The determination of the optimal dose of milnacipran in the olfactory bulbectomized rat model of depression

Olfactory bulbectomy (OB) is associated with a variety of behavioral abnormalities such as hyperactivity in the open-field test. Previous studies have shown that chronic administration of antidepressants can reverse this behavioral deficit. The activity of milnacip ran (20, 30, and 40 mg kg, PO bid) administered in two equally divided doses twice daily was assessed in the olfactory bulbectomized rat model of depression. It was found that chronic treatment with milnacipran at the doses of 30 and 40 mg kg, but not 20 mg kg, attenuated the lesion-induced hyperactivity of the OB rat in the open-field test following 14 days of treatment. In the step-through passive avoidance test, administration of milnacipran at doses of 20, 30, and 40 mg kg had no effect on the performance deficit associated with olfactory bulbectomy. Olfactory bulbectomy reduced the concentration of noradrenaline (NA) in the frontal cortex. However, chronic milnacipran treatment did not significantly alter this deficit. It is concluded that milnacipran, when administered chronically at doses of 30 and 40 mg kg, are effective at reversing the open-field deficit associated with olfactory bulbectomy, and that a dose of 30 mg kg is an optimal dose. (C) 1999 Elsevier Science Inc.