Cholecystokinin antagonists proglumide, lorglumide and benzotript, but not L-364,718, interact with brain opioid binding sites

It has been reported that proglumide and L-364,718 potentiate opioid-induced antinociception. However, their mode of action in pain modulation is still not understood. To evaluate a possible interaction with opioid receptors, we determined the affinities of the CCK antagonists proglumide, lorglumide, benzotript and L-364,718 on mu, delta and kappa binding sites, using guinea pig brain crude synaptosome preparations. These affinities were compared to that of the central CCK binding site, using rat brain slide-mounted sections. At 100 microM, proglumide competed for 13% and 17% of mu and kappa binding sites, but did not interact with delta and CCK sites. At this concentration, lorglumide reduced mu, delta, kappa and CCK specific binding by 44%, 69%, 35% and 88%, whereas benzotript diminished it by 16%, 13%, 38% and 48%, respectively. L-364,718 did not interact with opioid receptors (assay limit of solubility, 10 microM) but had a high affinity for CCK binding sites (IC50, 126nM). The lack of selectivity of proglumide, lorglumide and benzotript for CCK receptors suggests that their reported ability to potentiate morphine analgesia may be related to an interaction with opioid receptors.     

Subtype-selective cholecystokinin receptor antagonists block cholecystokinin modulation of dopamine-mediated behaviors in the rat mesolimbic pathway.

Subtype-selective antagonists of the peripheral-type (CCK-A) and the central-type (CCK-B) cholecystokinin (CCK) receptors were employed to determine the receptor subtype(s) mediating the modulatory actions of CCK on dopamine-induced changes in exploratory activity at three sites in the mesolimbic pathway of the rat. The CCK-A antagonist L-364,718 (10 ng) blocked CCK potentiation of dopamine-induced hyperlocomotion in the medial posterior nucleus accumbens. The CCK-B antagonist CI-988 (20 ng) blocked CCK inhibition of dopamine-induced hyperlocomotion in the anterior nucleus accumbens. The CCK-B antagonists CI-988 (20 ng) and L-365,260 (10 ng) blocked CCK potentiation of dopamine-induced hypolocomotion in the ventral tegmental area. These data indicate a CCK-B pharmacology in the cell body and anterior terminal field, and a CCK-A pharmacology in the posterior terminal field, of the mesolimbic dopamine pathway. Behavioral analyses using the selective CCK antagonists did not detect a contribution of endogenous CCK to exploratory locomotion. L-364,718 (10 ng), L-365,260 (10 ng), and CI-988 (20 ng or 2 micrograms), microinjected into the medial posterior nucleus accumbens, anterior nucleus accumbens, or ventral tegmental area, had no effect on baseline exploratory locomotion or on dopamine-induced changes in exploratory locomotion. Using a dark-induced hyperlocomotion paradigm, the CCK antagonists at these doses at these sites and intraperitoneally had no effect on the high levels of exploratory locomotor activity exhibited by the rats in the dark testing environment, or the lower levels of exploratory activity in the lighted environment. Endogenous CCK may not be released during dopamine-induced hyperlocomotion or dark-induced hyperlocomotion, or endogenous CCK may not contribute significantly to exploratory behaviors mediated through the mesolimbic dopamine pathway. Utilization of these potent, selective, nonpeptide CCK antagonists, with the doses, vehicles, and routes of administration developed in the present studies, will guide further investigations into the role of endogenous CCK in other facets of mesolimbic function.     

Receptor selectivity of cholecystokinin effects on mesoaccumbens dopamine neurons

Extracellular recording techniques were combined with antidromic stimulation to examine the effects of C-terminal cholecystokinin (CCK) fragments and CCK antagonists on the activity of identified mesoaccumbens dopamine (MADA) neurons in chloral hydrate-anesthetized rats. These experiments were designed to determine the receptor selectivity of sulfated CCK octapeptide (CCK-8S) effects on MADA cells. Neither CCK tetrapeptide (CCK-4) nor unsulfated CCK octapeptide (CCK-8U) significantly altered MADA cell basal firing rate or responsiveness to the inhibitory effects of the D2 DA agonist quinpirole. As reported previously for ventral tegmental area DA cells, CCK-8S produced increases or decreases in the firing rate of most MADA cells sampled. CCK-8S also enhanced the sensitivity of MADA neurons to quinpirole-induced inhibition. This increase in sensitivity to quinpirole was blocked by pretreatment with the nonselective CCK receptor antagonist proglumide and the preferential CCK-A receptor antagonist CR 1409 but not by the preferential CCK-B receptor antagonist L-365,260. The inactivity of CCK-4 and CCK-8U in these tests and the results with the antagonists suggest that the effects of CCK-8S on MADA neuronal activity are mediated by CCK-A receptors.     

Functional neuroanatomy of the ventral striopallidal GABA pathway. New sites of intervention in the treatment of schizophrenia

Microdialysis was employed to investigate the dopamine, cholecystokinin (CCK) and neurotensin receptor regulation of ventral striopallidal GABA transmission by intra-accumbens perfusion with selective receptor ligands and monitoring local or ipsilateral ventral pallidal GABA release. In the dual probe studies intra-accumbens perfusion with the dopamine D1 and D2 receptor agonists SKF28293 and pergolide had no effect on ventral pallidal GABA, while both the D1 and D2 receptor antagonists SCH23390 and raclopride increased ventral pallidal GABA release. In contrast, intra-accumbens CCK decreased ventral pallidal GABA release and this was reversed by local perfusion with the CCK2 receptor antagonist PD134308 but not the CCK1 receptor antagonist L-364,718. In a single probe study intra-accumbens neurotensin increased local GABA release, which was strongly potentiated when the peptidase inhibitor phosphodiepryl 08 was perfused together with neurotensin. In addition, the neurotensin receptor antagonist SR48692 counteracted this phosphodiepryl 08 induced potentiated increased in GABA release. Taken together, these findings indicate that mesolimbic dopamine and CCK exert a respective tonic and phasic inhibition of ventral pallidal GABA release while the antipsychotic activity associated with D1 and D2 receptor antagonists may be explained by their ability to increase ventral striopallidal GABA transmission. Furthermore, the findings suggest that CCK2 receptor antagonists and neurotensin endopeptidase inhibitors may be useful antipsychotics.     

Autoradiographic localization and biochemical characterization of peripheral type CCK receptors in rat CNS using highly selective nonpeptide CCK antagonists

Two potent and highly selective nonpeptide antagonists, L-365,031 [1-methyl-3-(4-bromobenzoyl)amino-5-phenyl-3H-1,4 benzodiazepin-2-one] and 3H-L-364,718 [1-methyl-3-(2-indoloyl)amino-5-phenyl-3H-1,4 benzodiazepin-2-one] were used to localize "peripheral" CCK receptors in rat brain. In autoradiographic experiments, L-365,031 displaced 125I-Bolton Hunter CCK-8 binding from the interpeduncular nucleus (IPN) (IC50 = 7 X 10(-8) M), the area postrema (AP), and the nucleus tractus solitarius (NTS) without influencing specific binding to other areas, such as the cerebral cortex or the spinal tract of the trigeminal nerve. Desulfated CCK preferentially inhibited 125I-CCK binding to cerebral cortex (IC50 = 7 X 10(-8) M) rather than IPN (IC50 greater than 1 X 10(-6) M) or AP-NTS. In the medulla the localization of 3H-L-364,718 binding was similar to L-365,031-sensitive 125I-CCK-8 binding and was found in the AP and medial, but not lateral, aspects of the NTS. In membranes prepared from IPN, NTS, and AP, 3H-364,718 binding was of high affinity (Kd = 0.14 nM), saturable (Bmax = 20 fmol/mg protein), and inhibited by compounds previously shown to act at pancreatic CCK receptors. The receptors labeled by 3H-364,718 were modulated by guanyl nucleotide, which reduced agonist affinity 10-fold without affecting antagonist binding. The localization and high density of CCK receptors in AP and NTS suggest that these receptors may play an important role in processing sensory afferent information.     

Pharmacological and molecular characterization of muscular cholecystokinin receptors in the human lower oesophageal sphincter

In vitro cholecystokinin (CCK) contracts the human lower oesophageal sphincter by stimulating muscular receptors. The aim of this study was to characterize the muscular CCK receptor subtypes in the human lower oesophageal sphincter. Twenty-five circular strips from six patients were studied. RNA was extracted, reverse transcribed, and cDNAs were amplified with primers for human CCK-A and B receptors. The potency of the contraction induced by CCK-8, desulphated CCK-8, and gastrin-I, and the effect of the CCK-A (loxiglumide and SR 27897) and the CCK-B (YM022 and L-365 260) specific receptor antagonists were compared. Both CCK-A and CCK-B receptor mRNAs were found in functional lower oesophageal sphincter strips. The potency of the CCK-8 concentration-dependent contraction was two and three orders of magnitude higher than that of desulphated CCK-8 and gastrin-I, respectively. The CCK-8-induced contraction was blocked by the CCK-A receptor antagonists loxiglumide (IC50 11 micromol L-1) and SR 27897 (IC50 74 nmol L-1) but not by CCK-B receptor antagonists (1 micromol L-1).Our data suggest that, although the human lower oesophageal sphincter expresses both CCK-A and CCK-B receptors, the contractile effect of CCK-8 on the circular muscle is mainly due to the activation of CCK-A receptors.     

Cholecystokinin and an evoked response in the dentate gyrus

Cholecystokinin (CCK) as the sulfated (CCK-8S) and unsulfated (CCK-8U) octapeptide sequences, and CR 1409 were administered intraventricularly while the action potential (EAP) in the granular cell layer of the hippocampal dentate gyrus evoked by perforant path stimulation was recorded. No consistent effect of the test substances on the amplitude of the EAP was found at doses corresponding to those previously reported to cause an increase in the EAP when administered systemically. Similarly, no effect of CCK on the EAP could be found when the peptide was administered iontophoretically in the granular cell layer. In contrast, iontophoretically applied CCK-8S, CCK-8U and CR 1409 slightly but consistently reduced the slope of the evoked response recorded in the dentate gyrus molecular layer. These results are interpreted as indicating that the CCK receptor on granular cell dendrites is likely to be the central type that is activated by both CCK-8S and CCK-8U, but that any effects of systemically administered CCK on the EAP are probably mediated in the periphery.     

Brain CCK-B receptors mediate the suppression of dopamine release by cholecystokinin

The sulfated octapeptide of cholecystokinin (CCK-8S) and CCK fragments were administered to mice to determine the subtype and central versus peripheral location of the CCK receptor that modulates dopamine release in the neostriatum. Dopamine release was decreased when unsulfated CCK (CCK-8U) or the butoxycarbonyl tetrapeptide of CCK (t-boc-CCK-4) was infused into the brain ventricles but not when injected subcutaneously. These CCK fragments bind to the brain-type (CCK-B) but not alimentary-type (CCK-A) receptor. Centrally or peripherally administered CCK-8S also lowered dopamine release and this action was not blocked by the selective CCK-A receptor antagonist, L 364,718. The increase in dopamine release following amphetamine administration was attenuated by central injections of t-boc-CCK-4, CCK-8U, or CCK-8S, and this action of CCK-8S was not prevented by L 364,718. These data are the first to demonstrate that CCK-B receptors in brain mediate the suppression of dopamine release by cholecystokinin, especially when release is augmented. CCK-B receptor agonists should be useful for the treatment of psychiatric conditions that result from hyperactive dopamine neurons.     

The CCK-B Agonist, BC264, Increases Dopamine in the Nucleus Accumbens and Facilitates Motivation and Attention After lntraperitoneal Injection in Rats

Although it is known that panic attacks are triggered by the cholecystokinin fragment CCK₄, the specific involvement of peripheral or central cholecystokinin CCK receptors in various adaptive processes such as emotion, memory and anxiety has yet to be demonstrated. With this aim, we have investigated the biochemical and pharmacological effects resulting from the administration of BC264, a highly potent and selective CCK-B agonist able to cross the blood-brain barrier. Very low doses of BC264 (μg/kg i.p.), increased the exploration of animals submitted to an unknown territory but were devoid of anxiogenic properties in the elevated plus maze. BC264 increased locomotion and rearings of rats newly placed in an open field and improved their spontaneous alternation in a Y-maze. The use of vagotomized animals showed that the increased alternation induced by BC264 did not require an intact vagus nerve, unlike the locomotor activation. These behavioural effects, prevented by the prior i.p. administration of the CCK-B antagonist L-365,260 but not by the CCK-A antagonist L-364,718, were shown to depend on dopaminergic systems, since they were blocked by D₁ (SCH23390, 25 μg/kg i.p.) or D₂ (sulpiride, 50 or 100 mg/kg i.p.) antagonists. In addition, bilateral perfusion in freely moving rats of BC264 at pharmacologically active doses, using a newly designed microdialysis system, was found to increase the extracellular levels of DA, DOPAC and HVA in the anterior part of the nucleus accumbens. These results show that activation of CCK-B receptors by BC264 does not produce anxiogenic-like effects but appears to improve motivation and attention, whereas other CCK-B agonists such as BocCCK4 induce anxiogenic responses. Several explanations, including the existence of different sub-sites of the CCK-B receptor, could account for these differential effects.     

Effects of gastrin-releasing peptide (GRP) on the mechanical activity of the human ileocaecal region in vitro

Mechanical activity was recorded in muscle preparations isolated from the human ileocaecal region. Gastrin-releasing peptide (GRP, 10⁻⁹− 10⁻⁷ mol L⁻¹) produced two types of response in the different muscle layers. Longitudinally cut strips showed a concentration-dependent increase in the rhythmic activity, whereas the circularly orientated layers generally reacted with a small decrease in tone. These effects could not be influenced by blockade of adrenergic or cholinergic receptors or nerve blockade with tetrodotoxin (TTX). Application of pentagastrin did not mimic the action of GRP. These findings suggest a direct action of GRP on smooth muscle via distinct receptors which have already been demonstrated to exist in human gastrointestinal tract. The opposite effects on circular and longitudinal strips might indicate a modulatory role of GRP in the control of ileocolonic transit.     

Microinjection of cholecystokinin into the rat ventral tegmental area potentiates dopamine-induced hypolocomotion

Cholecystokinin, (CCK) 1-400 ng, significantly potentiated the hypolocomotion induced by dopamine, when simultaneously microinjected bilaterally into the ventral tegmental area (VTA) of rat brain. Within this dose range, CCK had no effect alone on ambulatory locomotion. Topographical analysis indicated that the modulatory effect of CCK was greatest in the central and caudal regions of the VTA, and absent at sites lateral, dorsal, rostral, and caudal to the VTA. Pharmacological analysis indicated that both unsulfated CCK octapeptide (100 ng) and the C-terminal tetrapeptide of CCK (400 ng) potentiated dopamine-induced hypolocomotion in a manner identical with sulfated CCK octapeptide (100 ng). Proglumide, an antagonist of the peripheral-type CCK receptor, did not block the potentiating actions of CCK, at doses of proglumide up to 500 mg/kg i.p., or 100 micrograms into the ventral tegmental area. L-364,718, an antagonist of the peripheral-type CCK receptor with lesser affinity for the central-type CCK receptor, blocked the potentiating actions of CCK at relatively high doses of L-364,718 (1-10 mg/kg i.p.). These findings suggest that CCK acts as a facilitatory modulator of dopamine at a central-type CCK receptor on the A10 cell bodies.     

Structure-activity studies of C- and N-terminal fragments of cholecystokinin 26-33 in guinea pig isolated tissues

In vitro structure-activity studies with cholecystokinin (CCK)/gastrin-related peptides, including C- and N-terminal fragments of CCK 26-33, were undertaken in guinea pig gallbladder and ileum. The general order of potency in both smooth muscle preparations is CCK 26-33 greater than CCK 1-33 greater than 27-33 much much greater than nonsulfated (NS) CCK 26-33 greater than pentagastrin greater than CCK 30-33. None of the CCK fragments exhibit antagonistic properties such as in guinea pig, rat and mouse pancreatic acinar cells and hog duodenum. These observations suggest the existence of CCK receptor sub-types in peripheral tissues.     

Role of Cholecystokinin in Gallbladder and Duodenal Motility in the Interdigestive State of Dogs

This study was designed to determine the role of cholecystokinin (CCK) in the motility patterns of duodenum and gallbladder in fasted conscious dogs. During the naturally occurring activity front in the duodenum a significant increase in the motility index, (MI) of the gallbladder was accompanied by a decrease in the gallbladder volume from about 28 ± 4 ml (control) to 21 ± 3 ml. Similar changes in the gallbladder were observed after intravenous bolus injections of motilin (20 to 40 ng/kg), which gave increments in plasma motilin comparable to those occurring spontaneously during the activity front but failed to affect plasma levels of CCK. Blocking of CCK receptors by L-364, 718 (0.5 to 1 mg/kg) delayed the occurrence of the spontaneous activity front in the duodenum and the accompanying alterations in the gallbladder motility. CCK receptor antagonism abolished the premature activity front induced by motilin in both the duodenum and the gallbladder, converted the fed-like pattern induced by exogenous CCK to a fasted motility pattern in the duodenum and prevented CCK-induced reduction in the gallbladder volume. Atropine (12.5 μg/kg) blocked the spontaneous activity front in the duodenum and accompanying alterations in the gallbladder motility and volume but failed to affect those induced by motilin. We conclude that the motility of the gallbladder in fasted dogs shows cyclic changes with typical reduction in the organ volume coinciding with the spontaneous or motilin-induced activity front in the duodenum, and that both CCK and muscarinic receptors are involved in the MMC-related alterations in the motor activity of the gallbladder.     

Anticholinesterase Activity of Histamine H2-Receptor Antagonists in the Dog: Their Possible Role in Gastric Motor Activity

We studied the anticholinesterase activity of three H₂-receptor antagonists (cimetidine, ranitidine, and famotidine) in vitro and in conscious dogs with chronically implanted strain-gauge force transducers. In vivo, acetylcholine (ACh) was infused intravenously at a dose of 0.05 mg/(kg · min) for 5 minutes with or without a background continuous intravenous infusion of H₂-receptor antagonists or neostigmine during the quiescent period of the interdigestive state. Cimetidine and ranitidine enhanced the ACh-induced contractions in a dose-dependent manner in the gastric antrum, whereas famotidine did not. In vitro, the median inhibitory concentration (IC₅₀) of the acetyl-cholinesterase activity of ranitidine was 3.5 × 10⁻⁶ M, and that of cimetidine 2.5 × 10⁻⁴ M, whereas famotidine had no effect on cholinesterase activity even at concentrations up to 10⁻³ M. The effects of a bolus intravenous injection of the three H₂-receptor antagonists on gastric motor activity also were examined in the digestive state. Cimetidine at 10.0 mg/kg and ranitidine at 3.0 mg/kg significantly increased gastric motor activity. This dose of ranitidine, however, sometimes caused the dogs to collapse and significantly decreased blood pressure in the anesthetized dogs. In conclusion, the H₂-receptor antagonists cimetidine and ranitidine enhanced gastric motor activity through the mechanism of their anticholinesterase activity, but further studies on gastric emptying and the circulatory system are needed.     

Overexpression of 5-HT2C receptors in forebrain leads to elevated anxiety and hypoactivity

The 5-HT_2C receptor has been implicated in mood and eating disorders. In general, it is accepted that 5-HT_2C receptor agonists increase anxiety behaviours and induce hypophagia. However, pharmacological analysis of the roles of these receptors is hampered by the lack of selective ligands and the complex regulation of receptor isoforms and expression levels. Therefore, the exact role of 5-HT_2C receptors in mood disorders remain controversial, some suggesting agonists and others suggesting antagonists may be efficacious antidepressants, while there is general agreement that antagonists are beneficial anxiolytics. In order to test the hypothesis that increased 5-HT_2C receptor expression, and thus increased 5-HT_2C receptor signalling, is causative in mood disorders, we have undertaken a transgenic approach, directly altering the 5-HT_2C receptor number in the forebrain and evaluating the consequences on behaviour. Transgenic mice overexpressing 5-HT_2C receptors under the control of the CaMKIIα promoter (C2CR mice) have elevated 5-HT_2C receptor mRNA levels in cerebral cortex and limbic areas (including the hippocampus and amygdala), but normal levels in the hypothalamus, resulting in > 100% increase in the number of 5-HT_2C ligand binding sites in the forebrain. The C2CR mice show increased anxiety-like behaviour in the elevated plus-maze, decreased wheel-running behaviour and reduced activity in a novel environment. These behaviours were observed in the C2CR mice without stimulation by exogenous ligands. Our findings support a role for 5-HT_2C receptor signalling in anxiety disorders. The C2CR mouse model offers a novel and effective approach for studying disorders associated with 5-HT_2C receptors.     

Cholecystokinin-induced anxiety in rats: relevance of pre-experimental stress and seasonal variations

OBJECTIVE: To examine the influence of pre-experimental stress on the anxiogenic-like action of caerulein, an agonist of cholecystokinin (CCK) receptors. Differences in the anxiety levels of rats in summer and winter, and the role of CCK in these behavioural alterations, were also examined. DESIGN: Prospective animal study. INTERVENTIONS: Male Wistar rats were injected with the CCK agonist caerulein, or the CCK antagonists L-365,260 or devazepide, after being exposed to pre-experimental stress (handling and isolation). OUTCOME MEASURES: Performance in the plus-maze model of anxiety; serum levels of prolactin, thyrotropin and growth hormone; brain density and affinity of dopamine D2, serotonin 5-HT2 and CCK receptors. RESULTS: Caerulein (5 micrograms/kg, subcutaneous injection) caused the strongest action in animals brought to the experimental room immediately before the experiment and kept in isolation after the administration of caerulein. Caerulein did not cause any reduction of exploratory activity in rats made familiar with the experimental room and kept in the home-cage after the injection of the CCK agonist. The anti-exploratory action of caerulein in stressed rats was reversed by the CCK antagonist L-365,260 (100 micrograms/kg, intraperitoneal injection), demonstrating the involvement of the CCKB receptor subtype. In addition, seasonal fluctuations occur in the exploratory activity of rats; such activity was much lower in July than in November. The rats displaying the reduced exploratory activity had an increased number of CCK receptors in the frontal cortex and hippocampus. Simultaneously, the density of serotonin 5-HT2 receptors in the frontal cortex, but not that of dopamine D2 receptors in the striatum, was elevated. The blood level of growth hormone was also higher in July. CONCLUSIONS: The anti-exploratory action of caerulein appears to be dependent on the pre-experimental stress of rats. Moreover, the seasonal variations of exploratory behaviour of rats are evident in the plus-maze model of anxiety. The reduced exploratory activity in summer appears to be related to the elevated density of CCK and 5-HT2 receptors in the brain.     

μ-Opiate receptor agonist loperamide blocks bethanechol-induced gallbladder contraction, despite higher cholecystokinin plasma levels in man

mu-Opiate receptor agonists, such as loperamide, influence biliary excretion and suppress cholecystokinin (CCK)-induced gallbladder contraction. Loperamide decreases cholinergic mechanisms, like pancreatic polypeptide (PP) release, while muscarinic agonist (bethanechol)-induced PP release remains unaffected. The effects of loperamide on gallbladder contraction and peptide release were performed to resolve this discrepancy. METHODS: Six subjects (27.6 +/- 2.0 years) received bethanechol (12.5, 25 and 50 microg kg(-1) h(-1) continuously over 40 min) after oral 16 mg loperamide (vs placebo) in a crossover design. Gallbladder volume and plasma levels of CCK, PP, motilin, gastrin, neurotensin, cholylglycine were measured regularly. RESULTS: Bethanechol significantly reduced gallbladder volume (26.7 +/- 1.9 to a nadir of 15.3 +/- 2.2 mL, P < or = 0.05), and this action was inhibited by loperamide. Basal CCK levels increased significantly after loperamide. Incremental integrated CCK release after bethanechol was higher under loperamide (P < or = 0.05), as placebo CCK release was significantly decreased under bethanechol (2.0 +/- 0.4-0.8 +/- 0.3 pmol L(-1)). In both settings, PP levels were significantly increased after bethanechol, while release of neurotensin, motilin, gastrin and cholylglycine was unaffected. CONCLUSION: The mu-opiate receptor agonist loperamide inhibits bethanechol-induced gallbladder contraction. This effect is not mediated by inhibition of CCK release, as loperamide even enhances basal CCK plasma levels. As cholinergic mechanisms, like bethanechol-induced incremental PP release, were unaffected, mu-opiate agonists might influence gallbladder contraction via vagal-cholinergic pathways.     

Actions of excitatory amino acid acid agonists and antagonists on the primary afferents of the vestibular system of the axolotl (Ambystoma mexicanum)

In order to determine the nature of the transmitter in the synapse between hair cells and primary afferent fibers, both resting and evoked spike activity of vestibular system afferents were recorded. Excitatory amino acid agonists and antagonists were applied by micro perfusion. Excitatory amino acid agonists consistently increased the firing rate of these afferents. The rank order in potencies of the agonists tested was: kainate greater than or equal to quisqualate greater than D-aspartate greater than or equal to L-glutamate greater than or equal to L-aspartate greater than N-methyl D-aspartate. Blockade of synaptic transmission with high-Mg2+ and low-Ca2+ solutions did not seem to affect the responses to the excitatory amino acid agonists indicating their postsynaptic action. Excitatory amino acid antagonists inhibit both resting and physiologically evoked activity. The rank order of inhibitory potency was: kynurenate greater than L-glutamate diethyl ester greater than D,L-2-amino-4-phosphono-butyrate greater than D-alpha-amino adipate greater than D,L-2-amino-5-phosphonovalerate. These findings suggest that an amino acid-related compound may be the transmitter at this synapse. The relative potencies of agonists and antagonists tested provide evidence that the transmitter released from the hair cells' basal pole in the axolotl vestibular system interacts with postsynaptic kainic/quisqualic type receptors.     

Calcitonin gene-related peptide (CGRP), a potent regulator of biliary flow

This study was designed to investigate the effect of porcine calcitonin gene-related peptide (CGRP) on the motility of the porcine biliary tract in vivo. We measured the pressure in the gallbladder and sphincter of Oddi and, in separate experiments, the biliary flow into the duodenum during local intra-arterial infusions of CGRP. To determine if the observed effect could be caused by release of cholecystokinin (CCK), we measured the CCK release. The basal pressure in the sphincter of Oddi increased dose-dependently from 5.9 ± 0.5 mmHg to 11.5 ± 2.1 mmHg and the motility index of phasic contractions (amplitude × frequency) from 47 ± 8 to 347 ± 64 mmHg s⁻¹, at an infusion rate of 32.6 pmol kg⁻¹ min⁻¹. No effect was observed on the gallbladder pressure. CGRP at 6.5 pmol kg⁻¹ min⁻¹ significantly reduced the biliary flow into the duodenum to 47.7 ± 6% of the basal level. Atropine, injected intravenously, completely abolished the contractile effect of CGRP. CGRP had no effect on the release of CCK.
We conclude that CGRP increases biliary motility and hereby reduces bile flow, an effect which involves cholinergic but not cholecystokininergic mechanisms.     

Cholecystokinin: proofs and prospects for involvement in control of food intake and body weight

Evidence that CCK participates in the control of meal size is compelling, but the avenues by which CCK may affect daily food intake and body weight regulation are still uncertain. Although participation of brain CCK in control of food intake is acknowledged, our focus here is on participation of peripheral CCK in the control of food intake. Therefore, in this article we (1) review evidence for CCK's participation in control of meal size, (2) document involvement of CCK-A receptors located on vagal sensory neurons in control of food intake by exogenous and endogenous CCK, (3) point out apparent discrepancies in the experimental record, which auger for non-endocrine sources of CCK and non-vagal sites of CCK action, and (4) summarize recent observations, suggesting mechanisms by which CCK could participate in the control of daily food intake and body weight regulation.