in preventing this complication.     

Effect of selective mu 1, mu 2 and delta 2 opioid receptor agonists on gastric functions in the rat

Because the role of mu and delta opioid receptors in modulating gastric functions remains uncertain, we studied whether intracerebroventricular (i.c.v.) and subcutaneous (s.c.) injections of new opioid peptides with high selectivity for mu 1 (Lys7-dermorphin), mu 2 (Trp4-Asn7-dermorphin) and delta 2 (D-Ala2-deltorphin II) opioid receptors would modify gastric secretion (after 2 hr pylorus ligature) and transit (after a phenol red meal) in the rat. Neither i.c.v. nor s.c. injections of the delta 2 opioid agonist affected the gastric functions. In contrast, the mu opioid agonists decreased gastric acid secretion and emptying, i.c.v. injections inducing more potent inhibition than s.c. administration. The mu 1 selective opioid antagonist naloxonazine had no effect on the inhibition of the gastric secretory and motor response to these peptides but naloxone completely blocked their effects. Our findings suggest (1) that in rats, stimulation of central naloxonazine insensitive opioid receptors (mu 2 sites) inhibits gastric acid secretion and emptying; and (2) that delta opioid receptors take no part in mediating these functions.     

Behavioral and neurochemical study on the role of the brain cholecystokinin system in anxiety

In order to elucidate the involvement of cholecystokinin (CCK) in the regulation of anxiety, the author examined the effects of the selective non-peptide CCKB receptor antagonist LY288513 on freezing behavior induced by conditioned fear stress, an animal model of anxiety. Rats were individually subjected to 5 min of inescapable electric footshock in a shock chamber. Twenty-four hours after the footshock, the rats were again placed in the shock chamber and observed for 5 min without shocks: this procedure is termed conditioned fear stress. Subcutaneous administration of LY288513 30 min before footshock (0.3 mg/kg) and 30 min before conditioned fear stress (0.03-0.3 mg/kg) reduced conditioned freezing. This indicates that LY288513 blocked both the acquisition and expression of conditioned fear. The relatively selective non-peptide CCKA receptor antagonist, lorglumide, blocked the expression of conditioned fear, but only at a high dose (1.0 mg/kg). The peripheral non-peptide CCKA/B receptor antagonist, loxiglumide, failed to do so. Subcutaneous administration of LY288513 (3 mg/kg) enhanced the conditioned fear-induced in 3, 4-dihydroxy-phenylacetic acid (DOPAC) contents in the medial prefrontal cortex, which was assayed by high performance liquid chromatography with electrochemical detection. Thirty min of inescapable electric footshock decreased CCK8S contents in the amygdala, which was assayed by radioimmunoassay. These results suggest that the brain CCKB receptors are involved in the regulation of anxiety, and that the anxiolytic effects of CCKB receptor antagonists are mediated by increasing dopamine activity in the medial prefrontal cortex. Furthermore, it is possible that the CCK neurons in the amygdala are also associated with anxiety.     

Arthroscopic-assisted allograft anterior cruciate ligament reconstruction in patients with symptomatic arthrosis

BACKGROUND: Antral motility and the hormone cholecystokinin (CCK) are major determinants of the rate of gastric emptying. The relation between CCK and antral neurons in regulating gastric emptying is uncertain. Benzalkonium chloride (BAC) causes selective lesions in gut myenteric neurons after serosal application. AIM: To develop a model of antral denervation using BAC to enable the study of the relation between CCK and antral neurons in regulating gastric emptying. METHODS: BAC, vehicle or the afferent neurotoxin capsaicin were applied to the serosal surface of the rat antrum or corpus; neurochemical markers of intrinsic and afferent neurons were detected by using immunohistochemistry and radioimmunoassay. Gastric retention of solids was determined after fasting, and emptying of liquids was measured in rats with gastric fistulae. RESULTS: In BAC treated rats radioimmunoassay of tissue extracts revealed a dose related specific loss of gastrin releasing peptide, substance P, and vasoactive intestinal polypeptide immunoreactivities from the treated region, and immunohistochemistry revealed loss of the neuronal marker PGP 9.5 and the afferent neuropeptide calcitonin gene related peptide (CGRP). Adjacent untreated regions were unaffected by BAC, with the exception that CGRP was depleted in both corpus and antrum after antral treatment. After antral BAC treatment fasted rats retained solids for over 48 hours. Moreover, in antrally denervated rats with gastric fistulae, the emptying of saline, acid and peptone was delayed substantially. The CCK dependent inhibition of gastric emptying of peptone was preserved after antral treatment with BAC. CONCLUSIONS: Serosal BAC causes lesions in the innervation of the treated region of the stomach. The innervation of the antrum is essential for normal emptying of both liquids and solids, but the inhibition of gastric emptying produced by CCK is not dependent on antral neurons.     

Cholecystokinin antagonistic activities of loxiglumide

Cholecystokinin (CCK) antagonistic activities of loxiglumide ((+/-)-4-(3,4-dichlorobenzamido)-N-(3-methoxypropyl)-N-pentylgl utaramic acid, CR1505, CAS 107097-80-3) were investigated in the gastrointestine and gallbladder in vivo. Intravenous administration of loxiglumide antagonized the CCK-induced reduction of gastric emptying in rats, acceleration of intestinal transport in mice, increase in ileal motility in rabbits, gallbladder contraction in guinea pigs and acceleration of gallbladder emptying in mice. Orally administered loxiglumide also antagonized the CCK-induced gallbladder emptying in mice. Furthermore, egg yolk-stimulated gallbladder emptying in mice was also inhibited by loxiglumide, indicating that this agent antagonizes not only exogenous but also endogenous CCK. These results demonstrate that loxiglumide is an intravenously and orally effective, potent CCK antagonist.     

AMPA-receptors are involved in the expression of amphetamine-induced behavioural sensitisation, but not in the expression of amphetamine-induced conditioned activity in mice

We investigated the role of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline (NBQX) in the expression of amphetamine-induced behavioural sensitisation and amphetamine-induced conditioned activity in mice. Repeated weekly administration of amphetamine (0.375 mg/kg) for 7 weeks led to an increased locomotor response when challenged with amphetamine 1 week later. NBQX attenuated this increased response at doses (3 and 30 mg/kg) which had no effect on the acute locomotor response to amphetamine. In a separate experiment, mice given amphetamine (1 mg/kg) in a distinctive environment, showed an increased locomotor response within this environment following a subsequent saline administration. NBQX (5-20 mg/kg) had no effect on the expression of this conditioned response. These results suggest that AMPA receptors are involved in the expression of amphetamine-induced behavioural sensitisation in mice, and that this involvement is limited to either the neurobiological effects of amphetamine or the effects of amphetamine on conditioned associations, rather than drug environment conditioned associations.     

Solution and gel rheology of a new polysaccharide excreted by the bacterium Alteromonas sp. strain 1644

The present series of experiments were designed to examine a potential role for central descending pain facilitatory systems in mediating secondary hyperalgesia produced by topical application of mustard oil and measuring the nociceptive tail-flick reflex in awake rats. Topical application of mustard oil (100%) to the lateral surface of the hind leg produced a facilitation of the tail-flick reflex that was significantly reduced in spinal transected animals. Mustard oil hyperalgesia was also inhibited in animals that had received electrolytic lesions in the rostral ventromedial medulla (RVM). Intrathecal (i.t.) administration of the non-selective cholecystokinin (CCK) receptor antagonist proglumide (10 micrograms) prior to mustard oil application completely blocked both the lesser and greater hyperalgesic responses observed in spinal transected and normal animals, respectively, and produced an inhibition of the tail-flick reflex in normal animals. Administration of the selective CCKB receptor antagonist L-365260 i.t. dose-dependently inhibited mustard oil hyperalgesia (ID50 = 364 ng) at doses approximately 5-fold less than the CCKA receptor antagonist devazepide (ID50 = 1760 ng). Similar to spinal proglumide, microinjection of the neurotensin antagonist SR48692 (3.5 micrograms) into the RVM blocked mustard oil hyperalgesia and inhibited the tail-flick reflex. These data suggest that secondary hyperalgesia produced by mustard oil is mediated largely by a central, centrifugal descending pain facilitatory system which involves neurotensin in the RVM and spinal CCK (via CCKB receptors). The inhibition of the tail-flick reflex produced by mustard oil following spinal or supraspinal administration of receptor antagonists suggests concurrent activation of central descending facilitatory and inhibitory systems.     

They''re playing our song: gene expression and birdsong perception

The locomotor stimulating effect of d-amphetamine in mice was counteracted by the administration of l-naloxone [(-)-naloxone], a known opiate receptor antagonist. Mice injected with amphetamine reached a peak locomotor activity within 30 min. When treated simultaneously with amphetamine and l-naloxone, these subjects showed low motility. Furthermore, when mice were treated not with l-naloxone but with its mirror image, d-naloxone [(+)-naloxone], a compound that by itself does not antagonize opiates and does not affect spontaneous motility, they showed no amphetamine-induced hyperactivity. The finding that an enantiomer of naloxone, with no opiate antagonist activity, is able to block the excitatory action of amphetamine, suggests the existence of a hitherto unknown mechanism of counteracting some of the effects of stimulants and euphoriants like amphetamine and cocaine.     

Antipsychotic potential of CCK-based treatments: an assessment using the prepulse inhibition model of psychosis

Systemic injections of cholecystokinin (CCK), a "gut-brain" peptide, have been shown to modulate brain dopamine function and produce neuroleptic-like effects on such dopamine-regulated behaviors as locomotor activity. However, clinical trials of CCK agonists in schizophrenia patients showed mixed results. To re-examine the antipsychotic potential of CCK-based treatments, we examined systemic injections of CCK analogs in an animal model with strong face and construct validity for sensorimotor-gating deficits seen in schizophrenia patients and with strong predictive validity for antipsychotic drug activity. Prepulse inhibition (PPI) occurs when a weak acoustic lead stimulus ("prepulse") inhibits the startle response to a sudden loud sound ("pulse"). PPI is significantly reduced in schizophrenia patients and rats treated with dopamine agonists. Antipsychotics reverse decreased PPI in rats to a degree highly correlated with their clinical efficacy. Subcutaneous (s.c.) injections of caerulein (10 micrograms/kg) a mixed CCKA/B agonist, partially reversed amphetamine-induced reduction of PPI; whereas, s.c. haloperidol (0.5 mg/kg) totally reversed amphetamine-induced disruption of PPI. Caerulein's effect on PPI was blocked by pretreatment with a CCKA antagonist (devazepide) but not a CCKB antagonist (L-365,260). CCK-4, a preferential CCKB agonist, had no significant effect on PPI. These results suggest that caerulein produces a weak neuroleptic-like effect on PPI that is mediated by stimulation of CCKA receptors. Possible circuities in this effect are discussed. In a separate experiment, s.c. caerulein produced to a more potent neuroleptic-like profile on amphetamine-induced hyperlocomotion, suggesting that selection of preclinical paradigms may be important in evaluating the antipsychotic potential of CCK-based treatments.     

The role of cholecystokinin and the cholinergic system in intravenous amino acid-induced gallbladder emptying

BACKGROUND: Recent studies have demonstrated that separate intravenous infusion of amino acids (IVAA) at high doses induces gallbladder emptying. However, little is known about the mechanisms mediating IVAA-induced gallbladder contraction. OBJECTIVE AND METHODS: To investigate whether the effect of IVAA on gallbladder motility is mediated by the cholinergic system and/or cholecystokinin (CCK), the major hormonal stimulus for gallbladder contraction. Six healthy male volunteers were studied in random order on five occasions using: (a) IVAA, (b) loxiglumide (CR 1505, a selective CCK-A receptor antagonist), (c) IVAA plus loxiglumide, (d) atropine and (e) IVAA plus atropine. Gallbladder volumes (ultrasonography) and plasma CCK levels (radioimmunoassay) were determined every 15 min for 60 min before and for 120 min during intravenous infusion of amino acids (Vamin 18EF; 250 mg protein/kg/h) and/or loxiglumide (10 mg/kg/h) and/or atropine (0.005 mg/kg/h). RESULTS: IVAA significantly (P < 0.05) reduced gallbladder volume from 32 +/- 5 ml to 17 +/- 2 ml but induced only a small and transient increase in plasma CCK levels. Loxiglumide given alone significantly (P < 0.05) increased fasting gallbladder volume to 190% of the basal value. IVAA-induced gallbladder emptying was completely abolished by loxiglumide. Maximal gallbladder relaxation during IVAA plus loxiglumide was not significantly different compared to loxiglumide given alone. Concomitant administration of atropine also significantly (P < 0.05) inhibited IVAA-induced gallbladder emptying. CONCLUSION: In healthy volunteers intravenous infusion of high doses of amino acids results in a significant gallbladder contraction, which is inhibited by CCK-A receptor blockade and by atropine.     

Review of pharmacodynamics, pharmacokinetics, and therapeutic properties of sulodexide

The study was conducted to assess the bioavailability of avitriptan after a standard high fat meal, in relation to gastrointestinal transit. Six healthy male subjects were enrolled in a four-period study with a partial replicate design where each was administered 150-mg avitriptan capsule (i) after an overnight fast, (ii) 5 min after a standard high-fat breakfast, and (iii) 4 hr after a standard high fat breakfast. The treatment administered in Period 3 was repeated in Period 4 to assess intrasubject variations in pharmacokinetics and gastrointestinal (GI) transit. Avitriptan capsules were specially formulated with nonradioactive samarium chloride hexahydrate which was neutron-activated to gamma-emitting samarium before dosing. Serial blood samples were collected for analysis of avitriptan up to 24-hr postdose, and serial scintigraphic images were obtained to assess the plasma concentration-time profile in relation to the GI transit of the avitriptan capsule contents. Bioavailability of avitriptan was reduced when administered in the fed condition but only the decrease in AUC(INF) was statistically significant. Tmax was significantly delayed between the fed conditions and the fasted condition. Qualitative appearance of plasma concentration-time profiles for avitriptan could be related to the manner in which the drug emptied from the stomach. It was also apparent that avitriptan exerted a secondary pharmacologic effect that temporarily suspended gastric emptying in the fasted treatment. Thus, when gastric emptying was interrupted and then resumed, the net result was a double peak in some of the individual plasma concentration profiles. Scintigraphic analysis also demonstrated that upon emptying from the stomach, avitriptan was rapidly absorbed from the upper small intestine. In the fed state, gastric emptying was slow and continuous resulting in extended absorption and a lower occurrence of double peaks. Qualitatively, the intrasubject variability in Cmax and AUC could be explained by the intrasubject variability in gastric emptying in both fasted and fed conditions.     

CCKB receptors mediate CCK-8S-induced activation of dorsal hippocampus CA3 pyramidal neurons: an in vivo electrophysiological study in the rat

The sulphated octapeptide C-terminal fragment of cholecystokinin (CCK-8S) is present in high concentration in the mammalian brain, where it acts via two types of receptor denoted CCKA and CCKB. In the dorsal hippocampus, CCK-8S exerts a potent excitatory effect on pyramidal neurons. The present electrophysiological study was undertaken to determine which CCK receptor type mediates this neuronal activation. Using in vivo extracellular unitary recordings of CA3 pyramidal hippocampal neurons, we compared the effect of SNF-8702, a potent selective CCKB receptor agonist, to that of CCK-8S, and assessed the effects of selective CCKA and CCKB antagonists. CCK-8S and SNF-8702, microiontophoretically applied on the same neurons produced a similar degree and pattern of activation. Both CCK-8S- and SNF-8702-induced activations were suppressed by the microiontophoretic application of the CCKB antagonist CI-988, but not by that of the CCKA antagonist SR 27897. CCK-8S-induced activation was not significantly modified by the intravenous administration of the CCKA antagonists devazepide and SR 27897. However, it was reduced by the CCKB antagonist PD 135158, administered intravenously or intracerebroventricularly, and by the intravenous administration of the CCKB antagonist L-365,260. The intravenous administration of PD 135158 also reduced SNF-8702-induced activations. These results indicate that CCKB receptors mediate CCK-8S-induced activation of rat CA3 pyramidal neurons.     

Effects of ondansetron on gastrointestinal symptoms in carcinoid syndrome

The effect of short-term treatment with the highly selective serotonin receptor antagonist ondansetron on symptoms and gastric emptying in 11 carcinoid patients was studied. Diarrhoea improved in 6 of 6 patients, nausea in 3 of 4 patients. Flushing was not affected. The rate of gastric emptying increased during ondansetron treatment (P = 0.08). No changes in serotonin in platelets and urinary excretion of 5-hydroxyindoleacetic acid were found. It is concluded that ondansetron can improve gastrointestinal symptoms in carcinoid patients and possibly slows gastric emptying.     

Modulation of fatty acid-binding protein content of adult rat heart in response to chronic changes in plasma lipid levels

Cholecystokinin-octapeptide (CCK8) administered intraperitoneally (i.p.) in rats induces a rapid elevation in serum oxytocin (OT). The receptor subtype mediating this action of CCK was investigated with selective CCK-A and CCK-B receptor agonists and antagonists. CCK8 and A-71623, a potent CCK-A selective agonist, were similar in efficacy and potency for stimulating OT secretion. Both compounds at 10 nmol/kg elicited approximately one-half the response of 100 nmol/kg, which elevated serum OT to approx. 20 to 30-fold above basal level. The potent CCK-B selective agonist, A-63387, at doses up to 100 nmol/kg did not increase serum OT. MK-329, a CCK-A receptor selective antagonist, at a dose of 20 nmol/kg fully inhibited the action of 20 nmol/kg CCK8, while 100 nmol/kg of (R)L-365,260, a CCK-B selective antagonist, had no effect on the CCK8 response. These results, together with previous lesion studies, suggest that vagal CCK-A receptors in the periphery mediate the activation of the oxytocinergic pathway in vivo.