Abstract: Interactions between ovarian hormones and cocaine may underlie gender and estrous cycle differences in cocaine-induced behavioral and neurochemical alterations. The aim of this study was to further understand how ovarian hormones modulate cocaine-induced behavioral alterations. Ovariectomized rats received acute or chronic saline or cocaine (15 mg/kg i.p.) administration and were further subdivided into one of four hormone-treatment conditions: cholesterol (vehicle-control), estrogen, progesterone, or estrogen+progesterone. Overall, acute and chronic cocaine administration increased all locomotor measurements (total locomotor, ambulatory, and rearing counts). Estrogen administration augmented cocaine-induced increases in ambulatory and rearing activity. After chronic cocaine administration, rats in the vehicle-control group developed behavioral tolerance (exhibited by a decrease in activity) in rearing and ambulatory activity. Estrogen replacement not only prevented the development of tolerance in ambulatory and rearing activities, but also enhanced total locomotor activity (sensitization) in response to chronic cocaine. Progesterone treatment did not alter the behavioral responses to acute or chronic cocaine administration. Estrogen+progesterone-treated animals had higher counts of locomotor activity in response to chronic cocaine than did vehicle-control or progesterone-treated rats. In stereotypic behaviors, the different hormonal treatments did not affect activity in cocaine- or saline-treated rats after acute or chronic drug administration. Plasma levels of cocaine did not change after different hormonal treatments. Interestingly, animals' coadministered chronic cocaine and estrogen had higher levels of corticosterone than did nonestrogen cocaine-treated rats. Thus, it is likely that alterations in HPA activation may underlie the observed behavioral differences. In summary, these data suggest that there are interactions between ovarian hormones and cocaine-induced behavioral alterations in female rats, and they extend previous results by showing that estrogen and progesterone affect the development of sensitization.