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


OBJECTIVE
We address issues (1) and (2) and ascertain potential mechanisms mediating anxiolytic effects demonstrated.


METHODS
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.


RESULTS
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 approximately 75% compared to control, with no effect on NET density in the hippocampus. Citalopram and amitriptyline significantly reduced SERT density by approximately 20%, whereas reboxetine selectively reduced NET density. All drugs reduced the hypothermic response to 8-OHDPAT and mCPP.


CONCLUSIONS
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.
Troelsen
K B
KB
NeuroSearch A/S, 93 Pederstrupvej, Ballerup, 2750, Denmark.
Nielsen
E Ø
EØ
Mirza
N R
NR
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D000928:Antidepressive Agents / Q000494:pharmacology*; D001143:Arousal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D002352:Carrier Proteins / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology; D000068736:Duloxetine Hydrochloride; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D018782:Maze Learning / Q000187:drug effects*; D051379:Mice; D009638:Norepinephrine / Q000378:metabolism; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects; D044302:Receptor, Serotonin, 5-HT1B / Q000187:drug effects; D050486:Serotonin Plasma Membrane Transport Proteins / Q000187:drug effects*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*
D018759:Adrenergic Uptake Inhibitors; D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D002352:Carrier Proteins; D000068736:Duloxetine Hydrochloride; D009638:Norepinephrine; D044282:Receptor, Serotonin, 5-HT1A; D044302:Receptor, Serotonin, 5-HT1B; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D013876:Thiophenes