Implication of 5-HT2 receptor subtypes in the mechanism of action of the GABAergic compound etifoxine in the four-plate test in Swiss mice.
Etifoxine is an anxiolytic compound structurally unrelated to benzodiazepine and neurosteroids but potentiating GABA(A) receptor function by a dual mode of action including a direct positive allosteric modulation through a site distinct from that of benzodiazepines. Etifoxine has been shown to possess some anxiolytic-like effects in rodents. Using the four-plate test (FPT) model of anxiety in mice the potential anxiolytic-like effect of etifoxine was first to re-evaluate. In a second part, in order to better understand the mechanism of action of etifoxine, interaction studies with 5-HT(2) ligands were performed in the FPT as mixed serotonergic and GABAergic mechanisms are highly implicated in the anxiolytic-like effect observed in the FPT. A dose response effect was observed for etifoxine from the dose of 40-100 mgkg. Doses above to 60 mgkg induced a sedative effect as was determined in the actimeter test. The 5-HT(2A) receptor antagonist SR 46349B blocked the anti-punishment activity of etifoxine (40 and 50 mgkg), while the 5-HT(2B2C) receptor antagonist, SB 206553 and the 5-HT(2C) receptor antagonist, RS 10-2221 did not alter its effects. In a same way, only the 5-HT(2A) agonist DOI induced anti-punishment effect when co-administered with subthreshold doses of etifoxine. The present results demonstrated that etifoxine effect was modulated by 5-HT(2A) ligands co-administration. The large literature concerning GABA and 5-HT suggests that they could be co-released and could act as co-transmitters in some regions of the CNS and cross-communication between the two neurotransmitters might be an important modulator process of neuronal activity.