Effects of the brain-penetrant and selective 5-HT6 receptor antagonist SB-399885 in animal models of anxiety and depression

Abstract

The effects of a selective 5-HT6 receptor antagonist, SB-399885 (N-[3,5-dichloro-2-(methoxy)phenyl]-4-(methoxy)-3-(1-piperazinyl)benzenesulfonamide), were evaluated in behavioural tests sensitive to clinically effective anxiolytic- and antidepressant-compounds using diazepam and imipramine as reference drugs. In the Vogel conflict drinking test in rats, SB-399885 (1–3mg/kg i.p.) caused an anxiolytic-like activity comparable to that of diazepam (2.5–5mg/kg i.p.). An anxiolytic-like effect was also seen in the elevated plus-maze test in rats, where SB-399885 (0.3–3mg/kg i.p.) was slightly weaker than diazepam (2.5–5mg/kg i.p.). In the four-plate test in mice, SB-399885 (3–20mg/kg i.p.) showed an anxiolytic-like effect which was weaker than that produced by diazepam (2.5–5mg/kg i.p.). In the forced swim test in rats, SB-399885 (10mg/kg i.p.) significantly shortened the immobility time and the effect was stronger than that of imipramine (30mg/kg i.p.). In the forced swim test in mice, SB-399885 (20–30mg/kg i.p.) had an anti-immobility action, comparable to imipramine (30mg/kg i.p.) and also in the tail suspension test in mice, SB-399885 (10–30mg/kg i.p.) had an antidepressant-like effect, though was weaker than imipramine (10–20mg/kg i.p.). The tested 5-HT6 antagonist (3-20mg/kg i.p.) shortened the walking time of rats in the open field test and, at a dose of 30mg/kg i.p. reduced the locomotor activity of mice. SB-399885 (in doses up to 30mg/kg i.p.) did not affect motor coordination in mice and rats tested in the rota-rod test. Such data indicate that the selective 5-HT6 receptor antagonist SB-399885had specific effects, indicative of this compound's anxiolytic and antidepressant potential.