Simultaneous Increases of Extracellular Monoamines in Microdialysates from Hypothalamus of Conscious Rats by Duloxetine, a Dual Serotonin and Norepinephrine Uptake Inhibitor

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.

Comparative Affinity of Duloxetine and Venlafaxine for Serotonin and Norepinephrine Transporters in vitro and in vivo, Human Serotonin Receptor Subtypes, and Other Neuronal Receptors

“…Results from microdialysis studies indicate that duloxetine increases extracellular 5-HT and NE levels in frontal cortex and hypothalamus (Gobert et al 1997;Kihara and Ikeda 1995;Engleman et al 1995) in a similar dose range to doses that block both 5-HT and NE transporters, consistent with uptake blockade increasing extracellular levels of the neurotransmitters. Selective blockade of 5-HT and NE autoreceptors markedly augmented the duloxetine-induced increase of extracellular levels of 5-HT and NE, respectively, suggesting that increased levels of monoamines activated inhibitory autoreceptors (Engleman et al 1996;Millan et al 1998;Gobert et al 1997).…”

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

“…Thus, an enhancement of the function of ␣ 2 -adrenoceptors or a reduction of the ␣ 1 -mediated tone on serotonergic neurones (secondary to the inhibition of the firing of NA neurones (Mongeau et al 1998) might also be involved in the comparatively lower increases of the 5-HT output produced by the systemic milnacipran administration. In support of this possibility, duloxetine increased the NA output more than that of 5-HT in hypothalamus and frontal cortex (Engleman et al 1995;Kihara and Ikeda 1995), despite the fact that it preferentially blocks the 5-HT reuptake (relative 5-HT/ NA ratio of 2.7; Artigas 1995). These observations are difficult to reconcile with the desipramine-induced potentiation of the increase in frontocortical 5-HT output produced by the SSRI fluoxetine (Bel and Artigas 1996).…”

“…Despite the potential advantages of SNRIs, the information on their in vivo effects on serotonergic transmission is scarce (e.g., Engleman et al 1995;. In particular, a comparison of their effects in the somatodendritic region in the raphe nuclei and in forebrain has not been performed.…”

“…6 drugs, mainly derived from their affinity for ␣ -adrenergic, cholinergic, and histamine receptors (Richelson 1978;Richelson and Nelson 1984). Milnacipran is one such drug that blocks in vitro and in vivo the reuptake of 5-HT and noradrenaline, although it displays a slightly higher affinity for the latter (Moret et al 1985;Stenger et al 1987).Despite the potential advantages of SNRIs, the information on their in vivo effects on serotonergic transmission is scarce (e.g., Engleman et al 1995;. In particular, a comparison of their effects in the somatodendritic region in the raphe nuclei and in forebrain has not been performed.…”

“…The absence of such a response in milnacipran-treated rats suggests that chronic treatment with this agent may prevent the rise in 5-HT produced by injection stress. Interestingly, unlike milnacipran, a 2-week treatment with duloxetine, which increases the 5-HT output more than milnacipran after a single treatment (Engleman et al 1995;Kihara and Ikeda 1995), facilitated the effects of a challenge dose (Kihara and Ikeda 1995). Again, this difference may lie in the greater potency of duloxetine to inhibit the 5-HT reuptake.…”