Memory impairments induced by peripherally administered cholecystokinin a-type receptor antagonists in rats

Intraperitoneal injection of cholecystokinin (CCK) A-type receptor antagonists, L-364,718 and CR 1409, caused dose-dependent memory impairments in passive and active avoidance responses and in Morris water pool test in rats. These antagonist effects were significant at a dose of 1 mg/kg, while with proglumide, 50–100 mg/kg were required to produce a similar memory deficit. The results suggest that loss of biologically active CCK octapeptide (CCK-8), not only in the brain but also in the peripheral tissues, causes memory impairmets in rats. © 1992 Wiley-Liss, Inc.     

Antinociceptive effect of centrally administered caerulein and cholecystokinin octapeptide (CCK-8)

When injected into the brain (periaqueductal gray (PAG), caudate nucleus, ventromedial thalamus) or subarachnoidal space of the lumbar spinal cord of rats, caerulein and CCK-8 produced a long-lasting (2 h) inhibition of the tail-flick response to thermal stimulation. The effective dose range for caerulin was from 1 to 5 ng per rat, for CCK-8 from 10 to 40 ng, and for morphine from 1 to 20 μg. On a molar basis and dependent upon the site of administration, caerulein was 4000–7000 times and CCK-8400-700 times more potent than morphine. Unsulphated caerulein (injected into the PAG) was less active than caerulin by a factor of 9. Sedation was seen after intracerebral, but not after spinal administration of the peptides; it was not observed after morphine or unsulphated caerulin. Naloxone (0.5 mg/kg i.p.) abolished the antinociceptive but not the sedative effect. It is concluded that caerulin and CCK-8 are very potent in reducing nociception by acting at both spinal and supraspinal levels.     

Effect of cholecystokinin octapeptide antagonists on the extinction of an active avoidance task in the rat

Cholecystokinin octapeptide (CCK-8) has been shown to be involved in memory processes. For example, in the absence of endogenous CCK-8 in the brain, memory processes are imparied. In order to extend the understanding of this relationship, the present study observed the effect of novel potent CCK-8 antagonists, L-364,718 and CR 1409, on active avoidance responding in the rat. These antagonists caused marked impairment in the performance of the learned task when administered intracerebroventricularly immediately after the learning trials. The results suggest that CCK-8 is indispensable for memory processes.     

Preventive effect of cholecystokinin octapeptide on scopolamine-induced memory impairment in the rat

In a passive avoidance response, intraperitoneal administration of scopolamine (0.5 mg/kg) at 15 min before the training trials produced a marked impairment of memory in the rat. However, pretreatment with cholecystokinin octapeptide (CCK-8) either given subcutaneously or intracerebroventriculary (i.c.v.) prevented the scopolamine-induced amnesia. Continuous i.c.v. infusion of CCK-8 (1 ng/day) for 7 days significantly prevented the amnesia. The results support our previous findings that CCK-8 has a protective effect against experimental amnesia in the rat.     

Prevention of scopolamine effect on the decrease of acetylcholine content by peripherally administered cholecystokinin octapeptide in some regions of the rat brain

Intraperitoneal injection of scopolamine at a dose of 0.5 mg/kg produced a marked decrease after 15 min in the acetylcholine (ACh) content of the frontal and temporal cortices and the hippocampus in the rat. In the parietal and occipital cortices and the striatum, the decrease in ACh content was less extensive. When rats were treated with cholecystokinin octapeptide 15 min before the scopolamine administration, the decrease in ACh was prevented in a dose-dependent manner. The choline content was not affected significantly by these treatments.     

Potential cognition-enhancing properties of S 9977 in three moenls of amnesia in the mouse

The effects of S 9977 (1,3,7-trimethyl 8-[3-(4-diethylaminocarbonyl-l-piperazinyl) 1-propyl]-3,7-dihydro(1H)2,6-purinedione hydrochloride) on the amnesias induced by scopolamine, diazepam, and electroconvulsive shock (ECS) were studied in a passive avoidance procedure in the mouse. Amnesia was induced by injecting scopolamine or diazepam (1 mg/kg i.p.) 30 min before or ECS administered immediately after the first session (S1) of the passive avoidance task. S 9977 was studied in a dose range of 0.0312–16 mg/kg administered p.o. 60 min before S1. Retention was measured 24 hr later (S2) in the absence of any treatment. S 9977 was also investigated after repeated administration (twice daily for 3 days and then 60 min before acquisition on the 4th day) using the scopolamine-induced amnesia model. Additional experiments investigated the interactions of the compound with the major behavioral effects of the amnesic treatments, namely scopolamine-induced hyperactivity (activity meter test), diazepam-induced release of punished behavior (four plates test), and ECS-induced convulsion. S 9977 at low doses (0.0312–0.5 mg/kg p.o.) clearly attenuated the memory deficits induced by the three amnesic treatments after acute treatment and no tolerance was observed after repeated treatment in the scopolamine model. S 9977 did not affect either scopolamine-induced hyperactivity, diazepam-induced release of punished behavior, or ECS-induced convulsions. These results point to the specificity of S 9977's antiamnesic activity and suggest that it might be a useful agent for the treatment of memory deficits of different origins in humans. © 1992 Wiley-Liss, Inc.     

Effects of cholecystokinin octapeptide on striatal dopamine metabolism and on apomorphine-induced stereotyped cage-climbing in mice

The effects of sulfated (CCK-8-SE) and non-sulfated (CCK-8-NS) cholecystokinin octapeptide on striatal dopamine (DA) metabolism have been investigated on mice. CCK-8-NS facilitated the disappearance of striatal DA, measured after synthesis inhibition with 350 mg/kg of alpha-methyl-p-tyrosine. CCK-8-SE did not affect DA disappearance. In vitro uptake of [3H]DA by striatal slices was affected by neither CCK-8-SE, nor CCK-8-NS (10(-5) M). Potassium-induced in vitro release of [3H]DA from striatal slices was significantly increased by 10(-5) M CCK-8-NS: however, CCK-8-SE likewise increased DA release in this model system. Apomorphine-induced (1.0 mg/kg) stereotyped cage-climbing behavior was not affected by CCK-8-SE but was enhanced by CCK-8-NS. This effect could be antagonized by haloperidol, but not by naloxone. The data suggest that CCK-8-NS affects striatal DA release, disappearance and receptor sensitivity in the mouse. Dopaminergic mechanisms should therefore be regarded as a possible mode of action of CCK-8-NS on brain functions.     

Antiamnesic effects of magnesium pyrrolidone carboxylate (MAG 2) in three models of amnesia in the mouse

The effects of magnesium pyrrolidone carboxylate (MAG 2) on the amnesias induced by scopolamine, diazepam, and electroconvulsive shock (ECS) were studied in a passive avoidance procedure in the mouse and compared with the effects of a standard dose of piracetam. Amnesia was induced by injecting scopolamine or diazepam (1 mg/kg intraperitoneally [i.p.]) 30 min before or ECS administered immediately after the first session (S1) of the passive avoidance task. MAG 2 was studied in a dose range of 128 to 1,024 mg/kg and compared with piracetam (2,048 mg/kg), both drugs being administered orally (p.o.) 60 min before S1. Retention was measured 24 hr later (S2) in the absence of any treatment. Further experiments investigated the effects of repeated administration of MAG 2 (twice daily for 3 days) on diazepam-induced amnesia. Additional experiments investigated the interactions of the compound with the major behavioral effects of the amnesic treatments, namely scopolamine-induced hyperactivity, diazepam-induced release of punished behavior (four plates test), and ECS-induced convulsions. MAG 2 dose-dependently attenuated the memory deficits induced by the three amnesic treatments after acute treatment and more effectively antagonized diazepam-induced amnesia after repeated than after acute treatment. It did not affect either scopolamine-induced hyperactivity, diazepam-induced release of punished behavior or ECS-induced convulsions. These results point to the specificity of MAG 2′s antiamnesic activity and suggest that it might be a useful agent for the treatment of memory deficits of different origins in man.     

Antistereotypic effects of cholecystokinin octapeptide (CCK-8), ceruletide and related peptides on apomorphine-induced gnawing in sensitized mice

Cholecystokinin octapeptide (CCK-8), ceruletide (caerulein, CER) and 7 analogues of ceruletide, were studied for antagonism of stereotyped gnawing and cage climbing, induced by apomorphine in mice that were sensitized by either administration of scopolamine (1 mg/kg, s.c., 15 min before) or teflutixol (5 mg/kg, i.p., 4 days before). Three neuroleptics (haloperidol, trifluoperazine and teflutixol) served as reference drugs. All peptides reduced or abolished the fully developed gnawing activity and were (on a molar basis) often more potent than the reference drugs. In contrast to the neuroleptics, the peptides did not antagonize the climbing activity. In mice pretreated with scopolamine, the peptides were more potent than in mice pretreated with teflutixol. With the neuroleptics, the influence of the sensitizing pretreatments was converse, and this applied also to the anticlimbing effect. The relationships between peptide structure and antistereotypic effect were different from those found previously in a study on the antagonism of gnawing induced by methylphenidate. Conclusions: CCK-like peptides are able to antagonize stereotyped behaviour caused by direct and indirect dopaminergic agonists; the mechanism of action of the peptides differs from that of the reference neuroleptics.     

八肽胆囊收缩素对抗吗啡抑制大鼠脑突触小体钙摄取的作用

用大鼠脑的膜制备观察吗啡和CCK-8对突触小体摄取~(45)Ca~(2+)的影响。吗啡(10 nmol/L～1μmo1/L)抑制突触小体对~(45)Ca的摄取,该作用能被1μmol/L纳洛酮完全阻断。CCK-8(10nmol/L～1μmol/L)本身能抑制突触小体~(45)Ca摄取,但它在10nmol/L和100 nmol/L时能对抗吗啡对~(45)Ca摄取的抑制作用,浓度提高到1μmol则不能对抗吗啡的这一作用。CCK-8抑制突触小体摄取~(45)Ca,以及对抗吗啡的~(45)Ca摄取抑制的作用,皆能被CCK受体拮抗剂丙谷酰胺(2μmol/L)所阻断.捉示CCK-8是通过激动CCK受体而拮抗吗啡抑制~(45)Ca摄取的,CCK-8的这一拮抗作用可能是其抗阿片作用的机理之一.     

Effects of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) after repeated administration on a conditioned avoidance response (CAR) in the rat

8-OH-DPAT, a selective 5-HT_1A agonist, has variously been found to impair, have no effect on or enhance the conditioned avoidance response (CAR). Procedural differences may account for the difference in results. In the first experiment in the present study rats were trained in the two-way active avoidance procedure to a criterion of 65% avoidance. Separate groups of rats were treated with 0.01, 0.1 or 1.0 mg/kg 8-OH-DPAT SC once per day for 14 days. The rats were tested in the CAR each day 5 min after treatment, using a 10 s light and tone conditioned stimulus and five 0.2 mA/0.5 s electric shocks. On the first day the doses of 0.1 and 1.0 mg/kg impaired avoidance, but by the end of training these two doses increased avoidance. This change in effect was accompanied by a 15-fold increase in the number of trials in which the subject crossed during a 10 s period of the ITI, which in turn led to a significant impairment in the discrimination ratio. The results of this experiment show that with repeated treatment 8-OH-DPAT changes from being antipsychotic like to being stimulant-like. The latter effect produces an improvement in avoidance, probably due to a non-specific increase in activity. In the second experiment, the rats were divided into groups based upon the undrugged performance. The avoidance-enhancing effect of 8-OH-DPAT was greater in magnitude in a group of poor performers, but was qualitatively similar in good performers. In the second stage of the experiment, gradual withdrawal from the drug was compared with sudden withdrawal. In the gradual withdrawal group, a reduction in the dose from 0.085 mg/kg to 0.01 mg/kg resulted in a gradual disappearance of the enhanced activity. There was an almost linear relationship between performance and the log dose of the drug, suggesting that the increase in activity seen after repeated administration of 8-OH-DPAT is directly related to the acute level of drug administered. This effect was evident in both good and poor performers. On the basis of these results it is suggested that many, but not all, antidepressant-like effects of 8-OH-DPAT may result from changes in activity.     

Suppressive action of cholecystokinin octapeptide on the behavioral effects of L-DOPA in the rat

Intracerebroventricular (i.c.v.) administration of cholecystokinin octapeptide (CCK-8) appeared to suppress the effects of L-DOPA and antagonize the actions of thyrotropin-releasing hormone (TRH). This was not only proved by the behavioral rating, but also by locomotor activity counting. thus, the sedative action of CCK-8 and the antagonizing effect of this peptide on the central actions of TRH were clearly demonstrated.     

Opioid receptors in the brain of the rat following chronic treatment with desipramine and electroconvulsive shock

The effect of chronic administration of electroconvulsive shock and the antidepressant drug desipramine on binding to opioid receptors was studied in the cerebral cortex, the basal ganglia and the hippocampus of the forebrain of the rat. In vitro, desipramine inhibited the binding of enkephalinamide to opioid receptors through a reduction in the number of binding sites, whereas the affinity was unchanged or only slightly decreased. In vivo desipramine, injected daily (10 mg/kg) for three weeks, did not change the number of opioid binding sites in the forebrain of the rat. Chronic electroconvulsive shock, given twice a week for three weeks, had no effect on the number of opioid binding sites in the forebrain of the rat. The data do not support the hypothesis of shared effects of lithium, tricyclic antidepressants and electroconvulsive shock on the opiod peptide-opioid receptor systems.     

Ethological analysis of cholecystokinin (CCKA and CCKB) receptor ligands in the elevated plus-maze test of anxiety in mice

The literature on the effects of CCK receptor manipulations in animal models of anxiety is rife with inconsistency, and the data subject to a variety of methodological and interpretative difficulties. In the present paper, the effects of a range of CCK receptor ligands on anxiety in male mice have been assessed using an ethological version of the elevated plusmaze test. Compounds selected for study were the agonists, CCK-4 and CCK-8s (12.5–100µg/kg), and the antagonists, devazepide, L-365, 260 and PD 135158 (1.0 µg/kg–1.0mg/kg). CCK-4 failed to produce any significant behavioural effects over the dose range tested, while treatment with the sulphated octapeptide, CCK-8s, induced signs of behavioural inhibition at 100 µ/kg without altering anxiety-related indices. Furthermore, in contrast to the clear anxiolytic profile of diazepam (1 mg/kg), and despite the comprehensive behavioural profiles yielded by ethological analysis, all three CCK receptor antagonists studied (devazepide, L-365, 260 and PD 135158) were found to be without significant effect under present test conditions. Together, present findings provide little support for the involvement of CCK receptor mechanisms in anxiety and, in particular, the form of anxiety evoked in mice by exposure to a plus-maze.     

Memory-enhancing effect of a cerulein analogue following peripheral administration in the rat

Our previous studies demonstrated that cerulein (CER) has a potent preventive action on amnesia induced by electroconvulsive shock, administration of scopolamine, puromycin, anisomycin, NMDA receptor antagonists, and protein kinase C inhibitors. The present study was aimed at finding more effective CER analogues which could enhance memory processes. Five CER analogues were synthesized and the potencies in passive and active avoidance responses and in the Morris water pool test were examined in the rat. Among the preparations, des-Gln²-[Leu⁵, Nle⁸]-CER was found to possess particularly potent effects on memory acquisition and/or storage. The effects were apparent in less than 1 μg/kg single subcutaneous (s.c.) injection for at least 120 hr in passive avoidance response and 15 days in active avoidance response. Memory impairments induced by scopolamine and puromycin were well improved in passive avoidance response. In the Morris water maze test, disordered behaviors caused by scopolamine and protein kinase C inhibitor were totally restored to the normal state by s.c. injection of this CER analogue. © 1992 Wiley-Liss, Inc.     

Effect of cholecystokinin octapeptide and ceruletide on release of acetylcholine from cerebral cortex of the rat in vivo

The effect of cholecystokinin octapeptide (CCK-8) and its analogue, ceruletide on release of acetylcholine (ACh) from the cerebral cortex was investigated in urethane-anaesthetized and in unanaesthetized rats. Cholecystokinin octapeptide and ceruletide markedly stimulated output of ACh at doses of 1.5 and 5.0 micrograms/kg (i.p.), respectively. This effect was prevented by proglumide (160 mg/kg i.p.), a specific cholecystokinin receptor antagonist. At doses of 10 micrograms/kg (i.p.) and more, both CCK-8 and ceruletide decreased output of ACh from the cerebral cortex. The decrease was prevented by naloxone (1 mg/kg, s.c.), and replaced by a short-lasting increase. Cholecystokinin octapeptide and ceruletide appear therefore to affect the activity of cortical cholinergic fibres by acting upon both specific and opiate receptors. The interaction between CCK-8 and ceruletide, and opiate receptors either direct or through the release of endogenous opiates, was also demonstrated by the antagonism between ceruletide (1, 5 and 10 micrograms/kg, i.p.) and analgesia induced by morphine (5 mg/kg, s.c.), evaluated by the tail-flick test in the rat.     

CCK-8对大鼠肺间质巨噬细胞cAMP-PKA信号通路的激活作用

目的探讨八肽胆囊收缩素(CCK-8)对大鼠肺间质巨噬细胞(PIMs)cAMP-PKA信号通路的激活作用。方法分离纯化大鼠PIMs,采用放射免疫分析法测定细胞内cAMP含量,放射激酶法测定PKA活性,受体拮抗剂的IC50值由对数-几率单位法求得。结果正常对照组大鼠静息状态下PIMscAMP含量和PKA活性分别为(2.04±0.13)nmol·g-1和(118.3±11.2)nmol·min-1·g-1。低浓度CCK-8[(10-12～10-10)mol·L-1]对细胞内cAMP含量和PKA活性没有影响(与正常对照组比较:P>0.05);高浓度CCK-8[(10-9～10-5)mol.L-1]可明显提高细胞内cAMP含量和PKA活性(与正常对照组比较:P<0.05)。10mg·L-1脂多糖(LPS)刺激大鼠PIMs,可明提高细胞内cAMP含量和PKA活性,分别为(5.15±0.12)nmol·g-1和(188.6±13.5)nmol·min-1·g-1。不同浓度的CCK-8与LPS共同孵育PIMs,细胞内cAMP含量和PKA活性的变化趋势与CCK-8作用于静息状态下大鼠PIMs的变化趋势完全相同。CCK受体拮抗剂丙谷胺、CR-1409、CR-2945可呈剂量依赖性地抑制CCK导致的cAMP含量的升高,它们的IC50值分别为(0.5×10-6、4.1×10-6、7.2×10-4)mol·L-1。丙谷胺、CR-1409、CR-2945也可明显减弱CCK-8所导致的PKA活性的升高;其中,丙谷胺的抑制作用最强,CR-1409次之,CR-2945的抑制作用最小。结论CCK-8可剂量依赖性地激活静息状态和LPS诱导的大鼠PIMscAMP-PKA信号转导途径,这可能是CCK抗炎作用的分子机制之一。CCK激活cAMP-PKA通路是通过CCK受体来实现的,且CCK-AR的作用比CCK-BR的作用更为明显。     

Effects of RO 15-4513 and FG 7142 alone and in combination with ethanol on avoidance in the rat

Rats were trained on a complex avoidance schedule in which responses on one lever postponed shock and responses on another lever occasionally (variable-interval 45 sec schedule) produced 2 min periods of timeout from avoidance. As shown in previous experiments, ethanol (1.5 or 2.0 g/kg) produced an increase in timeout responding relative to avoidance lever rates. These effects were attenuated in five of the six rats by 6 mg/kg RO 15-4513, a dose that did not produce consistent intrinsic effects. In contrast, FG 7142 (10 mg/kg) reliably reversed ethanol effects in only one of the six rats tested. These results support the notion that RO 15-4513 possesses specific ethanol antagonist properties.     

Effects of nimodipine, felodipine and amlodipine on electroconvulsive shock-induced amnesia in the rat

The effects of various doses (0.03, 0.1, 0.3 or 1.0 mg/kg) of the Ca²⁺ channel blockers nimodipine, felodipine and amlodipine on the learning ability of rats exposed to electroconvulsive shock were examined. The animals were trained in a passive avoidance procedure. The drugs tested were injected 30 min before the learning trial started. The electroconvulsive shock was given immediately after the learning trial response had been acquired. A passive avoidance retention test was performed 24 h later. It was found that electroconvulsive shock strongly impaired the retention of the passive avoidance response. Nimodipine, felodipine and amlodipine did not influence the passive avoidance behavior in the sham electroconvulsive shock group, but significantly improved the retention deficits in the animals exposed to electroconvulsive shock. These findings support the hypothesis that perturbations in Ca²⁺ homeostasis can contribute to the memory deficits associated with electroconvulsive shock. The antiamnestic effects of the substances tested make them interesting candidates for clinical trials in patients with cognitive impairment caused by electroconvulsive shock therapy.