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Background The effects of stress, including neuroendocrine and behavioral sequelae aimed at maintaining homeostasis, are associated with increased alcohol consumption. Because both stress and drinking are multifactorial, the mechanisms underlying the relationship are difficult to elucidate. We therefore employed an animal model investigating the influence of blocked access to a running wheel on drinking in C57 BL/6J (B6) mice. Methods In the first experiment, naïve, adult male and female subjects were individually housed for 2 weeks with 24-hour access to a running wheel and 12% ethanol (EtOH) in a 2-bottle, free choice paradigm. After determining baseline consumption and preference, experimental subjects had the running wheel placed in a locked position for 6 hours, and the Et OH bottle was removed during the first half of this period. Two subsequent experiments, again in adult, naïve B6 mice, examined the influence of locked running wheels on self-administration of 20% Et OH in a limited access paradigm, and blood Et OH concentrations ( BECs) were determined on the final day of this protocol. Results In all 3 studies, using both between- and within-subject analyses, females showed transient yet reliable increases in alcohol drinking during blocked access to a rotating activity, while drinking in male mice was largely insensitive to this manipulation, although both sexes showed appreciable BECs (>130 mg/dl in females and 80 mg/dl in males) following a 2-hour EtOH access period. Conclusions These data add to a burgeoning literature suggesting that the factors contributing to excessive alcohol use differ between males and females and that females may be especially sensitive to the influence of wheel manipulation. Elucidating the sex-dependent mechanisms mediating differences in alcohol sensitivity and response is critical to understanding the causes of alcoholism and in developing effective treatments and interventions. [ABSTRACT FROM AUTHOR]