FG7142 combined with restraint stress induces anxiogenic-like effects via downregulation gamma-aminobutyric acid type A receptor subunit alpha1 and 5-hydroxytryptamine 1A receptors expression in the hippocampus.

Objectives: The existing anxiety animal models are susceptible to interference, and no single animal anxiety model can predict the future anxiolytic potential and profile of new putative anxiolytics. Therefore, to find a better anxiety animal model, we used FG7142, a nonselective benzodiazepine inverse agonist. This anxiety animal model was established by intraperitoneal injection of FG7142 combined with restraint stress.

Methods: Adult male C57BL/6J mice (18-20 g) were randomly classified into five groups (n = 10 per group), namely the control, restraint stress, restraint stress + 10 mg/kg FG7142, restraint stress + 20 mg/kg FG7142, restraint stress +30 mg/kg FG7142. The impact on behavior was explored by elevated plus maze, and marble burying test, followed by immunohistochemistry and quantitative real-time PCR enabled the elucidation of the possible mechanism.

Results: Compared with the control group and restraint stress group, intraperitoneal injection of FG7142 combined with restraint stress model group was found to induce anxiogenic-like behavior in elevated plus maze and marble burying test. Moreover, relative to the control group, significantly increased expression of c-fos in the hippocampus and amygdala in the model group was evident, whereas the expression of gamma-aminobutyric acid type A receptor subunit alpha1 and 5-hydroxytryptamine receptor 1A mRNA was significantly decreased in the hippocampus.

Conclusions: These results indicated that FG7142 combined with restraint stress is sufficient to induce anxiety, and its mechanism is associated with downregulation of hippocampal gamma-aminobutyric acid type A receptor subunit alpha1 and 5-hydroxytryptamine 1A receptors.