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Significance of GABAA receptors to the development of panic and the pathogenesis and therapy of panic disorders

English title Significance of GABAA receptors to the development of panic and the pathogenesis and therapy of panic disorders
Applicant Sabin-Crestani Florence
Number 113799
Funding scheme Project funding
Research institution Institut für Pharmakologie und Toxikologie Universität Zürich
Institution of higher education University of Zurich - ZH
Main discipline Neurophysiology and Brain Research
Start/End 01.10.2006 - 30.09.2009
Approved amount 260'000.00
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Keywords (6)

anxiety disorder; panic; GABAA receptor; breathing; emotion; cognition

Lay Summary (English)

Lead
Lay summary
Panic disorders are life-long disabling anxiety disorders, affecting 2 to 3% of individuals in Europe and North America. Although these are the mental disorders most commonly encountered in primary care, they are poorly recognized, because of clinical heterogeneity, and consequently undertreated. Normal panic refers to a specific emergency reaction to suffocation, including cardiorespiratory (palpitations, dyspnea, fear of dying), autonomic/somatic (sweating, trembling) and cognitive (fear or going crazy or losing control) signs. The panic disorder combines recurrent unexplained panic attacks with severe chronic anxiety and phobic avoidance. Panic attacks are also frequent among patients with other anxiety disorders, chronic respiratory diseases (e.g. asthma), functional gastrointestinal disorders (e.g. irritable bowel syndrome, diabetes) and alcoholism history, and represent increased risk factors for major depression, cardiovascular diseases, stroke and suicidal behavior.
The causes and physiopathological mechanisms underlying panic disorders remain poorly understood. Abnormalities in the neurophysiological mechanisms controlling respiration behaviour have been posited as central to panic disorder etiology. Alternative hypotheses propose that panic disorder develops from a greater tendency to fear and misinterpret anxiety-related cardiorespiratory symptoms. Human brain imaging and pharmacological studies consistently implicate dysfunction in the central GABAergic system and its cognate GABAA-receptors in the pathogenesis of panic disorder. Animal studies have shown that GABAergic neurons, through GABAA-receptors, exert tonic inhibitory control within the fear network and the cardiorespiratory control centres.
Our research project addresses basic questions on the significance of GABAA-receptors 1) in the neurobiology of respiration behaviour and its relation to emotion and cognition and 2) in the pathogenesis of anxiety disorders and chronic respiratory diseases. Mice represent a species of choice to address these questions because they are widely used for genetic, anxiety and lung research. To date no mouse model has been developed for studying the psychoneurobiology of panic and its relation with chronic anxiety. We envisage modelling panic-like cardiorespiratory symptoms and phobic avoidance reactions, using plethysmography, electrocardiography, and behavioural and pharmacological techniques in normal and mutant mice. Relationships between panic and chronic anxiety will be studied in mice that are heterozygous for the deletion of the GABAA-receptor g2-subunit gene (g2+/0) and that represent a genetic model of chronic anxiety (Crestani et al., 1999). The brain networks and metabolic processes underlying chronic anxiety and panic-like symptoms will be further investigated using functional brain imaging techniques.Altogether, this work should shed light on the brain circuits and mechanisms involved in anxiety-driven panic and allow identifying GABAA-receptor dysfunction as potential risk markers for panic susceptibility.
Direct link to Lay Summary Last update: 21.02.2013

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