Administration Of CCK-4 Research Articles

Interactions of Cholecystokinin and Glutamatergic Systems in Feeding Behavior of Neonatal Chickens.

This study aimed to assess the possible feeding behavior alterations by central interactions of cholecystokinin (CCK) and glutamatergic systems in neonatal chickens. In experiment 1, chickens received intracerebroventricular (ICV) administration of saline and CCK (CCK₄; 0.25, 0.5, and 1 nmol). In experiment 2, birds were ICV injected with saline, CCK_8s (0.25, 0.5, and 1 nmol). In experiment 3, chickens received the ICV injection of saline, CCK_8s (1 nmol), MK-801 (15 nmol), and co-injection of the CCk_8s+MK-801. Experiments 4-7 were performed similar to experiment 3, except for chickens that were injected with CNQX (390 nmol), AIDA (2 nmol), LY341495 (150 nmol), and UBP1112 (2 nmol) instead of MK-801. Subsequently, the total amount of the consumed food was determined. According to the results, the ICV administration of CCK₄ (0.25, 0.5, and 1 nmol) could not affect the food intake in chickens (<i>P</i>&gt;0.05). The ICV injection of the CCK_8s (0.25, 0.5, and 1 nmol) led to a dose-dependent hypophagia (<i>P</i>&lt;0.05). Moreover, hypophagia induced by CCK_8s decreased by the co-injection of the CCK_8s+MK-801 (<i>P</i>&lt;0.05). These results showed that the hypophagic effects of the CCK on food intake can be mediated by NMDA glutamate receptors in layer-type chickens.

Behavioral and cortical EEG evaluations confirm the roles of both CCKA and CCKB receptors in mouse CCK-induced anxiety

This study investigated the roles of cholecystokinin (CCK)A and CCKB receptors on CCK-4-induced anxiety-like behaviors in mice through behavioral and neural evaluations. Anxiety-like behaviors in mice were induced by an intracerebroventricular (i.c.v.) administration of CCK-4, which can bind to both CCKA and CCKB receptors. The effects of CCKA and CCKB receptor antagonists (devazepide and CI-988, respectively) were examined using mouse anxiety tests (elevated-plus maze and light–dark box) and also by examining neuronal activities through EEG monitoring and c-Fos immunohistochemistry in the cortex and amygdala. CCK-4 (3μg/kg of body weight i.c.v.) significantly induced mouse anxiety-like behaviors in the anxiety tests and also affected their EEG patterns with respect to pre-drug tracing, resulting in increase in spectral power in relative power distribution in the delta and theta bands (0.5–5Hz frequency bands) and also in increase in c-Fos immunopositive neuron counts. These CCK-4 effects were completely suppressed by 1.0mg/kg CCKB receptor antagonist, CI-988, while the same amount of CCKA receptor antagonist, devazepide was partly able to suppress the same effects. These findings indicated that not only CCKB receptors but also CCKA receptors in the brain play important roles in regulating anxiety-like behaviors in mice. The present study also proposed a possibility that cortical EEG is useful for assessing anxiety.

NEURONAL NETWORK OF PANIC DISORDER: THE ROLE OF THE NEUROPEPTIDE CHOLECYSTOKININ

Panic disorder (PD) is characterized by panic attacks, anticipatory anxiety and avoidance behavior. Its pathogenesis is complex and includes both neurobiological and psychological factors. With regard to neurobiological underpinnings, anxiety in humans seems to be mediated through a neuronal network, which involves several distinct brain regions, neuronal circuits and projections as well as neurotransmitters. A large body of evidence suggests that the neuropeptide cholecystokinin (CCK) might be an important modulator of this neuronal network. Key regions of the fear network, such as amygdala, hypothalamus, peraqueductal grey, or cortical regions seem to be connected by CCKergic pathways. CCK interacts with several anxiety-relevant neurotransmitters such as the serotonergic, GABA-ergic and noradrenergic system as well as with endocannabinoids, NPY and NPS. In humans, administration of CCK-4 reliably provokes panic attacks, which can be blocked by antipanic medication. Also, there is some support for a role of the CCK system in the genetic pathomechanism of PD with particularly strong evidence for the CCK gene itself and the CCK-2R (CCKBR) gene. Thus, it is hypothesized that genetic variants in the CCK system might contribute to the biological basis for the postulated CCK dysfunction in the fear network underlying PD. Taken together, a large body of evidence suggests a possible role for the neuropeptide CCK in PD with regard to neuroanatomical circuits, neurotransmitters and genetic factors. This review article proposes an extended hypothetical model for human PD, which integrates preclinical and clinical findings on CCK in addition to existing theories of the pathogenesis of PD.

Megestrol attenuates the hormonal response to CCK-4–induced panic attacks

Progestational hormones may have anxiolytic properties. CCK-4 (cholecystokinin tetrapeptide) can be used pharmacologically to induce panic attacks both in normal controls and patients suffering from panic disorder. In this study we compared the effects of pretreatment with the progestational hormone megestrol and placebo on CCK-4-induced panic attacks and stress hormone release in healthy male controls. Using a double-blind balanced design, we pretreated 10 medically and psychiatrically healthy male controls with placebo or megestrol 160 mg at 11 p.m. and 8 a.m. (sigma=320 mg) prior to the experiment. Following 1 h of rest, 12 blood samples were drawn between 1,000 h and 1,300 h and analyzed for ACTH and cortisol levels. At 1,100 h, subjects received an intravenous injection of 50 microg CCK-4. Clinical ratings were performed at 1,045 h and 1,110 h, and included the Acute Panic Inventory (API), International Diagnostic Checklist (IDCL), as well as a visual analog scale (VAS) for anxiety and tension. CCK-4 significantly increased anxiety and tension. Pretreatment with megestrol showed no significant effect on clinical ratings. Baseline ACTH and cortisol levels, as well as ACTH and cortisol levels after administration of CCK-4, were significantly reduced after pretreatment with megestrol. In a sample of healthy male controls, pretreatment with megestrol had a profound effect on the hypothalamic-pituitary-adrenal (HPA) axis, whereas the clinical effects on panic attacks were weak. Further studies in a larger sample of subjects, including both females and patients suffering from panic disorder, seem warranted.

Systemic and intra-dorsal periaqueductal gray injections of cholecystokinin sulfated octapeptide (CCK-8s) induce a panic-like response in rats submitted to the elevated T-maze

The neuropeptide cholecystokinin (CCK) has been implicated in fear and anxiety. CCK is found in the CNS in several molecular forms such as the tetrapeptide (CCK-4) and, mainly, the sulfated octapeptide (CCK-8s) fragments. Administration of CCK-4 induces panic attacks in humans and increases the expression of different anxiety-related behaviors in laboratory animals. The effects of CCK-8s on fear and anxiety are less straightforward and seem to be influenced, among other factors, by the route of the peptide administration and the animal model employed. In other to further investigate the role of CCK-8s in fear and anxiety, in the present study we analyzed the effect of CCK-8s in male Wistar rats submitted to the elevated T-maze. This animal model of anxiety was developed in order to separate generalized anxiety (inhibitory avoidance) and panic-like (escape) responses in the same rat. The effect of CCK-8s in this test was also investigated after injection of the peptide into the dorsal periaqueductal gray (DPAG). This brainstem area is rich in CCK receptors and has consistently been implicated in the mediation of fear and anxiety responses. The results showed that both the intraperitoneal and intra-DPAG injections of CCK-8s potentiated one-way escape behavior, suggesting a panicogenic action. In contrast, the injection of the CCK2 receptor antagonist CR2945 inhibited the expression of this behavior, a panicolytic-like effect. Therefore, the elevated T-maze, in contrast to other animal models of anxiety, can detect the anxiety-eliciting effects of CCK-8s both after its systemic and central administration. Also, the results provide further evidence about the involvement of a CCK-mediated mechanism within the DPAG in the regulation of panic-related defensive behaviors.

The Ventilatory Response to Cholecystokinin Tetrapeptide in Healthy Volunteers

The cholecystokinin (CCK) system, which has been shown to interact with both the panicogenic and respiratory systems, provides an interesting mechanism to further evaluate the central chemoreceptor and its effect on panic attack sensitivity. Intravenous CCK, a naturally occurring neuropeptide in the brain, has been found to induce the emotional and somatic symptoms of panic in both Panic Disorder (PD) and Normal Control (NC) subjects in a dose-dependent and reproducible fashion. To induce these effects, lower doses of intravenous CCK are required in the PD patients, relative to the NC subjects potentially suggesting that endogenous alterations in the CCK system may be contributing to the development of PD.Intravenous administration of CCK-4 in association with panic also results in subjective dyspnea, that is, diminution in vital capacity without an effect on the respiratory resistance. CCK-4 also causes a significant increase in tidal volume and minute ventilation but has no effect on breathing frequency. These observations suggest that a CCK-B receptor agonist may be acting as a respiratory stimulant, exerting its effect on anxiety through a direct effect on respiration.This study represents an examination of the specific effects of CCK-4 on the central chemoreceptor response.The study used a modified rebreathing technique, which accurately measures the ventilatory response to carbon dioxide in terms of both threshold and sensitivity. This technique requires the subject to rebreathe from a bag containing a hyperoxic and hypercapnic gas mixture resulting in rapid equilibration between alveolar gas and arterial blood. Use of a hyperoxic gas allows for the preferential examination of the central chemoreflexes (sensitive to CO2) with little if any effect of the peripheral (oxygen sensitive) chemoreflexes.After significant training, 15 healthy control subjects were assigned via a double blind procedure to receive an intravenous injection of placebo or CCK-4, using a between-subjects design. A between-subjects comparison was undertaken for the injection run (run #3) between subjects receiving the CCK-4 injection and those receiving the placebo injection. As well, a within-subject comparison was undertaken to compare the results of the run following the injection (run #3) vs. the previous run when no injection took place (run #2).No significant differences were noted between subjects who received CCK-4 as compared with placebo for: basal or sub-threshold ventilation, threshold CO2 resulting in a change in ventilation, or sensitivity of the central chemoreflex, regardless of whether a panic attack did or did not take place. In addition, within the group receiving the CCK-4 challenge, no significant differences were noted during run #3 (received the CCK-4 injection) and a prior run where no injection took place (run #2).We conclude that CCK-4 does not act to induce panic by altering the central (CO2 sensitive) chemoreceptor.

Sulfated Cholecystokinin [26–33]Induces Mild Taste Aversion Conditioning in Rats when Administered by Three Different Routes

We investigated the ability of sulfated cholecystokinin [26–33](CCK-8) and cholecystokinin [30–33](CCK-4) to induce taste aversion or avoidance conditioning (TAC) in a one-bottle testing paradigm after either intravenous (IV), intracerebroventricular (ICV), or intraperitoneal (IP) administration. Significant TAC was induced by IP administration of CCK-8 at 0.1 but not at 0.025, 0.5, or 1.0 μmol/kg; the TAC was not robust and, in this case, not even dose related. IP administration of CCK-4 at 0.05, 0.1, 0.5, or 1.0 μmol/kg did not induce TAC, replicating other studies from our lab. Mild but significant TAC was also induced by IV administration of CCK-8 (at 0.025 and 1.0 but not 0.1 or 0.5 μmol/kg) but not by IV administration of CCK-4 (at 0.05, 0.1, 0.5, or 1.0 μmol/kg). Finally, mild but significant TAC was induced by ICV (i.e., lateral ventricular) administration of CCK-8 (at 0.0015 but not at 0.015 μmol/brain) but not by ICV administration of CCK-4 (at 0.005 or 0.010 μmol/brain). Because CCK-4 failed to induce TAC, CCK-8 apparently induced TAC via all three routes by an action at a CCK A, not CCK B, receptor mechanism. Because ICV or IV administrations of CCK-8 were not more efficacious than IP administration, the taste avoidance induced by IP administration of CCK-8 was not so mild simply because it failed to reach a critical central locus adequately or because it failed to be delivered at a critical speed (i.e., via IV injections). We demonstrate that CCK-8 can induce mild TAC at either peripheral or central sites and suggest that these effects of CCK-8 may be independent and may be a sign of salience but not necessarily of toxicosis.

Effects of Cholecystokinin Tetrapeptide on Respiratory Function in Healthy Volunteers

The authors evaluated respiratory response to cholecystokinin tetrapeptide (CCK-4) in healthy volunteers. Subjects were randomly assigned to either a CCK-4 (N = 15) or placebo (N = 15) challenge under double-blind conditions. Dyspnea was reported by all of the subjects who received CCK-4 but only one subject who received placebo. CCK-4 caused a significant increase in tidal volume and minute ventilation but had no effect on breathing frequency. Placebo had no effect on any of the respiratory measures. These data indicate that the behavioral effects of CCK-4 are accompanied by changes in respiration in healthy volunteers.

The effect of cholecystokinin tetrapeptide on respiratory resistance in healthy volunteers

The effects of cholecystokinin tetrapeptide (CCK-4) on respiratory resistance were studied in 14 healthy volunteers by the registration of slow vital capacity and flow volume loop during forced respiration test. The administration of CCK-4 (50 micrograms) was performed in a double-blind and placebo-controlled design. Injections of CCK-4 induced prominent and time-limited paniclike symptoms in all healthy volunteers. Four volunteers (29%) experienced a panic attack. Subjective dyspnea was experienced by the majority of subjects at the peak of CCK-4 effect and seemed related to a diminution in vital capacity parameters; however, the forced respiration test did not reveal bronchoconstriction after CCK-4 challenge. Administration of CCK-4 also induced a short-lasting increase in heart rate and skin blood flow. This study suggests that dyspnea induced by CCK-4 is not related to changes in respiratory resistance.

Cholecystokinin tetrapeptide-induced calcium mobilization in T cells of patients with panic disorder, major depression, or schizophrenia

The localization of cholecystokinin in the brain has accelerated research efforts to define this biochemical's functional role in the central nervous system. The idea of cholecystokinin as a mediator of anxiety originated from electrophysiological experiments (Bradwejn and de Montigny 1984). Benzodiazepine antagonized cholecystokinin-8S-induced excitation of hippocampal pyramidal neurons in rats. This effect was reversed by pretreatment with the benzodiazepine receptor antagonist flumazenil (Csonka et al 1988). Recently, cholecystokinin-tetrapeptide (CCK-4) has been reported to have anxiogenic effects in humans. Intravenous injections of CCK-4 induced symptoms comparable to those of a panic attack (de Montigny 1989). CCK-8S-induced hippocampal pyramidal cell excitation was attenuated by benzodiazepines, but not by meprobamate or naloxone. In a double-blind study, patients were challenged with 50 ixg CCK-4 or saline on separate occasions (Bradwejn 1990). All patients panicked after administration of CCK-4, whereas none of the subjects panicked after receiving saline. The data indicated that patients with panic disorder have an increased sensitivity to CCK-4 (Bradwejn et al 1991). These findings may reflect a neurobiochemical range in CCK in panic disorder. It has been suggested that CCK receptor

O-24-4 - rCBF in panic disorder and obsessive compulsive disorder

We recently found that, compared with younger healthy subjects, older healthy subjects had less symptomatic and cardiovascular response to the panicogenic agent cholecystokinin tetrapeptide (CCK-4). As an exploratory part of that study, we also evaluated the effect of aging on neurohormonal responses to CCK-4. These hormonal data are the focus of this article. Forty healthy volunteers aged 20-35 years and 40 healthy volunteers aged 65-81 years, divided equally between men and women, were compared on their hormonal responses (maximum change from baseline in growth hormone [GH], prolactin, adrenocorticotropic hormone [ACTH], and cortisol) to the intravenous administration of 50 μg of CCK-4 or placebo. Blood samples for serum hormone determination were collected at 2 minutes prior to the intravenous challenge (baseline) and at 2, 5, and 10 minutes after the challenge. In both age groups, maximum increase in prolactin, ACTH and cortisol was significantly greater with CCK-4 than with placebo. Following administration of CCK-4, younger and older groups did not significantly differ in maximum increase in prolactin, ACTH, or cortisol. Older subjects had a statistically significant smaller increase in GH compared with younger subjects but the magnitude of the difference was small and of doubtful clinical relevance. Older subjects who had a panic attack had significantly greater elevations of all hormones compared with those who did not panic and younger panickers had a significantly greater elevation of GH compared with young nonpanickers. For the most part, maximum changes in hormonal levels were not correlated with symptom severity, suggesting that other factors may have contributed to the differential effect of panic on the HPA axis.

Central and no-mediated mechanisms are involved in the inhibitory effects of CCK on the chicken cecorectal area

In chickens CCK-8s induces defecation and causes an inhibition of rectal electrical activity (EA) and an increase in cecal motility. In contrast, CCK-4 inhibits the motility of both rectum and ceca. The cecorectal responses to CCK-8s and CCK-4, given intravenously (i.V.), were studied in conscious chickens prepared with electrodes for electromyography; the influence of atropine, phentolamine plus propranolol, hexamethonium and L-NAME on such responses was determined. Atropine and phentolamine plus propranolol did not cause any change in the response to CCK-8s or CCK-4 in the cecorectal area. Hexamethonium only induced a significant decrease in the number of defecations (ND) induced by CCK-8s. L-NAME slightly modified the decrease in rectal EA due to CCK-8s. The effects of intracerebroventricular (i.c.v.) administration of CCK-Ss and CCK-4 were also studied. CCK-8s and CCK-4, given i.c.v., caused, in conscious chickens, a slight decrease in cecal EA, in the 15 minutes following administration. This effect was similar to that seen after i.v. administration of CCK-4. In conclusion, our results suggest that the inhibitory action of CCK on chicken rectum is mediated, at least in part, through nitric oxide release. In addition, nicotinic receptors mediate the increase in the ND caused by CCK-8s. Ganglionic, muscarinic, adrenergic and nitrergic blockade were not able to modify the excitatory cecal response to CCK-8s, which may indicate that the receptor mediating this effect is located on the cecal smooth muscle. Finally, the inhibitory action of i.v. CCK-4 on chicken cecum seems to be centrally mediated, as suggested by the fact that i.c.v. administration of either CCK-8s or CCK-4 induce a similar effect.

Effect of cholecystokinin tetrapeptide amide on the metabolism of 5-hydroxytryptamine in the rat brain

The effect of cholecystokinin tetrapeptide amide (CCK-4) on the content of 5-hydroxytryptamine (5-HT) and its major metabolite, 5-hydroxyindole-3-acetic acid (5-HIAA), was studied in various regions of the brain of rat. After intracerebroventricular administration of CCK-4, the content of 5-HT decreased, while the content of 5-HIAA increased in some areas. These changes were marked 30 min after the injection and relatively small doses (10 and 100 ng) of CCK-4 produced a pronounced effect, but larger doses (1 and 10 μg) were less effective. The ratio of 5-HIAA/5-HT increased significantly in most regions of the brain, except in the striatum and the olfactory tubercle. The results indicate that exogenous CCK-4 in small doses stimulates the metabolism of 5-HT in the brain of rat.