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Sexual dimorphism has been described in various aspects of physiological and pathophysiological processes involving dopaminergic signaling. This might account for the different disease characteristics in men and women in e.g. Parkinson’s disease or ADHD. A better understanding might contribute to the future individualization of therapy.We examined spontaneous wheel running activity of male and female mice, homo- and heterozygote for dopamine D3 receptor deficiency (D3R −/− and D3R +/−), and compared them to wild type controls. We found higher wheel running activity in female mice than in their male littermates. D3−/− mice, irrespective of sex, were also hyperactive compared to both D3+/− and wild type animals. Hyperactivity of D3−/− female mice was pronounced during the first days of wheel running but then decreased while their male counterparts continued to be hyperactive. Physical activity was menstrual cycle-dependent. Activity fluctuations were also seen in D3 receptor knockout mice and are therefore presumably independent of D3 receptor activation.Our data underscore the complex interaction of dopaminergic signaling and gonadal hormones that leads to specific running behavior. Furthermore, we detected sex- and D3 receptor status-specific reactions during novel exposure to the running wheel. These findings suggest the need for adapting dopaminergic therapies to individual factors such as sex or even menstrual cycle to optimize therapeutic success.