Neurochemical and behavioural characterization of milnacipran, a serotonin and noradrenaline reuptake inhibitor in rats

Rationale: The prefrontal cortex is implicated in the pathophysiology of depression, and hypoactivity of this brain area has been found in depressed patients. Reduced function of the serotonergic and noradrenergic systems is another feature of depression. Objectives: The present study was aimed at characterizing neurochemically and behaviorally the serotonin and noradrenaline reuptake inhibitor (SNRI), milnacipran, in the prefrontal cortex in comparison with tricyclic antidepressants and selective serotonin reuptake inhibitors. Methods: Sodium-dependent monoamine uptake measurement, radioligand binding assays, microdialysis procedure, forced swimming test and conditioned fear stress test were carried out in rats. Results: Milnacipran selectively inhibited sodium-dependent [³H]serotonin (5-hydroxytryptamine, 5-HT) and [³H]noradrenaline (NA) uptake into the synaptosomes from rat cerebral cortex (IC₅₀=28.0 and 29.6 nM, respectively) without any affinities for various neuroreceptors. In the medial prefrontal cortex, milnacipran (10 and 30 mg/kg, PO) caused a dose-related increase in the extracellular levels of 5-HT and NA with similar potency, whereas imipramine (10 and 30 mg/kg, PO) caused a dominant increase in the output of NA compared to 5-HT. Milnacipran (30 and 60 mg/kg, PO) significantly reduced the duration of both the immobility time in the forced swimming test and the freezing time in the conditioned fear stress test in rats, which are animal behavioral models for depression and anxiety, respectively. Imipramine and maprotiline were active in the former test, but not in the latter. Fluoxetine and fluvoxamine on the other hand were more active in the conditioned fear test. Conclusion: These findings show that milnacipran acts as a SNRI in vitro and in vivo and may be useful for the treatment of anxiety as well as depression.