EFFECTS OF DULOXETINE, AN ANTIDEPRESSANT DRUG CANDIDATE, ON CONCENTRATIONS OF MONOAMINES AND THEIR METABOLITES IN RATS AND MICE

Duloxetine, thyl-3-(1-naphthalenyloxy)-2-thiophenepropanamine, is an i nhibitor of the serotonin and norepinephrine neuronal transporters (Wo ng at al., 1993). In mice, duloxetine antagonized the depletion of bra in serotonin by p-chloroamphetamine (ED(50) = 2.5 mg/kg, i.p.) and the depletion of heart norepinephrine by 6-hydroxydopamine (ED(50) = 1.1 mg/kg, i.p.). Brain concentrations of 5-hydroxyindoleacetic acid were decreased by duloxetine at 2 hr after doses of 1, 3 and 10 mg/kg and a t 1 to 8 hr (but not 24 hr) after a 10 mg/kg i.p. dose of duloxetine. Duloxetine antagonized norepinephrine depletion in frontal cortex, but not dopamine depletion in striatum, after treatment of mice with 1-me thyl-4-phenyl-1,2,3,6-tetrahydropyridine. In rats, duloxetine decrease d brain 5-hydroxyindoleacetic acid dose-dependently for up to 8 hr and decreased serotonin turnover measured by the accumulation of 5-hydrox ytryptophan in rat hypothalamus after decarboxylase inhibition. In rat s, duloxetine antagonized the depletion of brain serotonin by p-chloro amphetamine and the depletion of norepinephrine and epinephrine in hyp othalamus after i.c.v. injection of 6-hydroxydopamine. In vitro, dulox etine had little effect on either type A (serotonin as substrate) or t ype B (phenylethylamine as substrate) monoamine oxidase, IC50 concentr ations being above 10(-5) M. These data extend evidence that duloxetin e inhibits serotonin and norepinephrine transporters in vivo, actions that may lead to therapeutic efficacy in mental depression.