Modulation of the Extracellular 5-Hydroxytryptamine Brain Concentrations by the Serotonin and Noradrenaline Reuptake Inhibitor, Milnacipran: Microdialysis Studies in Rats

Abstract

We examined the effects of the administration of milnacipran, a dual inhibitor of serotonin (5-hydroxy-tryptamine, 5-HT) and noradrenaline uptake on the 5-HT output in rat brain. Local milnacipran administration increased the 5-HT output in frontal cortex and the midbrain raphe nuclei 7- and 10-fold by a Ca2+- and tetrodotoxin-dependent mechanism. However, the subcutaneous administration of milnacipran (1–60 mg/kg SC) elevated the 5-HT output much less in these areas (200–230% of baseline at 60 mg/kg). In hypothalamus, 10 mg/kg SC raised 5-HT levels to 170%. The 5-HT1A antagonist WAY-100635 caused a small potentiation of the effects of milnacipran. The baseline 5-HT output was unaffected by 2-week treatments with milnacipran (30 and 60 mg/kg·day). The distinct regional profile and the lack of enhancement of its effects by WAY-100635 and prolonged treatment suggest that milnacipran does not exert its antidepressant action through an enhancement of the serotonergic function.