Role of the GABAA Receptor in Anxiety: Evidence from animal models, molecular and clinical psychopharmacology, and brain imaging studies

Several converging lines of evidence from molecular, animal, and clinical studies have demonstrated that the gamma-aminobutyric type A (GABAA) receptor complex plays a central role in the modulation of anxiety. While currently available therapeutic agents that act on this receptor (e.g., benzodiazepines) are effective anxiolytics, they are limited by side effects, tolerance, and abuse potential. Promising strategies to address these limitations include the development of subunit-selective agonists and partial agonists, which specifically ameliorate anxiety without causing sedation or motor impairment. In vivo neuroimaging studies have identified several limbic and paralimbic brain regions involved in the generation or modulation of anxiety and fear responses, suggesting that the neuroinhibitory processes of GABAA receptors may be localized in certain brain areas which may serve as specific sites for drug action. Indeed, neurochemical brain imaging studies have reported decreased ligand binding to GABAA benzodiazepine receptors in prefrontal and medial temporal cortex in a variety of anxiety disorders. This paper reviews recent findings from molecular neuropsychopharmacology and in vivo neuroimaging of GABAA benzodiazepine receptors which offer novel perspectives on the genesis of normal anxiety and on pathophysiology of anxiety disorders. Collectively, these findings suggest several potentially successful avenues for future development of GABAA receptor-mediated anxiolytic treatments, and prompt further exploration of this neurochemical system in pathogenesis of anxiety disorders.