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

Department of Pharmacology, School of Medicine, University of São Paulo, 14049-900 Ribeirão Preto, SP, Brazil.
Peptides (Impact Factor: 2.62). 12/2004; 25(11):1935-41. DOI: 10.1016/j.peptides.2004.06.016
Source: PubMed


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.

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    • "dwejn and Koszycki , 2001 ) . This effect seems to involve the dPAG since systemic administration of the latter drug induced Fos immunoreactivity in this area ( Singewald and Sharp , 2000 ) . Further evidence for the involvement of CCK in panic is that intra - dPAG or systemic injection of CCK - 8s induced escape or panic - like reaction in rats ( Zanoveli , et al . , 2004 ) . This finding was also in consistent with previous reports that intra - dlPAG injection with CCK 2 receptor agonist CCK - 4 facilitated escape behaviour when the animals were tested in the elevated T - maze ( Bertoglio , et al . , 2006 , Bertoglio and Zangrossi , 2005 ) and in the bowl - shape cage ( Bertoglio , et al . , 2007 ) . On"
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    ABSTRACT: Recent findings on the different functional properties of the neuroanatomical columnar subdivision of the Periaqueductal Gray (PAG) have provided a fundamental understanding for the pathophysiology of panic and anxiety disorder. In this review, we focus mainly on the prominent role of the PAG in defensive behaviour by combining both the behavioural and neuroanatomical data. We have applied the theoretical model of the "two dimensional defence system" by McNaughton and Corr (2004), and thereby constituted an organizational structure on the neuronal circuitry of the different brain regions in relation with this panic-and fear-like behaviour. It has become clear that the dorsal and lateral PAG are involved in the active emotional coping (fight and flight reaction), whereas the ventrolateral PAG is responsible for the passive emotional coping (quiescence/freezing). In this regard, the PAG and other related brain structures are working in concert with different neurotransmitters providing animals with defensive strategies in response to predatory threats. The functional roles of the PAG in these behaviours as characterized in animals warrants further translational studies in humans which may eventually lead to novel approaches in anxiety-and panic-related disorders.
    05/2009; 26(1). DOI:10.5835/jecm.omu.26.01.001
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    • "Previous studies have reported that CCK receptor agonists (e.g., CCK-8s) and CCK receptor antagonists (e.g., LY225910) are anxiogenic and anxiolytic, respectively (Biro et al. 1997; Zanoveli et al. 2004; Wang et al. 2005). Prodynorphin is processed into several smaller peptides which act on kappa opioid receptors. "
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    ABSTRACT: Type 5 adenylyl cyclase (AC5) is highly concentrated in the dorsal striatum and nucleus accumbens (NAc), two brain areas which have been implicated in motor function, reward, and emotion. Here we demonstrate that mice lacking AC5 (AC5-/-) display strong reductions in anxiety-like behavior in several paradigms. This anxiolytic behavior in AC5-/- mice was reduced by the D(1) receptor antagonist SCH23390 and enhanced by the D(1) dopamine receptor agonist, dihydrexidine (DHX). DHX-stimulated c-fos induction in AC5-/- mice was blunted in the dorso-lateral striatum, but it was overactivated in the dorso-medial striatum and NAc. The siRNA-mediated inhibition of AC5 levels within the NAc was sufficient to produce an anxiolytic-like response. Microarray and RT-PCR analyses revealed an up-regulation of prodynorphin and down-regulation of cholecystokinin (CCK) in the NAc of AC5-/- mice. Administration of nor-binaltorphimine (a kappa opioid receptor antagonist) or CCK-8s (a CCK receptor agonist) reversed the anxiolytic-like behavior exhibited by AC5-/- mutants. Taken together, these results suggest an essential role of AC5 in the NAc for maintaining normal levels of anxiety.
    Journal of Neurochemistry 09/2008; 107(1):105-15. DOI:10.1111/j.1471-4159.2008.05592.x · 4.28 Impact Factor
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    • "Molecular forms of CCK are cleaved from prepro-CCK and include CCK-8 sulfated (S), pentagastrin (CCK-5) and CCK-4 which are degraded by aminopeptidase (see [76] for review). Cholecystokinin-8S is the predominant central form of CCK and found in high concentrations in the cerebral cortex, nucleus accumbens, basal ganglia, thalamus, hypothalamus, periaqueductal grey, olfactory tubercle, olfactory bulb, VTA, some brain stem nuclei and the spinal cord [206] [267] [268] [269] [270] [271] [272]. Cholecystokinin is colocalized with DA in the mesencephalon [273], CRF in the paraventricular nucleus of the hypothalamus [274], oxytocin in the supraoptic and paraventricular nucleus of the hypothalamus [275], substance P in the central gray projecting to the spinal cord [276], GABA in the amygdala, frontal cortex and hippocampus [277] [278] and enkephalin in the hippocampus ([279]; (see [280] [281] for review of antagonistic role of CCK and enkephalin in stress, anxiety, cognition and pain). "
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    ABSTRACT: Panic disorder is characterized by a progression of panic symptom severity with repeated attacks. Repeated panic episodes evoke heightened anticipatory anxiety, phobic avoidance and are typically associated with comorbid symptoms of depression. Due to the heterogeneity of the disorder, reliable neurochemical correlates attending panic have not been identified. However, variable neuropeptide interfacing with major and minor transmitter systems may modulate individual vulnerability to panic and account for variable panic profiles. The extensive colocalization of cholecystokinin (CCK) with other neurotransmitters, including dopamine (DA), enkephalin (ENK) and GABA, in specific central sites may influence various aspects of anxiety and panic. The behavioral correlates attending panic likely follow from variable neurochemical release and conditioning/sensitization. Clinicians maintain that recurrent panic attacks are spontaneous (unexpected, uncued) and fail to acknowledge the wealth of information implicating a prominent role for stressful life events in panic. Conditioning and sensitization of both behavior (e.g., fear-motivated) and neurochemical events (e.g., DA and CCK) in response to uncontrollable stressors parallel the diverse heterogeneity of panic amongst clinical samples. Cholecystokinin-4, pentagastrin, lactate acid, and CO2 induce panic attacks that are dependent on subjective history, expectancy measures and panic profiles. Panic disorder is associated with chronic illness and familial sick-role modeling exacerbates the course of the illness. The current review outlines the evidence in support of a conditioning/sensitization model for panic, a model that may explain the variable efficacies of pharmacological interventions.
    The Open Psychiatry Journal 12/2007; 1. DOI:10.2174/187435440701011044
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