Modulating GABA modulators.

Benzodiazepines produce a broad spectrum of behavioral effects, which may be clinically desirable or undesirable, by positively or negatively modulating the effects of GABA at GABAA receptors. Over the past 20 years, much effort has been devoted towards identifying new compounds with limited undesirable effects. Most of this work has focused on developing drugs either with lower intrinsic activity than drugs such as diazepam, or with different binding profiles at subtypes of GABAA receptors. However, the benzodiazepine binding site is only one of multiple binding sites contained within the GABAA receptor complex, and other endogenous or exogenous compounds also may positively or negatively modulate the effects of GABA. Despite the availability of ligands for each of these distinct binding sites, very little research has examined the effects of GABA modulators given in combination. This may be due, in part, to the noncompelling results of those few studies which, depending on the particular drugs, have demonstrated site-selective antagonism or only additive effects, suggesting that each site modulates the effects of GABA independently. In this issue, McMahon and France challenge this view by showing that low-efficacy benzodiazepine ligands will effectively antagonize midazolam and, at the same doses, will enhance the effects of a neuroactive steroid. These studies raise interesting questions regarding the nature of the interaction between the benzodiazepine and neurosteroid binding sites on GABAA receptors.