Simultaneous increases of extracellular monoamines in microdialysates from hypothalamus of conscious rats by duloxetine, a dual serotonin and norepinephrine uptake inhibitor

Neuropsychopharmacology. 1995 Jul;12(4):287-95. doi: 10.1016/0893-133X(94)00093-F.

Abstract

Duloxetine (LY248686, [+]-N-methyl-3-(1-napthalenyloxy)-2-thiophene-propanamine) 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-hydroxyindoleacetic acid (5-HIAA), metabolites of NE and 5-HT, respectively, were reduced, whereas those of dopamine (DA) and its metabolite 3, 4-dihydroxyphenylacetic 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-HT 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 to inhibit 5-HT and NE uptake. The potential primary amine metabolite of duloxetine might contribute, in part, to the inhibition of 5-HT and NE uptake in vivo. Thus the ability to produce robust increases of extracellular 5-HT and NE levels suggests that duloxetine may potentially be a highly effective antidepressant agent.

MeSH terms

  • 3,4-Dihydroxyphenylacetic Acid / metabolism
  • Adrenergic Uptake Inhibitors / pharmacology*
  • Animals
  • Biogenic Monoamines / metabolism*
  • Blood Platelets / drug effects
  • Blood Platelets / metabolism
  • Dopamine / metabolism
  • Dose-Response Relationship, Drug
  • Duloxetine Hydrochloride
  • Hypothalamus / drug effects
  • Hypothalamus / metabolism*
  • In Vitro Techniques
  • Male
  • Microdialysis
  • Norepinephrine / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Serotonin / metabolism
  • Serotonin Uptake Inhibitors / pharmacology*
  • Synaptosomes / drug effects
  • Synaptosomes / metabolism
  • Thiophenes / pharmacology*

Substances

  • Adrenergic Uptake Inhibitors
  • Biogenic Monoamines
  • Serotonin Uptake Inhibitors
  • Thiophenes
  • 3,4-Dihydroxyphenylacetic Acid
  • Serotonin
  • Duloxetine Hydrochloride
  • Dopamine
  • Norepinephrine