Antidepressant effects of an inverse agonist selective for α5 GABA-A receptors in the rat forced swim test

Abstract

It has been shown in electrophysiological studies that the ligand L-655,708 possesses a binding selectivity and a moderate inverse agonist functional selectivity for α5-containing GABA-A receptors. The present study is aimed to investigate the antidepressant effects of the ligand L-655,708 in the forced swim test (FST) and its impact on locomotor activity in rats. The behavior of the animals was recorded with a digital camera, and the data were analyzed by one-way ANOVA, followed by Dunnett’s test. In FST, L-655,708 significantly decreased immobility time at a dose of 3 mg/kg after a single and repeated administration (p<0.05), exerting acute and chronic antidepressant effects. However, it did not induce significant differences in the time of struggling behavior during FST. Furthermore, L-655,708 did not show a significant effect on locomotor activity (p>0.05). These data suggest that negative modulation at GABA-A receptors containing the α5 subunit may produce antidepressant effects in rats. These effects were not confounded by locomotor influences.

U elektrofi ziološkim ispitivanjima pokazano je da ligand L-655,708 poseduje selektivnost u vezivanju i umerenu inverznu agonističku aktivnost za GABA-A receptore koji sadrže α5 podjedinicu. Ova studija ima za cilj ispitivanje antidepresivnih efekata liganda L-655,708 u testu forsiranog plivanja (FST) i njegov uticaj na lokomotornu aktivnost kod pacova. Ponašanje životinja je praćeno pomoću digitalne kamere, a podaci su analizirani primenom jednostepene analize varijanse (ANOVA) i Dunett-ovim testom. U testu forsiranog plivanja L-655,708 statistički značajno smanjuje vreme imobilnosti pri dozi od 3 mg/kg, nakon jednokratne i ponavljane primene (p0,05). Ovi podaci ukazuju da negativna modulacija GABA-A receptora koji sadrže α5 podjedinicu može ispoljiti antidepresivne efekte kod pacova. Ovi efekti su bez izraženih lokomotornih uticaja.