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Sex Differences in Behavioral Strategies are Accompanied by Differences in Accumbal Dopamine Release

While preclinical work has aimed to outline the neural mechanisms of drug addiction, it has overwhelmingly focused on male subjects. There has been a push in recent years to incorporate females into existing addiction models; however, males and females often have different behavioral strategies, making it important to not only include females, but to develop models that assess the factors that comprise female drug addiction. Although both males and females become addicted to cocaine, females transition to addiction faster, consume more cocaine, and have greater difficulty remaining abstinent. Clinical work shows that women also exhibit increased cue‐induced craving for cocaine, indicating that sex differences in cocaine addiction may not solely be due to reinforcing effects of cocaine and may include complicated interactions with drug‐associated stimuli. Here we define the circuit‐based mechanisms by which females exhibit enhanced vulnerability to cocaine addiction. By combining fast‐scan cyclic voltammetry, optogenetics, and drug self‐administration we link pathway‐specific dopamine signaling to the motivational state of females over the estrous cycle. We find that female mice are more motivated to take cocaine, and are more responsive to cocaine‐associated cues. Female mice also respond differently than males for optical stimulation of the ventral tegmental area to nucleus accumbens dopamine neurons. We link these changes to differences in dopamine release as well as the relationship between releasable pools and available calcium over the estrous cycle. These data suggest that several factors could be playing a role in sex differences in addiction and provide a mechanism by which the estrous cycle can modulate dopamine release which may produce long‐lasting effects on cues, cue learning, and drug‐taking behavior.