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Although the effects of chronic MPH exposure have been well\u2010documented in regard to reward\u2010related behaviors in adolescent and adult animals, there are few studies of the effects of MPH on depressive\u2010like behaviors and antidepressant responses, particularly in adult models. We examined the effects of chronic (14 days) high\u2010dose (20 mg\/kg i.p.) MPH exposure on locomotor activity and forced swim test behavior in C57Bl\/6J mice. We show that MPH treatment ameliorates the locomotor suppression seen in response to fluoxetine. In addition, chronic MPH treatment produces depressive\u2010like effects in the forced swim test, with decreased latency to first immobility and a trend toward increased immobility. These effects are reversed with acute fluoxetine administration, in contrast to saline\u2010treated animals, which show no response to fluoxetine. The induction of depressive\u2010like behaviors after chronic MPH treatment in adult mice is in agreement with previous studies in adolescent rats, and the marked alterations in fluoxetine responses implicate alterations in the serotonin system and possibly the dopamine system produced by MPH. 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