Investigation of the anticonvulsive effect of acute immobilization stress in anxious Balb/cByJ mice using GABA A-related mechanistic probes.
BACKGROUND
A disordered regulation of neuroactive steroids release in response to acute stress could induce GABAergic dysfunctions underlying anxiety disorders.


OBJECTIVE
First, we conducted studies indicating that a short immobilization stress in anxious Balb/cByJ mice produced an anticonvulsive effect. Second, the effects of different positive allosteric modulators (etifoxine, progesterone, clonazepam, and allopregnanolone) of GABA A receptors were compared in a mouse model mimicking the disruption of the acute stress-induced neuroactive steroids release with finasteride (types I and II 5alpha-reductase inhibitor).


RESULTS
The acute stress-induced anticonvulsive effect, expressed by the threshold dose of t-butylbicyclophosphorothionate-producing clonic seizures, was time-dependent. The extent of the enhancement of acute stress-induced anticonvulsive effect was lowered in the presence of finasteride. The same effect was observed with PK11195, which behaves as an antagonist of the peripheral benzodiazepine receptor in the dose range used in this study. Picrotoxin reduced the acute stress anticonvulsive effect, proving that this effect operates through the GABA A receptor. Contrary to progesterone (up to 30 mg/kg), etifoxine (50 mg/kg), allopregnanolone (10 mg/kg), and clonazepam (10 microg/kg) inhibited the finasteride effect in stressed animals. The effect of etifoxine was blocked in the presence of finasteride and picrotoxin combined in stressed animals.


CONCLUSIONS
These findings support the hypothesis suggesting an involvement of neuroactive steroids in the anticonvulsive effect of restraint stress. The dual and complementary mechanisms of action of etifoxine (directly on the GABA A receptor and indirectly via the neuroactive steroids) may represent a therapeutic benefit in the treatment of various anxiety disorders with abnormal production of neuroactive steroids.
Verleye
Marc
M
Département de Pharmacologie, Biocodex, Chemin d'Armancourt, 60200 Compiègne, France. m.verleye@biocodex.fr
Heulard
Isabelle
I
Gillardin
Jean-Marie
JM
D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D001007:Anxiety / Q000503:physiopathology*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002998:Clonazepam / Q000494:pharmacology; D003292:Convulsants; D004347:Drug Interactions; D018120:Finasteride / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010078:Oxazines / Q000494:pharmacology; D010852:Picrotoxin / Q000494:pharmacology; D011280:Pregnanolone / Q000494:pharmacology; D011374:Progesterone / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology*; D012149:Restraint, Physical; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology*; D013315:Stress, Psychological / Q000503:physiopathology*
D019086:Bridged Bicyclo Compounds, Heterocyclic; D002998:Clonazepam; D003292:Convulsants; D018120:Finasteride; D007546:Isoquinolines; D010078:Oxazines; D010852:Picrotoxin; D011280:Pregnanolone; D011374:Progesterone; D011963:Receptors, GABA-A; C037476:tert-butylbicyclophosphorothionate; C002125:etifoxine; C037850:PK 11195