Chronic treatment with duloxetine is necessary for an anxiolytic-like response in the mouse zero maze: the role of the serotonin transporter

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Abstract
Monoamine transporter inhibitor antidepressants have anxiolytic efficacy in man. However, preclinical data poorly reflect this, either because (1) few studies assess chronic antidepressant treatment in animal models, (2) antidepressants are anxiogenic after acute treatment; and (3) animal models of anxiety are insensitive to antidepressants. We address issues (1) and (2) and ascertain potential mechanisms mediating anxiolytic effects demonstrated. The effect of acute treatment with seven antidepressants covering the classes selective serotonin reuptake inhibitors, serotonin–noradrenaline reuptake inhibitors, noradrenaline reuptake inhibitors and tricyclic antidepressants were compared with the benzodiazepine, chlordiazepoxide, on the mouse zero maze, an unconditioned model of anxiety. Furthermore, citalopram, duloxetine, reboxetine and amitriptyline were assessed after chronic administration (10 mg/kg p.o., 21 days, twice daily) in this model. In mice treated chronically, (a) the hypothermic response to serotonin (5-HT)1A and 5-HT1B receptor ligands, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OHDPAT) and m-chlorophenyl piperazine (mCPP), respectively, was assessed and (b) serotonin transporter (SERT) and noradrenaline transporter (NET) densities in the cortex and hippocampus, respectively, were determined. None of the antidepressants were anxiolytic after acute treatment, although reboxetine, duloxetine and amitriptyline were anxiogenic. Only chronic treatment with duloxetine induced an anxiolytic effect, which was dissociable from nonspecific motor effects. Duloxetine reduced SERT density in the cortex by ∼75% compared to control, with no effect on NET density in the hippocampus. Citalopram and amitriptyline significantly reduced SERT density by ∼20%, whereas reboxetine selectively reduced NET density. All drugs reduced the hypothermic response to 8-OHDPAT and mCPP. Duloxetine was anxiolytic after chronic but not acute treatment, reflecting clinical experience with antidepressants in general. Duloxetine's anxiolytic-like profile may be ascribed to the considerable reduction in the density of the SERT in the cortex.