Reduction in preference for saccharin by repeated unpredictable stress in mice and its prevention by imipramine

The present study set out to establish the chronic mild stress (CMS) animal model of depression in male CD-1 mice, a commonly used mouse strain. Mice were exposed to a series of mild stressors (e.g. soiled bedding, paired housing, cage tilt, white noise) presented in a continuous unpredictable fashion. Intermittently, CMS was discontinued and the mice were presented with both water and a palatable saccharin solution (0.1% w/v) in a two-bottle choice test overnight (15 h). Repeated exposure of these mice to the stressors led to a reduction in preference for the saccharin solution. This change in preference was attributed to an increase in the consumption of water rather than a decrease in the consumption of saccharin solution. Over time and with extensive testing, CMS no longer affected performance in the two-bottle saccharin preference test. Treatment with the tricyclic antidepressant imipramine (20 mg/kg i.p., once daily) had a varied effect on the CMS-induced change in preference for saccharin, dependent on the timing of initiation of imipramine treatment. In the first instance, following 5 weeks of CMS where a reduction in saccharin preference was established, treatment with imipramine for a further 5 weeks maintained the stress-induced deficit in saccharin preference. However, using a different approach, pre-treatment with imipramine once daily for 2 weeks, prior to onset of CMS, and co-treatment thereafter, attenuated CMS-induced changes in saccharin preference. Finally, when imipramine treatment was scheduled to begin with the CMS procedure, imipramine failed to prevent the CMS-induced reductions in saccharin preference. Changes in behaviour observed after exposure to CMS may be linked to a stress-induced deterioration of the sensitivity of the mice to a rewarding stimulus. Treatment with imipramine can reduce these behavioural changes but is only effective when given repeatedly prior to onset of CMS.