Influence of cholecystokinin on central monoaminergic pathways

Dopamine (DA) and cholecystokinin octapeptide carboxy-terminal (CCK-8) have been found to coexist in some mesolimbic neurons. The present investigation was undertaken in order to study the biochemical and behavioral interactions between CCK-8 and some central monoaminergic pathways. The action of the sulfated form of CCK-8 (10 micrograms/10 microliter intracerebroventricularly) on DA turnover in nucleus accumbens, olfactory tubercles and corpus striatum of the rat was determined after DA synthesis inhibition with alpha-methyl-p-tyrosine (250 mg/kg i.p.). Also, CCK-8 action (1-30 micrograms intracisternally) on DA synthesis was assessed by measuring accumulation of dihydroxyphenylalanine (DOPA) after DOPA-decarboxylase inhibition with NSD-1015 (m-hydroxybenzylhydrazine, 100 mg/kg i.p.). The contents of DA and its main metabolites, dihydroxyphenylacetic acid and homovanillic acid, together with serotonin and its main metabolite, 5-hydroxyindoleacetic acid (5-HIAA), were measured in different brain areas after direct injection of CCK-8 into the ventral tegmental area (A10) or nucleus accumbens. Further, the effect of CCK-8 on amphetamine-induced locomotion and apomorphine-induced stereotypies was studied along with changes in spontaneous locomotion and rearing after CCK-8 injection into the ventral tegmental area and nucleus accumbens. No consistent statistically significant effects of CCK-8 on biochemical or behavioral assessments on measures of DA function were observed. However, injection of high doses of CCK-8 into the ventral tegmental area significantly decreased levels of 5-HIAA in the nucleus accumbens, olfactory tubercles and striatum.     

八肽胆囊收缩素对抗mu和Kappa型受体介导的镇痛作用

以往的资料表明,八肽胆襄收缩素(CCK-8)能对抗阿片镇痛,本实验进一步分析 CCK-8对抗哪一类型阿片受体激动剂的镇痛作用。给大鼠脊髓蛛网膜下腔(I.T.)注射 CCK-8(剂量4ng到1.0μg)既不产生痛敏也不产生镇痛。I.T.注射特异性的μ受体激动剂 PL01710 ng 或 k 受体激动剂 NDA P500 ng 引起的镇痛作用可被注射 CCK-8 4ng 所对抗。而L.T.注射δ受体激动剂 DPDPE(6.5,13.0和26.Oμg)引起的镇痛作用不能被 CCK-8(4ng,40ng I.T.)所对抗。但 CCK-8对抗 PL017和 NDAP 镇痛的作用可被 I.T.CCK 受体拮抗剂 proglumide(3μg)所翻转。以上结果表明,I.T.注射 CCK-8可有效地对抗μ和 k 受体介导的镇痛,并且这种对抗作用是经 CCK 受体介导而实现的。     

Cholecystokinin and bombesin act independently to decrease food intake in the rat

The satiating effects of cholecystokinin-octapeptide (CCK-8) and bombesin (BBS) when injected alone and in combination were compared in intact rats. When injected alone, both CCK-8 and BBS elicited a dose-related decrease of 30-minute food intake. Injections of BBS were less potent than the equivalent doses of CCK-8 in producing satiety. BBS reached an asymptotic level of suppression of approximately 40 percent at a dose of 2 micrograms/kg, whereas injections of 4 micrograms/kg of CCK-8 resulted in a 72 percent suppression of food intake. When the two peptides were administered in a single injection, the resulting suppression of food intake was equivalent to that which would be predicted if their effects were completely additive. These results support the hypothesis that CCK-8 and BBS act via independent mechanisms to induce satiety. A preliminary model of peptidergic satiety, based on this hypothesis, is proposed.     

Involvement of Dopamine Neurons in the Regulation of β-Adrenergic Receptor Sensitivity in Rat Prefrontal Cortex

The contribution of dopamine (DA) afferents to the regulation of beta-adrenergic receptor sensitivity (isoproterenol-stimulated adenylate cyclase activity) in the rat prefrontal cortex was investigated by comparing the effects of lesions affecting either both DA and noradrenaline (NA) or NA fibers alone. Bilateral 6-hydroxydopamine (6-OHDA) lesions made in the ventral tegmental area destroyed ascending DA and to a variable extent ascending NA fibers innervating the prefrontal cortex. Two opposite effects were observed depending on the extent of cortical NA denervation: (a) When NA denervation was complete (less than 4% of controls), a marked increase in the isoproterenol-sensitive adenylate cyclase activity (+78%) was found. The amplitude of this denervation supersensitivity was similar to that occurring following complete and selective destruction of NA innervation induced by bilateral 6-OHDA injections made into the pedunculus cerebellaris superior. (b) When 6-OHDA injections into the ventral tegmental area led to a partial destruction of cortical NA afferents (10-40% of control values), a hyposensitivity of the isoproterenol-induced adenylate cyclase activity (-30%) was observed. This effect contrasted with the moderate supersensitivity seen in rats with partial, but selective, destruction of NA innervation (pedunculus cerebellaris superior lesions). The hyposensitivity of beta-adrenergic receptors obtained in rats with partial lesions of cortical NA fibers, but devoid of cortical DA innervation, suggests that DA neurons may regulate, under certain conditions, the denervation supersensitivity of beta-adrenergic receptors.     

Preventive effect of cholecystokinin octapeptide on experimental amnesia in rats

The effect of intracerebroventricular (ICV) administration of cholecystokinin octapeptide (CCK-8) on electroconvulsive shock (ECS)-induced amnesia in passive avoidance response was studied in rats. In normal rats, CCK-8 in doses from 1 ng to 1 microgram had no effect on the response when injected before the training trials, immediately after foot shock or before the first retention test. However, proglumide, a CCK-8 receptor blocker, induced marked amnesia when injected in doses from 0.1 to 10 micrograms before the training trials and in doses of 1 and 10 micrograms before the first retention test, though not subsequent to foot shock. ECS given immediately after the foot shock caused amnesia in the 24 hr and 48 hr retention tests, which could have been prevented by CCK-8 injected in doses of 10 ng to 1 microgram prior to the training trials, of 10 ng to 1 microgram following ECS and of 0.1 and 1 microgram before the first retention test. In addition, the effects of CCK-8 and proglumide became pronounced following chronic ICV infusion, using an osmotic minipump, for 7 days at a dose of 1 ng/day and 10 ng/day, respectively. The amnesia induced by proglumide was not affected by arginine vasopressin (AVP), while AVP in doses of 10 ng and 100 ng given 30 min before the training trials prevented ECS-induced amnesia. The antiamnesic effect of AVP was abolished by simultaneous administration of proglumide. On the other hand, AVP-antiserum produced marked amnesia which could be antagonized by CCK-8. However, the antiamnesic effect of CCK-8 was not suppressed by AVP-antiserum.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of CCK-8 in the nucleus accumbens

The electrophysiological effects of CCK-8 were studied in the rabbit nucleus accumbens. CCK-8 was found to influence neurotransmitter (modulator) systems so as to enhance their action. For example, CCK-8 enhanced the effects of stimulation of the glutaminergic pathways, the fimbria. In addition, when CCK-8 was co-administered with dopamine and acetylcholine, their suppressive effect on the fimbria evoked response was enhanced. Therefore, CCK-8 appears to be capable of enhancing the influence of multiple neurotransmitter (modulator) systems.     

Cholecystokinin tetrapeptide,proglumide and open-field behavior in rats

The effect of cholecystokinin tetrapeptide (CCK-4) was studied in an open field situation. CCK-4 increased locomotion and rearing and the effect was enhanced by proglumide, a selective antagonist of CCK-8. This is in sharp contrast to our earlier findings that CCK-8 decreased the open-field behavior and that proglumide completely blocked the effect. Thus, the effects of CCK-4 and CCK-8 appear to be opposite to each other in that one is excitatory and the other inhibitory to open-field responses.     

Cholecystokinin octapeptide, proglumide, and passive avoidance in rats

Rats were conditioned to avoid a darkened chamber using electric footshock (0.25 mA for 2 sec). Cholecystokinin octapeptide (CCK-8), a CCK-8 antagonist proglumide, or 0.9% NaCl solution was injected immediately following the footshock to study the effect upon passive avoidance behavior. The passive avoidance behavior was observed one day following the conditioning footshock and treatment. CCK-8 produced a reduction of the passive avoidance latency of rats at doses ranging from 30 micrograms/kg to 500 micrograms/kg. Proglumide (5 mg/kg) was able to block the CCK-8 effect on rat passive avoidance conditioning. Proglumide by itself at a dose of 2 mg/kg decreased the latency to enter the darkened chamber. Endogenous CCK-8 activity may be involved in passive avoidance conditioning in rats.     

Passive avoidance deficit following intracerebroventricular administration of cholecystokinin tetrapeptide amide in rats

The effect of cholecystokinin tetrapeptide amide (CCK-4) injected into the lateral cerebral ventricle on memory processes was examined by a one-trial passive avoidance test in the rat. CCK-4 injection 30 and 60 min before the first retention test caused a shortened latency to response, and its chronic infusion into the lateral ventricle at a rate of 2 micrograms/day shortened the latency of the response to the level of almost complete amnesia. CCK-4 also reduced arginine-vasopressin effect on memory processes when administered simultaneously 30 min before the first retention test, but its amnestic action is short-lasting and antagonized by relatively small amounts of cholecystokinin octapeptide (CCK-8). In addition, the shortened latency to response was admitted to be not always associated with the motility effect of CCK-4.     

CCK-8 modulation of mesolimbic dopamine: Antagonism of amphetamine-stimulated behaviors

Rats (N=15) were implanted with cannulae above the dopaminergic A10 ventral tegmental area (VTA). Two weeks later, four measures of open field behavior were quantified for 10 minutes commencing 30 minutes after parenteral d-amphetamine (1.5 mg/kg) and directly after bilateral infusion of 1.5 μl of: (a) artificial CSF only (VEH), (b) 1.25 μg desulfated CCK (DS-CCK), or (c) 1.25 μg sulfated CCK (CCK). Additional rats with bilateral cannulae directed toward the A10 terminal zones of nucleus accumbens were similarly tested with either VEH (N=2) or sulfated CCK (N=2). With VTA infusions, both the number of occurrences and duration of rearing were significantly reduced in CCK rats, while neither the number of square crossings nor duration of forward locomotion were significantly modified from controls. With nuclei accumbens septi (NAS) infusions, CCK-8 reduced rearing behavior more than ambulatory behavior in this preliminary testing. With either VTA or NAS infusions, no significant differences from controls were found upon two derived measures of motoric performance, namely, “velocity” (number of squares crossed per second in locomotion) and “vertical stability” (seconds per rear). These results suggest a modulation of dopaminergically-mediated behavior by (sulfated) CCK-8 at the cell body region and terminal fields of the mesolimbic (A10) dopamine system.     

Neuroleptic-like properties of cholecystokinin analogs: distinctive mechanisms underlying similar behavioral profiles depending on the route of administration

Rats were trained to discriminate vehicle injections from intraperitoneal injections of 3 micrograms/kg caerulein, a cholecystokinin (CCK) neuropeptide analog. The reward that reinforced correct choices was an electrical brain stimulation self-administered by bar pressing. Dose-response quantitative generalization was obtained by using 1 and 2 micrograms/kg caerulein. Qualitative generalization to the vehicle occurred after injecting 10, 20 and 200 micrograms/kg unsulfated CCK-8, 10, 20 and 200 micrograms/kg CCK-4, 5 micrograms/kg CCK-8 and 1 microgram/kg caerulein, neurotensin or bombesin and 200 micrograms/kg apomorphine or 320 micrograms/kg amphetamine. Total generalization to the caerulein cue was obtained with 20 micrograms/kg sulfated CCK-8 or gastrin 2-17, 25 micrograms/kg somatostatin, 50 micrograms/kg haloperidol and 2 mg/kg chlorpromazine. The previous 5 mg/kg injection of an antiemetic drug such as chlorhydrate of trimethobenzamide did not eliminate the discriminative properties of a subsequent injection of caerulein. Our data thus tend to show that IP injection of caerulein produces effects similar to those of IP neuroleptics.     

Contribution of Noradrenergic Neurons to the Regulation of Dopaminergic (D1) Receptor Denervation Supersensitivity in Rat Prefrontal Cortex

3,4-Dihydroxyphenylethylamine (DA, dopamine) levels in the rat prefrontal cortex were selectively decreased by 52%, leaving noradrenaline (NA) levels unaffected, 4 weeks following restricted bilateral electrolytic lesions of the ventral mesencephalic tegmentum (VMT). These lesions also induced a significant increase in DA-sensitive, but not isoproterenol-sensitive, adenylate cyclase activity in tissue homogenates (+38%). We had shown previously that chemical (6-hydroxydopamine, 6-OHDA) lesions of the VMT destroy both ascending DA and NA fibers but do not alter the D1-receptor density in the prefrontal cortex. In this study, electrolytic lesions of the VMT were combined with bilateral injections of 6-OHDA made laterally in the pedunculus cerebellaris superior to assess the role of NA fibers in the development of D1-receptor supersensitivity. This combined treatment produces a large decrease of cortical NA levels (-95%), an increase in beta-adrenergic-sensitive adenylate cyclase activity (+110%), and a decrease in DA levels (-60%), but does not alter D1-receptor density in the prefrontal cortex. These results indicate that the development of D1-receptor supersensitivity in the prefrontal cortex following electrolytic lesion of the VMT depends on the presence of an intact NA innervation.     

Behavioral effect of cholecystokinin octapeptide in vagotomized rats

Cholecystokinin octapeptide (CCK-8) was administered intracerebroventricularly (icv) or subcutaneously (sc) into subdiaphragmatically vagotomized and sham-operated rats, and the behavioral effects were quantified by an open-field test. Intracerebroventricularly injection of CCK-8 decreased locomotion and rearing to the same extent in both vagotomized and sham-operated rats, while sc injection produced behavioral changes only in sham-operated rats but not in vagotomized ones. The results indicate that CCK-8 affects both central and peripheral receptors, and the vagal nerve may be the major pathway causing behavioral effects from the visceral organs to the brain.     

MK-329 blocks the inhibition of alcohol intake by CCK-8

Peripheral administration of sulfated cholecystokinin octapeptide (CCK-8) potently reduces alcohol intake, preference, and blood levels in rats. MK-329 (L-364,718 or Devazepide) acts at peripheral cholecystokinin (CCK_A) receptors to antagonize CCK-8's physiological and behavioral effects, such as pancreatic stimulation and inhibition of feeding. We determined whether CCK_A receptor blockade would also prevent CCK-8's alcohol satiety effect. Water-deprived female and male rats (n = 7 for each) received randomized combinations of intraperitoneal injections of MK-329 (0, 100, 200, or 400 μg/kg) followed by CCK-8 (0 or 4 μg/kg). Rats were then given access to 5% w/v ethanol for 30 min, followed by 30-min access to water, with food ad lib. MK-329 at all doses significantly (p < 0.05) reduced the suppression of alcohol intake and food intake by CCK-8. MK-329 alone increased alcohol intake at 400 μg/kg, and increased food intake, in females and males at 100 and 200 μg/kg, respectively. We concluded that CCK-8's alcohol and food satiation effects depend on specific, peripheral CCK_A receptors, and satiation of alcohol consumption and drinking-associated feeding reflect an endogenous functional interaction of CCK-8 with CCK_A receptors.     

Single doses of catecholamines in the rat: catecholaminotropic, but not hyperglycemic

1. As in two "lower" vertebrates, the lamprey and the eel, single intravascular injections of physiological doses (2.5 micrograms/kg) of epinephrine (E) into the rat immediately increased levels of plasma dopamine (DA) and norepinephrine (NE). 2. Single doses of DA (5 micrograms/kg) enhanced circulating NE and E, while NE (5 micrograms/kg) had no clear impact on the plasma levels of the other two catecholamines (CAs). 3. These data are at variance with findings in the eel, where all three CAs are mutually stimulatory; and in the lamprey, where only E stimulates release of the other two CAs. 4. It appears that E-stimulated CA release is widespread or ubiquitous among vertebrates, and that complex interactions between circulating CAs must be considered under experimental, physiological, and clinical conditions. 5. None of the injections had a significant hyperglycemic effect.     

八肽胆囊收缩素对抗阿片肽的中枢性降血压作用

过去的工作已经证明八肽胆囊收缩素(CCK-8)能够对抗阿片肽的镇痛作用,本工作探讨CCK-8是否能够对抗阿片肽的心血管抑制作用。给戊巴比妥钠麻醉大鼠脊髓蛛网膜下腔(ith)注射 CCK-8可以对抗 ith 注射 mu(μ)型阿片受体激动剂[NMePhe~3,D-Pro~4]Morphiceptin(PL017)(5μg)、delta(δ)型受体激动剂[D-Ala~2,D-Leu~5]Enkephalin(DADLE)(25μg)和 Kappa(K)型受体激动剂[N-Me Tyr,N-Me Arg~7,D-Leu~8]Dynorphin 1-8 ethyla-mide(66A-078)(1μg)引起的降低血压和减慢心率作用。在 MAP 的表现上,CCK-8的拮抗作用(10μg及以下剂量)具有量-效关系,并可被 CCK 受体阻断剂丙谷胺(Proglumide)(100μg)翻转。在 HR 的表现上,上述剂量的 CCK-8也显示了一定的拮抗作用,但量-效关系不如 MAP 表现得明显。单纯将 CCK-8或 Proglumide ith 注射,可见大剂量(50μg)CCK-8可以引起明显的降血压作用和短时的降心率作用,小剂量(0.05μg)CCK-8则表现出明显的降心率作用;ith 注射 Proglumide 100μg,30 min 后也表现出减慢心率的作用。以上结果提示:在脊髓水平,一定剂量范围内的 CCK-8能够对抗阿片肽的心血管抑制效应,此对抗作用是通过 CCK 受体实现的。本工作的结果支持关于 CCK-8是一种抗阿片物质的设想。     

Apneic effects of cholecystokinin in unanaesthetized fetal sheep

The effects on breathing movements and sleep state of cholecystokinin octapeptide (CCK-8) and its antagonist, proglumide, have been studied in unanaesthetised fetal lambs of 124-142 days gestation. CCK-8 when given into a lateral cerebral ventricle as bolus injections of 10-500 ng caused dose-related periods of apnea ranging from 63-214 min. When given as a 100 ng bolus followed by a 50 ng/h infusion for 2 h there was a prolonged period of apnea lasting 331 +/- 56 min. There was no effect of CCK-8 when given in higher doses (1-50 micrograms). The antagonist proglumide reversed the apnea induced by CCK-8 infusion, but had no effect when given alone, nor did it affect the normal fetal depressive response to hypoxia. Neither CCK-8 nor proglumide had any effect on electrocortical activity. We conclude that CCK has no role in the inhibitory mechanisms causing the apnea associated with high voltage electrocortical activity or hypoxia in the fetus. Furthermore CCK does not appear to be involved in the regulation of sleep state in the fetal lamb.     

Angiotensin II, bombesin and naloxone in tooth pulp and cutaneous nociceptive mechanisms in rabbits

The effects of angiotensin II (A II), bombesin (B) and naloxone (N) on the amplitude of the late component of the evoked potentials of the cortex (EP) were studied by electrocutaneous (ECS) and tooth pulp (ETS) stimulation. An intraventricular (50 ng/kg) or intravenous (5 micrograms/kg) injections decreased the amplitude of the negative-positive component with a 20-40 ms latency (NP20-40) EP to ETS, but not to ECS. Saralasin (A II antagonist) injected intraventricularly (130 ng/kg) abolished this effect of A II in response to ETS. N intraventricular injections (30 micrograms/kg) increased the amplitude of NP20-40 EP to ETS, but not to ECS. B (intraventricular injection 20 ng/kg decreased the amplitude of NP20-40 EP to ECS, but not to ETS. This suggests there are the specific mechanisms in analgesia induced by A II and B in the pathways activated by ECS and ETS.     

Effects of amylin on feeding of goldfish: interactions with CCK

In mammals, amylin (AMY) is a peptide that is secreted from the pancreas in response to a meal. AMY inhibits food intake and may also contribute to the anorectic effects of the brain-gut peptide cholecystokinin (CCK). In this study, we assessed the role of AMY in the regulation of food intake in goldfish (Carassius auratus) and its interactions with CCK. Fish were injected intraperitoneally (i.p.) with mammalian AMY and intracerebroventricularly (i.c.v.) with mammalian AMY, alone or in combination with the sulfated octapeptide CCK-8S. We also assessed the effects of i.c.v. injections of AC187, an amylin receptor antagonist on the central actions of both AMY and CCK-8S, as well as the effects of i.c.v. injections of proglumide, a CCK receptor antagonist, on the central effects of AMY. AMY injected i.p. at 100 ng/g but not 25 or 50 ng/g or i.c.v. at 10 ng/g but not 1 ng/g significantly decreased food intake as compared to saline-treated fish. Fish co-treated i.c.v. with AMY at 1 ng/g and CCK-8S at 1 ng/g had a food intake lower than that of control fish and fish treated with either 1 ng/g CCK-8S or 1 ng/g AMY, suggesting a synergy between the two systems. Whereas low i.c.v. doses of AC187 (30 ng/g) had no effect, moderate doses (50 ng/g) induced an increase in food intake, indicating a role of endogenous AMY in satiety in goldfish. Blocking central amylin receptors with i.c.v. AC187 (30 ng/g) resulted in an inhibition of both i.c.v. AMY- and CCK-induced reduction in feeding. Blocking central CCK receptors with i.c.v. proglumide (25 ng/g) resulted in an inhibition of both i.c.v. CCK-induced and AMY-induced decrease in food intake. Our results show for the first time in fish that AMY is a potent anorexigenic factor and that its actions are interdependent with those of CCK.     

Plant-Derived Neurotoxic Amino Acids (β-N-Oxalylamino-l-Alanine and β-N-Methylamino-l-Alanine): Effects on Central Monoamine Neurons

In the present study the subacute effects of beta-N-oxalylamino-L-alanine (BOAA) and beta-N-methylamino-L-alanine (BMAA) on CNS monoamine neurons in rats were investigated following intracisternal injections or local intracerebral administration into substantia nigra. In vitro effects of BOAA and BMAA on high-affinity synaptosomal uptake of dopamine (DA), noradrenaline (NA), and serotonin (5-HT) were also examined. Intracisternal administration of BMAA decreased NA levels in hypothalamus, whereas no effects were seen on DA or 5-HT levels. Following intranigral injections of BOAA, NA levels tended to decrease in several regions, whereas the DA levels and the levels of DA metabolites were unaffected in all regions analyzed. Loss of tyrosine hydroxylase (TH) immunoreactivity in the intranigral injection sites and the presence of TH-immunoreactive pyknotic neurons near the borders of the injection sites were observed following both BOAA and BMAA treatments. Furthermore, substance P-immunoreactive terminals in substantia nigra pars reticulata were also found to have disappeared within the lesioned area following either BOAA or BMAA injections. Incubations with both BOAA and BMAA (10(-5) M) reduced high-affinity [3H]NA uptake in cortical synaptosomes to 69% and 41% of controls, respectively, whereas the striatal high-affinity [3H]DA uptake and the cortical high-affinity [3H]5-HT uptake were unaffected by BOAA or BMAA. The results demonstrate that both BOAA and BMAA can affect central monoamine neurons, although the potency and specificity of these substances on monoamine neurons when administered acutely into cerebral tissue or liquor cerebri seem to be low. However, the in vitro studies indicate selective effects of both compounds on NA neurons in synaptosomal preparations.