Increased depression-like behaviors with altered brain dopamine metabolisms in male mice housed in large cages are alleviated by bupropion.

Psycho-environmental stress-based animal models of anxiety and depression are useful for investigating pathological mechanisms and drug development. Although several rodent-based studies have reported the beneficial effects of environmental enrichment (EE) on brain plasticity and anxiety- and depression-like behaviors, other studies have reported inverse effects. Here, we found that housing male mice in EE involving large cages and other EE materials increased anxiety- and depression-like behaviors in open field and tail suspension tests (TST). We further confirmed that housing in large cages was sufficient to induce increased depression-like behaviors in the TST and reduce the saccharine preference percentage, a sign of anhedonia, in male mice. In these experiments, the number of animals per cage was equivalent to that in standard cage housing, suggesting that low density in large cages may be a determining factor for behavioral alteration. In mice housed in large cages, sex-specific dysregulation of brain monoamine systems was observed; dopamine turnover to homovanillic acid or norepinephrine in the prefrontal cortex was elevated in males, while serotonin turnover to 5-hydroxyindoleacetic acid in the amygdala was increased in females. Finally, we demonstrated that daily intraperitoneal injections of bupropion, a dopamine and norepinephrine reuptake inhibitor, counteracted large-cage housing-induced changes in depression- and anhedonia-like behaviors in male mice. Our results suggest that housing in large cages with a low density of mice is a novel paradigm to clarify the mechanisms of environmental stress-induced emotional dysregulation and to identify drugs or food factors to alleviate the dysregulation.