GABA-A receptor subtypes in the brain: a paradigm for CNS drug discovery?

The clinical importance of benzodiazepines, barbiturates and general anesthetics, all of which act through the γ-aminobutyric acid (GABA)-A neurotransmitter receptor, is testament to its significance as a CNS drug target. These drugs were all developed before there was any understanding of the diversity of this receptor gene family. Recent studies using genetically modified mice and GABA-A receptor-subtype-selective compounds have helped to delineate the function of some of these subtypes, and have revealed that it might be possible to develop a new generation of selective drugs with improved profiles or novel applications. Target validation continues to be a critical challenge in drug discovery, particularly for central nervous system disorders. This review describes how the use of sophisticated genetic mouse models in combination with behavioural pharmacology can be a powerful approach to defining drug targets.