Differential effects of etifoxine on anxiety-like behaviour and convulsions in BALB/cByJ and C57BL/6J mice: Any relation to overexpression of central GABAA receptor beta2 subunits?

• Published in: European neuropsychopharmacology 2011-06, Vol.21 (6), p.457-470
• Main Authors: Verleye, Marc, Dumas, Sylvie, Heulard, Isabelle, Krafft, Nicolas, Gillardin, Jean-Marie
• Format: Article
• Language: English
• Subjects: Animals; Anti-Anxiety Agents - blood; Anti-Anxiety Agents - pharmacology; Anti-Anxiety Agents - toxicity; Anxiety - drug therapy; Anxiety Disorders - drug therapy; Behavior, Animal - drug effects; Brain - physiology; Brain - physiopathology; Hippocampus - physiology; Hippocampus - physiopathology; Internal Medicine; Intestine, Small - drug effects; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Motor Activity - drug effects; Oxazines - blood; Oxazines - pharmacology; Oxazines - toxicity; Psychiatry; Receptors, GABA-A - genetics; Receptors, GABA-A - metabolism; Seizures - drug therapy; Seizures - physiopathology
• ISSN: 0924-977X; 1873-7862
• DOI: 10.1016/j.euroneuro.2010.09.008

Abstract Dysfunction of GABAergic transmission related to abnormal expression of GABAA receptor subunits in specific brain regions underlies some pathological anxiety states. Besides involvement of the benzodiazepine recognition site of GABAA receptor in the expression of anxiety-like behaviour, the roles of the β2 /β3 subunits are not well characterized. To address this issue, the experimental design of this study utilized the GABAergic compound etifoxine (with a preferential effectiveness after binding to a specific site at β2 /β3 subunits) tested in two inbred mouse strains: BALB/cByJ and C57BL/6J mice using three behavioural paradigms (light/dark box, elevated plus maze and restraint stress-induced small intestinal transit inhibition) and the t-butylbicyclophosphorothionate-induced convulsions model. Etifoxine plasma and brain levels and β2 /β3 mRNAs and protein expression levels in various brain regions were compared between the two strains. The two mouse strains differed markedly in basal anxiety level. Etifoxine exhibited more pronounced anxiolytic and anticonvulsant effects in the BALB/cByJ mice compared to the C57BL/6J mice. The etifoxine brain/plasma ratios of the two strains were not different. Beta2 subunit mRNA and protein expression levels were around 25 and 10% higher respectively in the anterodorsal nucleus of the thalamus and the CA3 field of hippocampus of BALB/cByJ mice compared to C57BL/6J mice. Beta3 subunit mRNA and protein expression levels did not differ between the two strains. Based on these results, it is suggested that overexpression of GABAA receptor β2 subunit in BALB/cByJ mice relative to C57BL/6j mice contributes to the dysfunction in GABAA transmission in regions of brain known to regulate responses to stress. The dysregulated GABAA function in BALB/cByJ mice may be corrected by the administration of etifoxine.