The anxiolytic-like effect of MCI-225, a selective NA reuptake inhibitor with 5-HT3 receptor antagonism

We have previously reported that MCI-225, a selective noradrenaline (NA) reuptake inhibitor with serotonin (5-HT)(3) receptor antagonism, shows antidepressant-like properties in experiments using rodents. In this study, we investigated the effect of MCI-225 in anxiety models in comparison with diazepam, ondansetron, maprotiline, imipramine, and trazodone. In social interaction (SI) test in rats, MCI-225 (10 and 30 mg/kg, po), diazepam (1-10 mg/kg. po), and a selective 5-HT3 receptor antagonist ondansetron (1 mg/kg, po) significantly increased SI to an unfamiliar partner under high light conditions without changes in ambulation. The increase in SI induced by MCI-225 and ondansetron was blocked by a 5-HT3 agonist, 1-(m-Chlorophenyl)-biguanide(mCPBG, 1 mg/kg, ip), which did not change SI when administered alone. MCI-225 (10 mg/kg, po) showed comparable anxiolytic-like effect between single and 5-day repeated administration. On the other hand, maprotiline, trazodone, and imipramine did not affect SI at doses of 3-30 mg/kg, po. In the elevated plus-maze test in rats, MCI-225 (10-100 mg/kg, po) increased the number of entries into the open arms only while diazepam increased not only the number of open-arms entries (30 mg/kg, po), but also the total number of entries (10 mg/kg, po). Ondansetron (0.001-1 mg/kg, po) was less effective. Maprotiline, imipramine, and trazodone did not affect the number of open-arm entries, while trazodone and imipramine (100 mg/kg, po) decreased the total number of entries. These results show that MCI-225 has an anxiolytic-like effect without causing sedation and suggest that the 5-HT3 receptor antagonism of MCI-225 probably contributes to its anxiolytic-like property. (C) 2001 Elsevier Science Inc. All rights reserved.