Effects of duloxetine, an antidepressant drug candidate, on concentrations of monoamines and their metabolites in rats and mice.
Duloxetine, (+)-N-methyl-3-(1-naphthalenyloxy)-2-thiophenepropanamine, is an inhibitor of the serotonin and norepinephrine neuronal transporters (Wong et al., 1993). In mice, duloxetine antagonized the depletion of brain serotonin by p-chloroamphetamine (ED50 = 2.5 mg/kg, i.p.) and the depletion of heart norepinephrine by 6-hydroxydopamine (ED50 = 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 at 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-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. In rats, duloxetine decreased brain 5-hydroxyindoleacetic acid dose-dependently for up to 8 hr and decreased serotonin turnover measured by the accumulation of 5-hydroxytryptophan in rat hypothalamus after decarboxylase inhibition. In rats, duloxetine antagonized the depletion of brain serotonin by p-chloramphetamine and the depletion of norepinephrine and epinephrine in hypothalamus after i.c.v. injection of 6-hydroxydopamine. In vitro, duloxetine had little effect on either type A (serotonin as substrate) or type B (phenylethylamine as substrate) monoamine oxidase, IC50 concentrations being above 10(-5) M. These data extend evidence that duloxetine inhibits serotonin and norepinephrine transporters in vivo, actions that may lead to therapeutic efficacy in mental depression.
Fuller
R W
RW
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
Hemrick-Luecke
S K
SK
Snoddy
H D
HD
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D015306:Biogenic Monoamines / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D000068736:Duloxetine Hydrochloride; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism / Q000502:physiology*; D016627:Oxidopamine / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism / Q000502:physiology*; D013876:Thiophenes / Q000494:pharmacology*; D010133:p-Chloroamphetamine / Q000037:antagonists & inhibitors
D000928:Antidepressive Agents; D015306:Biogenic Monoamines; D008996:Monoamine Oxidase Inhibitors; D014179:Neurotransmitter Uptake Inhibitors; D013876:Thiophenes; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D010133:p-Chloroamphetamine; D016627:Oxidopamine; D000068736:Duloxetine Hydrochloride; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D004298:Dopamine; D009638:Norepinephrine