[Significance of GABAA receptors for the pathophysiology and therapy of panic disorders]

Abstract

Gamma aminobutyric acid (GABA) is the most important inhibitory neurotransmitter in the central nervous system. Its action is exerted in the brain through GABA(A) receptors which belong to the family of ligand-gated ion channels. These GABA(A) receptors consist of various subunits and are targets for benzodiazepines, barbiturates, neuroactive steroids, and distinct anticonvulsive agents. Meanwhile, there is considerable evidence that a dysfunction of GABA(A) receptors plays an important role in the pathophysiology of panic disorder. The anxiolytic effects of benzodiazepines are widely used in the treatment of panic disorder. Nevertheless, side effects of benzodiazepines, e.g., dependency and withdrawal symptoms, limit their use as a long-term treatment. In the meantime, antidepressants, especially selective serotonin reuptake inhibitors, comprise first-line treatment in the pharmacotherapy of panic disorder. They interfere with the synthesis of endogenous neuroactive steroids that allosterically modulate GABA(A) receptor function. With regard to experimentally evoked panic attacks in patients with panic disorder and healthy controls, recent investigations demonstrated that enhancing endogenous GABA through the blockade of the GABA transaminase by vigabatrin or inhibition of GABA transporters by tiagabine may exert anxiolytic effects. This novel strategy targeting the GABA binding site of the GABA(A)/benzodiazepine receptor complex and specific agonists for the benzodiazepine binding site present interesting perspectives for the future pharmacotherapy of panic disorder.