We previously demonstrated that repeated exposure of mice to different degrees of restraint stress could create stress-adaptive and -maladaptive models. Recently, the studies using these animal models suggested that maintenance of hippocampal myelination contributes to the development of stress adaptation. In the present study, we investigated whether cuprizone, a copper-chelating agent used to produce toxic demyelination, affects the development of stress adaptation. A single exposure to restraint stress for 1 h induced a significant decrease in the number and duration of head-dipping behaviors in the hole-board test. This stress response was not seen in mice that had been exposed to restraint stress for 1 h/day for 2 weeks, which is referred to as stress adaptation. In contrast, mice fed a diet containing 0.2 % cuprizone for 3 weeks from 1 week before stress exposure did not adapt to stress, and continued to show a decrease in head-dipping behaviors. Under this condition, the expression levels of myelin protein, MBP and CNPase, in the hippocampus of mice were significantly decreased. The present findings indicate that chemical damage to hippocampal myelin impairs the ability of mice to adapt to stress, supporting our hypothesis that the maintenance of myelination is important for the development of stress adaptation.