Subchronic lithium treatment increases the anxiolytic-like effect of mirtazapine on the expression of contextual conditioned fear.

Lithium not only has a mood-stabilizing effect but also the augmentation effect of an antidepressant, the mechanism of which remains unclear. Although lithium may augment the effect of mirtazapine, this augmentation has not been confirmed. Using a contextual fear conditioning test in rats, an animal model of anxiety or fear, we examined the effect of subchronic lithium carbonate (in diet) in combination with systemic mirtazapine on the expression of contextual conditioned fear. Mirtazapine (10mg/kg) reduced freezing one day after fear conditioning dose-dependently, whereas the anxiolytic-like effect of mirtazapine (10mg/kg) diminished seven days after fear conditioning. When the interval between fear conditioning and testing was seven days, only the combination of subchronic 0.2% Li2CO3 but not 0.05% Li2CO3 with acute mirtazapine (10mg/kg) reduced freezing significantly. These results indicate that subchronic 0.2% Li2CO3 treatment enhanced the anxiolytic-like effect of systemic mirtazapine. This augmentation therapy might be useful for the treatment of anxiety disorders.