Characterization of the anxiolytic-like effects of fluvoxamine, milnacipran and risperidone in mice using the conditioned fear stress paradigm.

It has been known that rodents exhibit the immobility when tested in the same environment in which they had been previously exposed to aversive stimuli. This behavior is called conditioned fear stress-induced freezing behavior, and has been used as a model of anxiety. Using this animal model, the present study tried to characterize the anxiolytic-like effects of fluvoxamine, a selective serotonin reuptake inhibitor, milnacipran, a serotonin noradrenaline reuptake inhibitor and risperidone, an atypical antipsychotic in mice. Fluvoxamine (1.25-10 mg/kg, intraperitoneally (i.p.)) and milnacipran (0.5-4 mg/kg, i.p.) each dose-dependently and significantly suppressed the conditioned fear stress-induced freezing behavior in mice, an indicator of anxiety, and milnacipran had a weaker effect than fluvoxamine. While risperidone also significantly suppressed freezing behavior at a low dose (0.01 mg/kg, i.p.), a high dose (0.04 mg/kg, i.p.) decreased spontaneous motor activity. On the contrary, sulpiride, a typical antipsychotic (2-8 mg/kg, i.p.), did not affect freezing behavior. In a combination study, the suppressive effect of a low dose of risperidone (0.01 mg/kg, i.p.) on freezing behavior was significantly antagonized by the co-administration of low/middle doses of fluvoxamine (1.25 and 2.5 mg/kg, i.p.), whereas a high dose of fluvoxamine (10 mg/kg, i.p.) was unaffected. Additionally, the co-administration of milnacipran (0.5-2 mg/kg, i.p.) also tended to inhibit the suppressive effect of risperidone (0.01 mg/kg, i.p.). These findings indicate that fluvoxamine, milnacipran and risperidone may each be clinically effective at treating anxiety disorders, but their effects may be attenuated in combination with other medications.