A comparison of the effects of a subtype selective and non-selective benzodiazepine receptor agonist in two CO2 models of experimental human anxiety

Studies in human volunteers that can demonstrate proof of concept are attractive in that possible mechanisms and potential new drug treatments can be examined. We have been developing models of anxiety disorders using the inhalation of 7.5% CO2 for 20 min to model generalised anxiety disorder, as well as using the previously reported 35% CO2 as a model for panic anxiety. In a double-blind, placebo-controlled, three-way crossover study in 12 healthy volunteer subjects, we compared a full agonist at the benzodiazepine receptor that binds to four alpha-subtypes of the receptor (alpha-1,-2,-3,-5) (alprazolam 1 mg), with zolpidem (5 mg), an agonist selective for the alpha-1 subtype of the gamma amino butyric acid-receptor subtype A (GABA-A) receptor, which is a widely used hypnotic drug. Compared with placebo, both drugs significantly attenuated peak CO2-induced changes in subjective feelings after the inhalation of 7.5% CO2 for 20 min. However, there were fewer significant differences after a single vital capacity inhalation of 35% CO2, where zolpidem was less efficacious than alprazolam at reducing CO2-induced symptoms. In conclusion, our results show that zolpidem shows some anxiolytic efficacy in the 7.5% CO2 model, similar to alprazolam, and this is the first report of such an effect of zolpidem in a model of anxiety. These and other studies of benzodiazepines in clinical and volunteer studies suggest a definite role of the GABA-A receptor in CO2-induced anxiety, and it would be of interest to examine other GABA-A receptor subtype selective drugs, which are now in early phase clinical studies and are showing selective efficacy in pharmacodynamic studies.