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) re uptake inhibitor with serotonin (5-HT)(3) receptor antagonism, shows antide pressant-like properties in experiments using rodents. In this study, we in vestigated the effect of MCI-225 in anxiety models in comparison with diaze pam, ondansetron, maprotiline, imipramine, and trazodone. In social interac tion (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 condit ions without changes in ambulation. The increase in SI induced by MCI-225 a nd 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, trazodon e, and imipramine did not affect SI at doses of 3-30 mg/kg, po. In the elev ated plus-maze test in rats, MCI-225 (10-100 mg/kg, po) increased the numbe r 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 en tries (10 mg/kg, po). Ondansetron (0.001-1 mg/kg, po) was less effective. M aprotiline, imipramine, and trazodone did not affect the number of open-arm entries, while trazodone and imipramine (100 mg/kg, po) decreased the tota l number of entries. These results show that MCI-225 has an anxiolytic-like effect without causing sedation and suggest that the 5-HT3 receptor antago nism of MCI-225 probably contributes to its anxiolytic-like property. (C) 2 001 Elsevier Science Inc. All rights reserved.