Objective To investigate the effect of chronic restraint stress on the comobidity behavior of anxiety and depression disorders in mice. Method C57BL/6J mice were randomly divided into 3 groups (n=10 per group): control (normal saline), chronic restraint stress (normal saline), and positive control (citalopram, 10 mg/kg). Citalopram and normal saline were administered by intraperitoneal injection. Chronic restraint stress and individual housing was applied to establish the stress model. The mice were individually housed and restrained for 4 h per day in a 50-mL polypropylene conical tube with ventilation holes. This daily restraint was repeated for 35 consecutive days. Sucrose preference test and forced swim test were applied to evaluate the depressive behavior of the mice. Open field test and elevated plus maze test were used to assess the anxiety effect of chronic restraint stress in the mice. Results The sucrose intake was significantly reduced in the chronic restraint stress models compared with the control mice (P<0.01). The immobility time was increased in the forced swim test (P<0.01). The cumulative duration and distance moved in the center were decreased in the open field test(P<0.01, P<0.05). Chronic treatment with citalopram reversed the above mentioned behavior change. The open arm entry and open arm time were decreased in the elevated plus maze test (P<0.05, P<0.05). Citalopram did not reverse this behavior change. Conclusions Mouse models created by chronic restraint and individual housing stress display both anxiety and depressive behavior making them a potent animal model in the treatment of comorbidity of anxiety and depression disorders.