Sub-chronic administration of rimonabant causes loss of antidepressive activity and decreases doublecortin immunoreactivity in the mouse hippocampus

Rimonabant is a cannabinoid receptor 1 antagonist, and is used to treat anorexia and obesity. However, it has been suggested that rimonabant may act as a depressant. In the present study, we investigated the depressive effects of rimonabant using behavioral and biochemical methods. A single treatment with rimonabant (10 mg/kg, p.o.) reduced immobility duration in the forced swimming test (FST) to a level similar to that observed for the tricyclic antidepressant, imipramine (15 mg/kg, i.p.). However, mice treated with rimonabant for 2 weeks did not show any significant reductions in immobility duration versus vehicle-treated controls. To investigate why the antidepressant effect of rimonabant disappeared after extended treatment, we carried out 5-bromo-2-deoxyuridine (BrdU) and doublecortin (DCX) immunohistochemistry assay. Numbers of BrdU-immunoreactive cells were not significantly changed after administering rimonabant (10 mg/kg, p.o.) for 2 weeks in the hippocampal dentate gyrus (DG), but interestingly, numbers of DCX-immunopositive cells in the DG were significantly reduced after 2 weeks of rimonabant treatment at doses of 1 or 10 mg/(kg day) compared with vehicle-treated controls (P < 0.05). These results suggest that sub-chronic treatments with rimonabant inhibit cell proliferation in DG, and that a lack of antidepressive activity may be related to a reduction in cell proliferation in this region.