Evaluation of the CCK-4 model as a challenge paradigm in a population of healthy volunteers within a proof-of-concept study

Eser, Daniela; Schüle, Cornelius; Baghai, Thomas C.; Floesser, Annette; Krebs-Brown, Axel; Enunwa, Michaela; Motte, Stephan de la; Engel, Rolf R.; Kucher, Klaus; Rupprecht, Rainer

doi:10.1007/s00213-007-0738-7

Cited by 41 publications

(33 citation statements)

References 44 publications

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“…Panickers and nonpanickers differed neither in baseline panic scores nor in the CCK-4-induced increase in heart rate, thereby confirming previous reports, which showed that neither baseline anxiety levels nor the cardiovascular response to CCK-4 is related to the severity of subjective panic response [Eser et al, 2007]. As to be expected, panickers scored significantly higher on the PSS after CCK-4 injection than nonpanickers.…”

Section: Discussionsupporting

confidence: 87%

“…This assumption was based on the fact that panic symptoms occur immediately following CCK-4 injection, which are paralleled by cardiovascular effects with a maximum increase in heart rate and systolic blood pressure in the first minute after CCK-4 administration [Eser et al, 2007]. Furthermore, a period of effects of AA in the 2 min before injection (predictor 2, AA period, corresponding to 30 images) was assumed.…”

Section: Image Processing and Statistical Analysismentioning

confidence: 99%

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Functional neuroanatomy of CCK‐4‐induced panic attacks in healthy volunteers

Eser¹,

Leicht²,

Lutz³

et al. 2009

Human Brain Mapping

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Experimental panic induction with cholecystokinin tetrapeptide (CCK-4) is considered as a suitable model to investigate the pathophysiology of panic attacks. While only a few studies investigated the brain activation patterns following CCK-4, no data are available on the putative involvement of the amygdala in the CCK-4 elicited anxiety response. We studied the functional correlates of CCK-4-induced anxiety in healthy volunteers by means of functional magnetic resonance imaging (fMRI) and region of interest (ROI) analysis of the amygdala. Sixteen healthy volunteers underwent challenge with CCK-4 compared with placebo in a single-blind design. Functional brain activation patterns were determined for the CCK-4-challenge, the placebo response and anticipatory anxiety (AA). CCK-4-induced anxiety was accompanied by a strong and robust activation (random effects analysis, P < 0.00001, uncorrected for multiple testing) in the ventral anterior cingulate cortex (ACC), middle and superior frontal gyrus, precuneus, middle and superior temporal gyrus, occipital lobe, sublobar areas, cerebellum, and brainstem. In contrast, random effects group analysis for placebo and AA using the same level of significance generated no significant results. Using a more liberal level of significance, activations could be observed in some brain regions such as the dorsal part of the ACC during AA (random effects analysis, P < 0.005). Overall functional responses did not differ between panickers and nonpanickers. Only 5 of 11 subjects showed strong amygdala activation. However, ROI analysis pointed towards higher scores in fear items in these subjects. In conclusion, while overall brain activation patterns are not related to the subjective anxiety response to CCK-4, amygdala activation may be involved in the subjective perception of CCK-4-induced fear. Hum Brain

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Section: Discussionsupporting

confidence: 87%

Section: Image Processing and Statistical Analysismentioning

confidence: 99%

Functional neuroanatomy of CCK‐4‐induced panic attacks in healthy volunteers

Eser¹,

Leicht²,

Lutz³

et al. 2009

Human Brain Mapping

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“…The provocation of panic attacks using cholecystokinin (CCK) is a well-characterized method for the study of anxiety in humans (Koszycki et al, 1991), and has proven to be of use in exploring the neurochemical (Zwanzger et al, 2003;Maron et al, 2009), genetic and psychological aspects of panic disorder, as well as representing a potentially useful screen for novel anxiolytic drugs (Kellner et al, 2005;Kronenberg et al, 2005;Eser et al, 2007). Anxiety in humans can also be generated experimentally using chemical agents such as caffeine (Nardi et al, 2007), m-chlorophenylpiperazine (mCPP) (Kahn et al, 1990), yohimbine (Charney et al, 1984), CO 2 inhalation (Nardi et al, 2007), sodium lactate (Liebowitz et al, 1984; and isoproterenol (Pohl et al, 1987;Balon et al, 1988;Yeragani et al, 2007).…”

Section: Human Models Of Anxiety: Translating and Adaptingmentioning

confidence: 99%

The age of anxiety: role of animal models of anxiolytic action in drug discovery

Cryan¹,

Sweeney²

2011

British J Pharmacology

230

188

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Anxiety disorders are common, serious and a growing health problem worldwide. However, the causative factors, aetiology and underlying mechanisms of anxiety disorders, as for most psychiatric disorders, remain relatively poorly understood. Animal models are an important aid in giving insight into the aetiology, neurobiology and, ultimately, the therapy of human anxiety disorders. The approach, however, is challenged with a number of complexities. In particular, the heterogeneous nature of anxiety disorders in humans coupled with the associated multifaceted and descriptive diagnostic criteria, creates challenges in both animal modelling and in clinical research. In this paper, we describe some of the more widely used approaches for assessing the anxiolytic activity of known and potential therapeutic agents. These include ethological, conflict-based, hyponeophagia, vocalization-based, physiological and cognitive-based paradigms. Developments in the characterization of translational models are also summarized, as are the challenges facing researchers in their drug discovery efforts in developing new anxiolytic drugs, not least the ever-shifting clinical conceptualization of anxiety disorders. In conclusion, to date, although animal models of anxiety have relatively good validity, anxiolytic drugs with novel mechanisms have been slow to emerge. It is clear that a better alignment of the interactions between basic and clinical scientists is needed if this is to change.

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“…In a recent test of CCK-4 induced panic, ACTH was found to be raised by CCK-4 regardless of whether or not a panic attack actually occurred (Eser et al 2007). Conversely, sodium-lactate-induced panic does not coincide with an increased ACTH response in anxiety disorder patients or control subjects (Otte et al 2002) and an anxiogenic effect but no HPA-axis activation was reported in a recent poster from Bailey et al following exposure to 7.5% CO 2 concentrations (Bailey et al 2007).…”

Section: Translational Research With Mglur Binding: Development Of a mentioning

confidence: 99%

Metabotropic glutamate receptor modulation, translational methods, and biomarkers: relationships with anxiety

Nordquist

Steckler²,

Wettstein

et al. 2008

Psychopharmacology

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Rationale The increasing awareness of the need to align clinical and preclinical research to facilitate rapid development of new drug therapies is reflected in the recent introduction of the term "translational medicine". This review examines the implications of translational medicine for psychiatric disorders, focusing on metabotropic glutamate (mGlu) receptor biology in anxiety disorders and on anxiety-related biomarkers. Objectives This review aims to (1) examine recent progress in translational medicine, emphasizing the role that translational research has played in understanding of the potential of mGlu receptor agonists and antagonists as anxiolytics, (2) identify lacunas where animal and human research have yet to be connected, and (3) suggest areas where translational research can be further developed.Results Current data show that animal and human mGlu 5 binding can be directly compared in experiments using the PET ligand 11 C-ABP688. Testing of the mGlu 2/3 receptor agonist LY354740 in the fear-potentiated startle paradigm allows direct functional comparisons between animals and humans. LY354740 has been tested in panic models, but in different models in rats and humans, hindering efforts at translation. Other potentially translatable methods, such as stress-induced hyperthermia and HPA-axis measures, either have been underexploited or are associated with technical difficulties. New techniques such as quantitative trait loci (QTL) analysis may be useful for generating novel biomarkers of anxiety. Conclusions Translational medicine approaches can be valuable to the development of anxiolytics, but the amount of cross-fertilization between clinical and pre-clinical departments will need to be expanded to realize the full potential of these approaches.

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Evaluation of the CCK-4 model as a challenge paradigm in a population of healthy volunteers within a proof-of-concept study

Cited by 41 publications

References 44 publications

Functional neuroanatomy of CCK‐4‐induced panic attacks in healthy volunteers

Functional neuroanatomy of CCK‐4‐induced panic attacks in healthy volunteers

The age of anxiety: role of animal models of anxiolytic action in drug discovery

Metabotropic glutamate receptor modulation, translational methods, and biomarkers: relationships with anxiety

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