The GABA system in anxiety and depression and its therapeutic potential

In the regulation of behavior, the role of GABA neurons has been extensively studied in the circuit of fear, where GABA interneurons play key parts in the acquisition, storage and extinction of fear. Therapeutically, modulators of α(2)/α(3) GABA(A) receptors, such as TPA023, have shown clinical proof of concept as novel anxiolytics, which are superior to classical benzodiazepines by their lack of sedation and much reduced or absent dependence liability. In view of the finding that anxiety disorders and major depression share a GABAergic deficit as a common pathophysiology, the GABA hypothesis of depression has found increasing support. It holds that α(2)/α(3) GABA(A) receptor modulators may serve as novel antidepressants. Initial clinical evidence for this view comes from the significantly enhanced antidepressant therapeutic response when eszopicole, an anxiolytic/hypnotic acting preferentially on α(2)/α(3) and α(1) GABA(A) receptors, was coadministered with an antidepressant. This effect persisted even when sleep items were not considered. These initial results warrant efforts to profile selective α(2)/α(3) GABA(A) receptor modulators, such as TPA023, as novel antidepressants. In addition, GABA(B) receptor antagonists may serve as potential antidepressants. This article is part of a Special Issue entitled 'Anxiety and Depression'.