Insight into the Mechanism of the Four-Plate Test-Retest Procedure Using Etifoxine as Compared with Gabapentin

Etifoxine is an anxiolytic compound structurally unrelated to benzodiazepines and neurosteroids but potentiating GABAA receptor function by a dual mode of action including a direct positive allosteric modulation through a site distinct from that of benzodiazepines. Gabapentin is an antiepileptic drug structurally related to GABA but with a mechanism of action that is still unclear. Methods: Using the four-plate test (FPT) model of anxiety in mice the potential anxiolytic-like effect of gabapentin was first evaluated. In a second part, the effects of both drugs were evaluated in a test retest procedure in the FPT. Results: Gabapentin, for non sedative doses, increased significantly the number of punished passages in the FPT as did etifoxine. In the test -retest procedure, etifoxine (40 and 50 mg.kg) increased the number of shocks accepted by the animal as compared with benzodiazepine. The same effect was observed with gabapentin (32 and 64 mg/kg) with an increase in retested mice responding during the second trial. However, the effect was smaller than that achieved with DOI (a 5-HT2A agonist). Those results are of importance as it was the first time that GABAergic like ligands respond, even weakly, in experienced mice in the FPT. Whether this effect is due to stress or anxiety is open to discussion.