SIMULTANEOUS INCREASES OF EXTRACELLULAR MONOAMINES IN MICRODIALYSATESFROM HYPOTHALAMUS OF CONSCIOUS RATS BY DULOXETINE, A DUAL SEROTONIN AND NOREPINEPHRINE UPTAKE INHIBITOR

Duloxetine (LY248686, thyl-3-(1-napthalenyloxy)-2-thiophene-propanamin e) is a potent dual inhibitor of serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine (NE) uptake in hypothalamus and cerebral cortex of rat brain (Wong et al. 1993; Fuller et al. 1994). Consistent with the dual mechanisms of inhibiting 5-HT and NE uptake, duloxetine at 15 mg /kg IP produced large increases in extracellular levels of 5-HT (250%) and NE (1,100%) 30 minutes after systemic administration. Levels of 3 -methoxy-4-hydroxy-phenylethyleneglycol (MHPG) and 5-hydroxyindoleacet ic acid (5-HIAA), metabolites of NE and 5-HT, respectively, were reduc ed, whereas those of dopamine (DA) and ifs metabolite 3, 4-dihydroxyph enylacetic acid(DOPAC) were not significantly altered. Duloxetine at 7 mg/kg produced less pronounced increases while no consistent effects were observed at 4 mg/kg. In this dose range, duloxetine inhibited 5-H T uptake in platelets ex vivo without inhibiting striatal dopamine (DA ) uptake. In the present study we also found that the primary amine (a racemate) of duloxetine is about one-fourth as active as duloxetine t o inhibit 5-HT and NE uptake. The potential primary amine metabolite o f duloxetine might contribute, in part, to the inhibition of 5-HT and NE uptake in vivo. Thus the ability to produce robust increases of ext racellular 5-HT and NE levels suggests that duloxetine may potentially be a highly effective antidepressant agent.