The Central Benzodiazepine Receptor

Benzodiazepines have been used clinically now for more than a half century for the management of anxiety and other conditions. Despite their widespread use, only now are their mechanisms of action and their pharmacologic implications, especially with long-term use, beginning to be appreciated. In the central nervous system, benzodiazepines act on an allosteric site of the GABAA receptor to enhance the activity of this inhibitory neurotransmitter. The GABA receptor consists of 5 subunits, which can vary among 19 different subtypes, resulting in a large number of possible configurations for the GABA receptor. Subunit structure can affect the binding of benzodiazepines to the receptor and can alter the nature of the interaction between the benzodiazepine binding site and the GABA binding site, resulting in different levels of receptor activation and allosteric enhancement. Moreover, the distribution of these different subtypes within the central nervous system, with their varying levels of benzodiazepine efficacy, can mean that benzodiazepines can have differential effects among the different sites of the brain. Consequently, in may be possible to design novel drugs that favor particular subunit configurations and thus produce different pharmacologic profiles. Drugs acting at the benzodiazepine site can be agonists, enhancing the activity of GABA; antagonists, blocking the effect of benzodiazepines at the binding site; or inverse agonists, producing an effect antipodal to that of benzodiazepine agonists.