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Several findings on sex differences in cocaine response suggest a role for hormonal milieu in modulating the subjective effects of cocaine. Nitric oxide (NO) has been involved in the neurochemical, hormonal, and behavioral changes related to stress and anxiety. Within the brain, the anteroventral subdivision of the medial amygdala (MeAV) is an important area involved in processing emotional responses such as anxiety and a high density of NO-producing neurons is observed in this area.In this study, we hypothesize the possibility of sex/hormonal differences in response to cocaine and that these differences may reflect a change in the MeAV nitrergic system. We have examined cocaine's acute effects on nicotinamide adenine dinucleotide phosphate diaphorase (nadph-d) expression, as well as its effect on motor activity and anxiety in male and estrus and diestrus females.Our results show that acute cocaine administration produces an increase in both anxiety behaviors and nadph-d expression in the MeAV. Male and diestrus female mice were more susceptible to these effects of cocaine than estrus female mice in which no differences were detected. In addition, we examined individual differences in male and female mice responding to intravenous cocaine reinforcement in a self-administration paradigm. Female mice acquired cocaine self-administration at a faster rate than males and showed a higher motivation to self-administer cocaine under a progressive ratio schedule of reinforcement.Our data suggest a complex interaction between hormonal milieu and the behavioral and reinforcing effects of cocaine.