Olfaction and Depression: Does the Olfactory Bulbectomized Rat Reflect a Translational Model for Depression?

Abstract

The olfactory bulbectomized (OBX) rat is extensively used as an animal model to detect putative antidepressant drugs. The model has some unusual characteristics, as it detects antidepressant activity of drugs only after medium to long-term administration, thereby reflecting the human situation, as antidepressants do not work acutely but only after long-term administration. The slow onset of action of antidepressants is a major drawback of current antidepressants and the availability of an animal depression model that potentially reveals rapid onset of antidepressant activity might be a great asset. Although an animal model of depression ideally should reflect correlates of human depression, several ‘surrogate’ parameters, like ‘hyperactivity’, reflect astonishingly well the ‘antidepressant’ profile of antidepressants in human depression. Using a new environment (open field) and a home cage to measure activity, imipramine, a classic tricyclic antidepressant, reduced hyperactivity in OBX rats, both in home cage and open field. Telemetrically measured, OBX-induced hyperactivity was already found after a couple of days and indicated that the OBX model is able to detect early (days) effects of (classic) antidepressants. Although imipramine treatment for 3, 7 and 14 days reduced OBX-induced hyperactivity, daily treatment with imipramine for 14 days, but not for 3 or 7 days, reduced hyperactivity (both in home cage and open field) of OBX rats up to 6 weeks after cessation of treatment, indicating neuroplastic changes in the brain. The attractiveness of the OBX model for detection of antidepressants lies in the resemblance to the human situation (onset of action). Moreover, the model suggests that long-term antidepressant treatment (in rats at least 14 days) leads to long-term behavioral changes that far outlast the presence of the antidepressant in the body. Whether this aspect contributes to efficient antidepressant effects needs further investigation.