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At least 19 recordsLinked to original sources
PubMed1983

Cholecystokinin octapeptide (CCK-8), ceruletide and analogues of ceruletide: effects on tremors induced by oxotremorine, harmine and ibogaine. A comparison with prolyl-leucylglycine amide (MIF), anti-Parkinsonian drugs and clonazepam.

Cholecystokinin octapeptide (CCK-8), ceruletide (caerulein, CER) and 10 analogues of ceruletide, were studied in mice for antagonism of the tremors induced by harmine (5 mg/kg, s.c.), ibogaine (20 mg/kg, s.c.) and oxotremorine (0.2 mg/kg, s.c.). The following reference drugs were tested for comparison: prolyl-leucylglycine amide (MIF), atropine, haloperidol, biperiden, ethopropazine, trihexyphenidyl, methixene and clonazepam. All treatments were subcutaneous, the antagonists being given 10 min (in some trials 30 min) before the tremorogen. Tremorolytic potency (ED50) was calculated from dose-response curves. Against the tremors induced by either harmine or ibogaine, CCK-8 and ceruletide, as well as many of the analogues of ceruletide had greater tremorolytic potency than the reference drugs. Against oxotremorine, however, ceruletide and its most potent analogue, Nle8-CER (other analogues were not tested) were inactive and MIF showed very little effectiveness. Additional experiments on hypothermia and sedation as well as evaluation of previous studies on other central actions suggested that the tremorolytic effect of CCK-like peptides is independent of other central effects. The CCK-like peptides may play a physiological role in the regulation of extrapyramidal motor activity.

Alkaloids↗
PubMedDate not supplied

Ceruletide, ceruletide analogues and cholecystokinin octapeptide (CCK-8): effects on motor behaviour, hexobarbital-induced sleep and harman-induced convulsions.

Ten ceruletide analogues and cholecystokinin octapeptide (CCK-8) were compared with ceruletide regarding neuropharmacological effects in mice after subcutaneous administration. The effects under study were catalepsy, prolongation of hexobarbital-induced sleep and delay in onset of harman-induced convulsions. Ceruletide and several analogues were more potent than the reference drugs, diazepam and haloperidol. Desulfation, deamidation and shortening of the peptide chain by five amino acids strongly reduced or abolished the pharmacological activities of ceruletide. Other chemical modulations mostly weakened the efficacy, but to an unequal extent for the three effects, which altered the pharmacological selectivity.

Animals↗
PubMed1991

Effects of ceruletide and haloperidol on the hypothalamo-pituitary beta-endorphin system and brain beta-endorphin contents in the rat: with special reference to effects of ceruletide in chronically haloperidol-treated rats.

Subcutaneous (sc) administration of 200 micrograms/kg ceruletide (CER), a decapeptide chemically related CCK-8, and 5 mg/kg haloperidol (HLP) to rats increased the plasma immunoreactive beta-endorphin (ir-beta-END) level. The combined injection of CER and haloperidol caused higher plasma ir-beta-END levels than either drug alone. High plasma ir-beta-END levels returned to control levels on the 2nd day. Prior intraperitoneal (ip) administration of a CCK receptor antagonist, L-364,718 (3 mg/kg), but not proglumide (400 mg/kg, ip), inhibited CER-induced, but not HLP-induced, elevation in plasma ir-beta-END levels. The dopamine agonist, bromocriptine (1 mg/kg, ip) decreased plasma ir-beta-END levels, but had not effect on CER-induced elevation in plasma ir-beta-END levels, whereas bromocriptine-induced reduction in plasma ir-beta-END levels was antagonised by HLP. CER injection to chronically HLP-treated rats caused a greater elevation of plasma ir-beta-END levels compared to saline-injected rats. In contrast to the acute experiment, plasma ir-beta-END levels remained elevated over a period of 24 h. In the acute experiment, CER, HLP or the combined treatment with these two drugs had no effect on ir-beta-END contents in the pituitary gland and brain. In the chronic experiment, HLP increased the adenohypophyseal and septal ir-beta-END contents and decreased the hippocampal ir-beta-END contents 24 h after the final HLP injection. CER caused a small reduction only in the hippocampal ir-beta-END contents of CER-injected rats 15 min after injection. When determined on the 2nd day, however, the increases in the adenohypophyseal and septal ir-beta-END contents and the decrease in the hippocampal ir-beta-END contents observed in CER-injected rats were of the same magnitude as those of rats not given the CER injection. These findings indicate that CER stimulates the release of ir-beta-END from the adenohypophysis through CCK-A receptors and that elevated plasma ir-beta-END levels is partly involved in some behavioural effects induced by CER. Furthermore, sustained elevation of plasma ir-beta-END levels after a single injection of CER to chronically HLP-treated rats may explain its long-lasting therapeutic and behavioural effects.

Animals↗
PubMedDate not supplied

Ceruletide, ceruletide analogues and cholecystokinin octapeptide (CCK-8): effects on isolated intestinal preparations and gallbladders of guinea pigs and mice.

The smooth muscle stimulatory effects of cholecystokinin octapeptide (CCK-8), ceruletide (CER), ten analogues of CER, and carbachol were studied in isolated organs of the guinea pig and the mouse (stomach, ileum, duodenum, colon and gallbladder). On a molar basis, CCK-8 and CER had in all organs except stomach greater potency (lower EC50) than carbachol. The effectiveness (Emax) of CCK-8 and CER was in the gut less than that of carbachol, in the guinea pig gallbladder equal with and in the mouse gallbladder superior to that of carbachol. The alteration of peptide structure was virtually without influence on effectiveness; however, it greatly modified the potency and the organ selectivity of the effect. There was no clear-cut correlation between the potency to stimulate smooth muscle and to alter the behavior of the mouse.

Animals↗
PubMed1991

Regional effects of ceruletide, a cholecystokinin-8 analog, on the striatal monoaminergic systems in food-deprived mice.

To clarify the pharmacological mechanism by which ceruletide affects involuntary movements, we used 20-h food-deprived mice to examine the acute effects of ceruletide (600 micrograms/kg, i.p.) on the histochemistry of striatal dopaminergic and serotonergic systems. The latter was unchanged but a reduction in catecholamine fluorescence was seen which was restricted to the ventrolateral (VL) portion of the striatum. Biochemical assays also indicated decreased levels of dopamine (DA) and its metabolites in this restricted region of the striatum with little or no change in noradrenaline, serotonin or their metabolites. In all regions examined, except the dorsomedial part of the mid-striatum, the ratio of dopamine metabolites to dopamine was higher in the ceruletide-treated group than in controls, suggesting increased DA release. Further pharmacological experiments showed that, compared to results in mice receiving only ceruletide: the ceruletide-induced decreases in DA and dihydroxyphenylacetic acid (DOPAC) in VL were less after alpha-methyl-p-tyrosine treatment; ceruletide caused no significant decrease in either DA or DOPAC after pargyline pretreatment, although the low levels of homovanillic acid (HVA) were still further significantly reduced; and the ceruletide-induced decrease of DA was reduced, that of DOPAC was abolished and that of HVA enhanced by nomifensine pretreatment. These results suggested that ceruletide might induce a more rapid degradation of DA in VL and increased efflux of HVA through the blood-brain barrier. This evidence suggests that ceruletide has a regionally specific effect on the striatal dopaminergic system which may relate to the amelioration of involuntary movements.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1993

Differential effects of ceruletide on amphetamine-induced behaviors and regional dopamine release in the rat.

This study concerned the effects of ceruletide, a cholecystokinin (CCK)-related peptide, on amphetamine-stimulated behaviors (hyperlocomotion and stereotypy) and amphetamine-induced dopamine (DA) release from the striatum and the nucleus accumbens of the rat. Also, behavioral alterations due to ceruletide administration were compared with the change in DA release from these areas. Ceruletide 160 micrograms/kg s.c., attenuated hyperlocomotion induced by amphetamine, 1 mg/kg and 3 mg/kg s.c., but had no effect on amphetamine-induced stereotypy. Results from in vivo microdialysis experiments showed that s.c. administration of ceruletide caused a significant inhibition of the amphetamine-induced increase in DA release in the nucleus accumbens but not in the striatum. These neurochemical inhibitory effects of ceruletide disappeared completely with bilateral subdiaphragmatic vagotomy. However, infusion of 1 microM of ceruletide into the nucleus accumbens through the dialysis probe had no effect on amphetamine-induced DA release. These results suggest that the inhibitory effect of peripheral administration of ceruletide on amphetamine-induced hyperlocomotion is closely related to the change in DA release from the nucleus accumbens. In the nucleus accumbens, systemically administered ceruletide acts initially on the peripheral organs and influences the activity of DA terminals via an unknown path related to the vagus. Ceruletide had different actions on the dopaminergic system in the striatum and that in the nucleus accumbens.

Amphetamine↗
PubMed1990

[Characteristics of antagonism between ceruletide and various central-acting drugs: investigation by means of ambulatory activity in mice].

Behavioral characteristics of ceruletide, a cholecystokinin-like decapeptide, were investigated by means of ambulatory activity in mice. Ceruletide at 100 and 300 micrograms/kg, i.p. slightly but significantly decreased the mouse's activity for 20 min. Therefore, 100 micrograms/kg of ceruletide was used in the experiment of combined administration with the central-acting drugs. Ceruletide reduced the increased activity which was produced by methamphetamine (2 mg/kg, s.c.), ephedrine (80 mg/kg, i.p.), methylphenidate (4 mg/kg, s.c.), cocaine (20 mg/kg, s.c.), mazindol (2.5 mg/kg, s.c.), apomorphine (0.5 mg/kg, s.c.), bromocriptine (8 mg/kg, i.p.), scopolamine (0.5 mg/kg, s.c.), caffeine (10 mg/kg, s.c.) and morphine (20 mg/kg, s.c.) with different potencies and durations. The mice that had experienced ceruletide at 3 micrograms/kg for 5 times at intervals of 3-4 days demonstrated a significant increase in the sensitivity to methamphetamine, although the same treatment with 10-300 micrograms/kg of ceruletide was without effect. On the other hand, when 3-300 micrograms/kg of ceruletide was combined with 2 mg/kg of methamphetamine, the development of reverse tolerance to the ambulation-increasing effect of methamphetamine was inhibited dependently on the doses of ceruletide. However, the reverse tolerance to methamphetamine once established was scarcely modified by ceruletide when it was administered afterwards.

Animals↗
PubMed1989

Ceruletide suppresses endogenous dopamine release via vagal afferent system, studied by in vivo intracerebral dialysis.

Ceruletide, a cholecystokinin-related decapeptide, has been reported to have some therapeutic effects on tardive dyskinesia and other involuntary movement disorders. In order to clarify the effects of ceruletide on dopaminergic activity in the rat striatum, we measured the release of endogenous dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) after intraperitoneal administration of ceruletide (2, 20, 200 micrograms/kg) using in vivo intracerebral dialysis techniques. After administration of ceruletide (200 micrograms/kg), extracellular DA decreased significantly (P less than 0.05) for 0.5-3 h. The maximal reduction of extracellular DA (by 29%) was observed for 2-2.5 h. Extracellular DA was reduced (21%) by 20 but not by 2 micrograms/kg ceruletide. DOPAC and HVA did not change at any dose of ceruletide. We also demonstrated that bilateral subdiaphragmatic vagotomy blocked this inhibitory effect of ceruletide on DA release. These findings indicate that peripherally administered ceruletide suppresses endogenous DA release via the vagal afferent system.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1994

Comparison of satiating effects of ceruletide and food intake using behavioral and electrophysiological indicators of memory.

Animal and human studies have suggested a satieting effect of ceruletide, an analog of cholecystokinin. In humans, signs of a selectively diminished central nervous processing of food stimuli may provide a more valid measure of satiety than overt eating behavior. To assess the satieting effects of ceruletide in humans, effects of ceruletide and food intake on memory of food stimuli and stimuli not related to food (neutral and sex) were compared with memory performance in fasted subjects. In experiment I, recall of slide-projected words was tested in 12 fasting men in a within-subject comparison (i) following intravenous administration of saline solution, (ii) of ceruletide (6.75 micrograms), and (iii) after having eaten a regular breakfast. The P3 component of the event-related potential to the stimuli was assessed as a physiological sign of memory processing. In experiment II, recognition of pictures was tested in a between-subject design in 36 fasting men following (i) administration of saline solution, (ii) of ceruletide (6 micrograms), and (iii) intake of an opulent meal. After food intake, recall and recognition of food and also of sex stimuli were diminished, but were increased for neutral stimuli. Ceruletide diminished recognition of food stimuli and increased that of neutral stimuli; similar effects on recall of food and neutral stimuli failed to reach significance. P3 amplitude did not reflect changes in memory performance. Memory of food stimuli declined after ceruletide as well as after food intake, suggesting ceruletide mediates satieting effects on memory processing.

Adult↗
PubMedDate not supplied

Ceruletide increases threshold and tolerance to experimentally induced pain in healthy man.

UNLABELLED: Previous studies suggested that ceruletide might be endowed with analgesic and sedative properties. To investigate the effects of ceruletide on experimentally induced pain and on central nervous functions, two studies, each involving 24 healthy subjects, were carried out in random double-blind fashion. Every subject participated in three experiments one week apart. In study 1, 120 and 60 ng/kg/hr ceruletide IV increased threshold and tolerance to electrically and threshold to thermally induced cutaneous pain significantly more than saline (p less than 0.001), the higher dose being slightly more active. Only mild sedative effects occurred. Study 2 compared the effects of 60 and 6 ng/kg/hr ceruletide IV to those of 0.4 mg/kg/hr pentazocine IV and investigated whether these effects were naloxone reversible. Both ceruletide doses, 60 ng/kg/hr slightly more than 6 ng/kg/hr, elevated threshold and tolerance to electrically induced and threshold to thermally induced pain markedly, pentazocine acted stronger and longer than ceruletide (p less than 0.001). Naloxone reversed the effects of pentazocine but not of ceruletide. CONCLUSION: ceruletide (1) exerts potent naloxone resistant analgesic effects, which, however, are inferior to those of pentazocine, and (2) produces only mild sedation.

Adult↗
PubMedDate not supplied

Ceruletide acts in the abdomen, not in the brain, to produce satiety.

Ceruletide (caerulein), a decapeptide extracted from the skin of the frog, Hyla caerulea, is very similar in structure to the C-terminal octapeptide of cholecystokinin (CCK-8). Although ceruletide and CCK-8 act through similar or identical receptors to produce the same visceral effects, previous studies in the rat suggested that peripherally administered ceruletide acted directly on the ventromedial hypothalamic (VMH) area to decrease food intake, but peripherally administered CCK-8 acted at a vagally innervated abdominal site to decrease food intake. Since it is unprecedented for these two peptides to produce the same effect by acting at different sites, we investigated the site of action of ceruletide's satiety effect in the rat and compared it to the site of action of CCK-8. The major results were: (1) intraperitoneal administration of ceruletide and CCK-8 inhibited food intake, but intraventricular administration did not; (2) the satiety effect of ceruletide and CCK-8 was not changed by bilateral lesions of the VMH; and (3) the satiety effect of ceruletide and CCK-8 was abolished or markedly reduced by bilateral abdominal vagotomy. We conclude that ceruletide acts at the same vagally innervated abdominal site to produce satiety as CCK-8 does and that neither peptide acts directly on the VMH area.

Abdomen↗
PubMedDate not supplied

Ineffectiveness of ceruletide to reduce food intake and body weight in obese women hospitalized for weight reduction and treated with a restricted diet. A double-blind study.

Ceruletide is a synthetic decapeptide closely resembling the 8-carboxy-terminal peptide of cholecystokinin (CCK-8) with which it shares several biological properties. In a double-blind study versus placebo, we evaluated the effects of ceruletide on self-rated hunger and food intake at lunch time, as well as on body weight in 14 obese women hospitalized for weight reduction and on a restricted diet. During two 6-day courses of treatment with ceruletide or placebo, ceruletide 0.3 microgram/kg b.wt. or an equivalent volume of its diluent were injected IM at 11.30 a.m., i.e., 30 min before lunch. Feelings of hunger were quantitated, using a visual analogue self-rating scale, prior to the injection of ceruletide or placebo and 30 min thereafter, i.e., just prior to the start of meal ingestion, as well as 2 hr after the start of the meal. Duration and caloric content of food ingested at lunch, as well as morning body weight, were recorded daily. Ceruletide, compared to placebo, did not significantly influence any of the above variables. However, in the first three experimental days, the increase in self-rated hunger from values before the injection to 30 min thereafter was less marked, though not significantly so (0.05 less than p less than 0.1), with ceruletide than with placebo. Thus, it appears that ceruletide, under the experimental conditions of the present study, was not effective in enhancing the patients' motivation to lose weight and to further restrict their food intake at lunch time.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1995

Improved event-related potential signs of selective attention after the administration of the cholecystokinin analog ceruletide in healthy persons.

Cholecystokinin (CCK) is co-localized with dopamine (DA) in neurons of the mesolimbic-frontocortical dopamine (DA) system, considered essential for the pathology of psychotic behavior and associated attention deficits. The present experiments in 13 healthy men aimed at examining the effects of the CCK analog ceruletide on attention as reflected by event-related brain potentials (ERPs). Subjects were tested according to a double-blind cross-over design on three occasions, following intravenous infusion of placebo, 0.5 microgram ceruletide, and 2.5 micrograms ceruletide. ERPs were recorded during the subject's performance on an auditory selective attention task including the concurrent presentation of frequent standard tones and infrequent deviant tones which the subject had to listen to, or to ignore. The processing negativity (PN) over frontocentral cortical areas, reflecting selective attention, was higher after ceruletide than placebo, this increase being most pronounced after the 2.5 micrograms dose (placebo -1.29 +/- 0.38 microV versus ceruletide -3.02 +/- 0.65 microV, p < .05). ERP signs of a general increase in cortical arousal after ceruletide did not reach significance. Likewise, mismatch negativity, an indicator of preattentive processing of stimulus deviance, was not significantly affected by the peptide. The results indicate that ceruletide affects human brain function primarily by improving selective attention.

Adult↗
PubMed1991

Long-lasting effect of ceruletide on dyskinesia and monoaminergic neuronal pathways in rats treated with iminodipropionitrile.

In a model of dyskinesia induced by the administration of iminodipropionitrile (IDPN) in the rat, we evaluated the effects of ceruletide, an analogue of cholecystokinin, on behavioral abnormalities and monoaminergic neuronal function. Vertical head twitching in the IDPN-treated animals was inhibited for over 5 h following a single subcutaneous dose of 160 micrograms/kg ceruletide. In animals dosed daily for 2 or 3 days, the number of head twitches at 24 h after the last dose was about one-third of the number before treatment. After repeated daily doses of ceruletide for 6 days, the number of head twitches was reduced to low levels and remained significantly below pretreatment levels until the 4th posttreatment day. These results indicate that the inhibition of dyskinesia by ceruletide was long-lasting. Assays of monoaminergic neurotransmitters and their metabolites in various brain regions indicate that an imbalance between dopaminergic and serotonergic neuronal systems plays a major role in the pathogenesis of the IDPN-induced dyskinesia, i.e. the ratio of (DOPAC+HVA)/5-HIAA was significantly greater in the striatum but significantly smaller in the hippocampus of the IDPN-treated vs normal animals. This initially abnormal ratio of (DOPAC+HVA)/5-HIAA in the striatum and hippocampus of IDPN-treated animals returned to normal following treatment with ceruletide, corresponding with the reduction of the head twitching. The alterations in monoaminergic neuronal function induced by repeated administration of ceruletide persisted for at least 3 days, even though its plasma half-life is several minutes. Ceruletide also exerted a marked effect on monoaminergic neuronal function in the IDPN-treated rats, in contrast to only a slight effect in normal animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Effect of chronic ceruletide treatment on dopaminergic neurotransmitters, receptors and their mRNAs in the striatum of rats with dyskinesia induced by iminodipropionitrile.

To clarify the mechanism of long-lasting ceruletide action, an analogue of cholecystokinin, in relieving the dyskinesia induced by the iminodipropionitrile (IDPN), we investigated the changes in dopaminergic neuronal system in the striatum. In the control rats, ceruletide had no significant effect on the concentrations of dopamine (DA), DOPAC or HVA or on the turnover of DA in the striatum. The concentration of DA was decreased and the turnover of DA [(DOPAC + HVA)/DA] was increased in the striatum of IDPN-treated rats. Chronic administration of ceruletide (160 micrograms.kg-1.day-1 x 10 days) increased DA concentration and decreased DA turnover only transiently. Both D1 and D2 receptors and their mRNAs were decreased in the striatum of rats given IDPN. After chronic ceruletide treatment, D1 receptor rose to the control level for 3 days, while the D2 receptor rose to a level 1.5 times the control level for 3 days. Even at the 7 days after chronic ceruletide treatment, D2-R rose significantly as compared with the IDPN-treated rats. Both D1 and D2 receptor mRNAs were significantly increased for 3 days in the IDPN-treated rats. These observations indicate that the synthesis of DA receptors is increased by ceruletide treatment in the striatum of IDPN-treated rats. These changes in DA receptors and their mRNAs closely paralleled the changes in dyskinetic movement of the IDPN-treated rats after repeated daily administration of ceruletide, as previously reported. The parallel changes between the DA receptors and dyskinetic movement suggest that an up-regulation of DA receptors in the striatum corresponds with an improvement of dyskinesia in the IDPN-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed1992

Systemic administration of a cholecystokinin analogue, ceruletide, protects against ischemia-induced neurodegeneration in gerbils.

The neuroprotective action of a cholecystokinin octapeptide analogue, ceruletide, was evaluated in models of cerebral ischemia using Mongolian gerbils. Ceruletide significantly suppressed the hyperactivity and amnesia induced by ischemia when injected s.c. 30 min before 5-min occlusion of the bilateral common carotid arteries at room temperature or immediately after their reperfusion. Ceruletide also reduced behavioral changes in ischemic gerbils whose body temperature was maintained at 37 degrees C during the 3-min occlusion. In these groups, delayed neuronal cell death in the hippocampal CA1 area following ischemia was markedly attenuated by s.c. administration of ceruletide. On the other hand, ceruletide could not inhibit the behavioral changes or the neurodegeneration induced in the hippocampal CA1 area by 5-min occlusion at 37 degrees C. These findings indicate that peripheral injection of ceruletide produces a neuroprotective action against moderate cerebral ischemia, which is the first evidence suggesting the efficacy of ceruletide in neurodegenerative diseases.

Amnesia↗
PubMed1991

Effect of ceruletide on plasma monoamine metabolites in the rabbit.

Ceruletide, a cholecystokinin octapeptide-like substance, has been shown to have some effect on tardive dyskinesia. We, too, previously examined the effect of ceruletide on various types of involuntary movement, and found that responders tended to have high plasma homovanillic acid (HVA) levels. It is generally accepted that both central and peripheral sources make a contribution of plasma HVA. In this study, the response of plasma HVA in rabbits to ceruletide was investigated after pretreatment with debrisoquin sulfate, a drug which selectively blocks peripheral HVA production by inhibition of MAO. As a result, 8 and 50 micrograms/kg ceruletide treatment showed a tendency to decrease plasma HVA levels, but showed no significant differences; however, 140 and 200 micrograms/kg ceruletide showed a significant reduction of plasma HVA. These results are important to the understanding of the mechanism of ceruletide's effect on the brain, as well as to predict the effect of ceruletide on involuntary movements.

Animals↗