A novel 5-HT(2A) receptor antagonist exhibits antidepressant-like effects in a battery of rodent behavioural assays: approaching early-onset antidepressants.

Collective evidence suggests that inhibition of neuronal 5-hydroxytryptamine type 2A (5-HT(2A)) receptors contributes to the assuagement of depression-like behaviour in rodents. The present study evaluated the antidepressant-like effect of the 5-((4-benzo [alpha] isothiazol-3-yl) piperazin-1-yl) methyl)-6-chloroindolin-2-one (BIP-1), a compound having affinity to 5-HT(2A) receptors, using a rodent behavioural test battery. Acute BIP-1 (0.25-4mg/kg) pretreatment reduced the quipazine-induced head twitches in mice and produced antidepressant-like effects in mouse forced swim and tail suspension tests. BIP-1 reversed the depressogenic-like effects of meta-chlorophenyl piperazine and augmented the antidepressant-like effects of amitryptiline and harmane. Chronic (14days) treatment with BIP-1 (1 and 2mg/kg) or amitriptyline (10mg/kg) alleviated the behavioural anomalies of olfactory bulbectomised rats in modified open field exploration, social interaction, hyperemotionality and sucrose preference paradigms. When BIP-1 treatment was combined with amitryptyline, a short duration regimen (7days) was sufficient to reverse the bulbectomy induced anomalies. This investigation revealed that 5-HT(2A) receptor antagonism is the principal mechanism behind the antidepressant-like effects of BIP-1. Finally, we propound the combination of 5-HT(2A) receptor antagonists and tricyclic antidepressants as a likely strategy to achieve an early-onset of antidepressant action.