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.


METHODS
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.


RESULTS
A dose response effect was observed for etifoxine from the dose of 40-100 mg/kg. Doses above to 60 mg/kg 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 mg/kg), while the 5-HT(2B/2C) 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.


CONCLUSIONS
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.
Bourin
Michel
M
Neurobiologie de l'anxiété et de la dépression, Faculté de Médecine, Nantes, France. michel.bourin@univ-nantes.fr
Hascoët
Martine
M
D000662:Amphetamines / Q000627:therapeutic use; D000704:Analysis of Variance; D000818:Animals; D014151:Anti-Anxiety Agents / Q000627:therapeutic use*; D001007:Anxiety / Q000188:drug therapy* / Q000209:etiology; D001522:Behavior, Animal / Q000187:drug effects; D003975:Diazepam / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004597:Electroshock / Q000009:adverse effects; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D010078:Oxazines / Q000627:therapeutic use*; D021122:Protein Subunits / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000008:administration & dosage; D017366:Serotonin Receptor Agonists / Q000627:therapeutic use
D000662:Amphetamines; D014151:Anti-Anxiety Agents; D010078:Oxazines; D021122:Protein Subunits; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine; D003975:Diazepam; C002125:etifoxine