Gamma-aminobutyric Acid Transporter 1 as a Promising Novel Target for the Treatment of Anxiety Disorders with Panic Symptoms

Christoph K Thoeringer
European Psychiatric Review, 2010;3(2):53-56
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Abstract

Panic disorder is a frequent and distressing psychiatric condition because of the burden of repeated panic attacks. These episodes of escalating fear and heterogeneous somatic distress also occur in several other anxiety disorders. Several lines of recent pre-clinical and clinical evidence suggest that re-uptake mechanisms of gamma-aminobutyric (γ-aminobutyric) acid (GABA) at cerebral synapses via GABA transporter subtype 1 (GAT-1) play a crucial role in the psychopathological process of panic. Clinical studies have demonstrated profound and lasting anxiolytic effects of pharmacological treatment strategies with GAT-1 inhibitors in patients with anxiety disorder. In addition, preliminary evidence suggests that GAT-1 inhibition has a specific antipanic effect in humans experiencing severe symptomatic panic. Although this approach requires refinement in additional studies, it may represent a promising novel psychopharmacological strategy in the therapy of anxiety disorders with panic symptoms.
Keywords
Gamma-aminobutyric acid transporter 1 (GAT-1), tiagabine, panic, anxiety disorders, animal models, genetic polymorphisms
Disclosure The authors have no conflicts of interest to declare.
Received: January 20, 2010 Accepted August 10, 2010
Correspondence: Christoph K Thoeringer, Max Planck Institute of Psychiatry, Kraepelinstrasse 2–10, 80804 Munich, Germany. E: thoeringer@mpipsykl.mpg.de

Anxiety disorders are frequent and distressing psychiatric conditions with the core clinical feature of pathological anxiety. A specific hallmark of several anxiety disorders is the occurrence of panic attacks,1 defined as brief, discrete and unpredictable episodes of escalating fear, physical discomfort and the fear of losing control. On a somatic level, these episodes are frequently accompanied by heart palpitations, dyspnoea, nausea and vertigo. Panic attacks typically occur spontaneously without any apparent trigger. Recurrent episodes of panic accompanied by persistent concerns of having additional attacks, worries about the implications or consequences of the attack and behavioural changes are defining features of panic disorder. However, it should be noted that panic attacks also occur regularly as symptoms of phobic disorders (e.g. social phobia or specific phobia) precipitated by feared stimuli. In addition, isolated panic attacks may occur sporadically in the absence of any anxiety disorder, with a high lifetime prevalence (23.5%).2 Lifetime prevalence rates for panic disorder range from 2.1 to 5.1% (panic disorder with/without agoraphobia),2–4 while those for phobic disorders are estimated to range between 7.7 and 12.5% for specific phobias, and 2.4 and 12.1% for social phobia.4,5 Panic and phobic anxiety disorders also show high co-morbidity rates with other psychiatric disorders and physical illnesses.6,7 Accordingly, quality of life is seriously compromised and social disadvantages often arise, resulting in a substantial burden of suffering and economic costs.8,9

The γ-aminobutyric Acid System and the Pathogenesis of Anxiety Disorders
Several lines of pre-clinical and clinical evidence support the view that the γ-aminobutyric acid (GABA) system is a crucial factor in the pathogenesis of anxiety, fear and related psychopathological conditions. From a pharmacological viewpoint, it has been shown that pentylenetetrazole, an agent that blocks GABAA receptor function, induces symptoms of anxiety, flashbacks of traumatic memories and strong avoidance behaviours.10 Conversely, augmentation of brain GABA function via positive allosteric modulators of GABAA receptors (e.g. benzodiazepines) promotes rapid and profound anxiolysis in patients suffering from excessive fear and anxiety.11

Additional insights into the role of GABAergic inhibition in anxiety disorders have been provided by neuroimaging studies. In recent positron-emission tomography (PET) and single-photon-emission computed tomography (SPECT) studies, a significant reduction of GABAA–benzodiazepine receptor binding was observed in several cortical areas, the anterior cingulate and the hippocampus in individuals with panic disorder.12–15 Interestingly, a significant association between symptom severity and a decrease in GABAA receptor binding was apparent in the prefrontal cortex of panic disorder patients.16 In addition to clinical evidence for decreased GABAA receptor binding in panic disorder, neuroimaging studies employing magnetic resonance spectroscopy have also revealed decreased GABA concentrations in several brain regions, such as the occipital cortex, anterior cingulate and basal ganglia.17,18

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Gamma-aminobutyric Acid Transporter 1 as a Promising Novel Target for the Treatment of Anxiety Disorders with Panic Symptoms

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