In the rat forced swimming test, NA-system mediated interactions may prevent the 5-HT properties of some subacute antidepressant treatments being expressed.

In the rat forced swimming test (FST), reuptake inhibitors selective of either serotonin (5-HT) or noradrenaline (NA) decrease immobility duration, and increase, respectively, swimming and climbing behaviour. In this study, an almost total 6-OHDA-induced NA-depletion prevented the behavioural effects of desipramine, but not fluoxetine. Interestingly, the serotonin/noradrenaline-reuptake-inhibitor milnacipran, as well as a (desipramine+fluoxetine) combination, could produce both swimming and climbing behaviour in NA-lesioned rats, but not in non-lesioned. The new antidepressant mirtazapine, which enhances both 5-HT and NA transmissions, supposedly through the antagonizing of alpha(2)-adrenoreceptors, dose-dependently reduced immobility and increased climbing behaviour. Interestingly, a (mirtazapine+fluoxetine) combination treatment resulted in additive anti-immobility effects and in the summation of fluoxetine-induced swimming with mirtazapine-induced climbing. Taken together, these data suggest that the NA system mediates presynaptic inhibiting interactions on the 5-HT system, that may involve alpha(2)-receptors, and that may limit the efficacy of mixed serotonin/noradrenaline reuptake inhibition in subacute antidepressant treatments.