Pharmacology Pharmacology: Relaxed but Not Sleepy; Receptor Subtype-Specific Actions of Benzodiazepines

Benzodiazepines such as Valium are widely prescribed for the treatment of anxiety. However, the drugs have undesirable side effects that include sedative effects and disruption of memory. The target of these drugs is the -aminobutyric acid (GABA)_A receptor. But there are several subtypes of GABA_A receptors that are composed of different subunits and differentially distributed in the nervous system. A key question has been whether the distinct receptor subtypes are responsible for the various effects of benzodiazepines and thus whether development of receptor-specific drugs might yield agents that retain the beneficial effects but have reduced deleterious side effects. Rudolph et al. created mice in which they altered the most abundant form of GABA_A receptor in the brain so that it was no longer sensitive to benzodiazepines. The mice still responded to anxiolytic effects of the drugs, but did not show sedative or amnesic effects. The results indicate that the various effects of benzodiazepines are mediated by different receptor subtypes and emphasize the potential value of development of a new generation of drugs that target the specific GABA receptor subtypes.

Rudolph, U., Cretani, F., Benke, D., Brunig, I., Benson, J.A., Fritschy, J.-M., Martin, J.R., Bluethmann, H., and Mohler, H. (1999) Benzodiazepine actions mediated by specific gamma-aminobutyric acid A receptor subtypes. Nature 401: 796 - 800. [Online Journal]