Neuroscience: Explaining sex-specific differences in cocaine reward

Cocaine reward is enhanced in female mice on heat (the estrus stage of the reproductive cycle), compared to females that are diestrus (in a stage of sexual inactivity) or males, reports a study published online in Nature Communications. The work identifies components of the brain reward circuit that seem to be involved in this response, which may help us to understand the neural basis of sex-specific differences in cocaine reward processing.

In humans, both males and females become addicted to drugs of abuse, including cocaine, but there is evidence that sex differences exist. For example, women may be more susceptible to craving and relapse, and there is evidence that in women, the physiological and subjective responses to cocaine fluctuate in different phases of the menstrual cycle. Studies in animal models have implicated ovarian hormone-dependent changes in drug reward; however, the underlying neural basis is unclear.

Ming-Hu Han, Eric Nestler and colleagues assessed cocaine preference in mice by training them to associate a particular environment with cocaine, and another with saline. When tested later in the absence of cocaine, mice preferred to spend more time in the cocaine-paired environment than the saline-paired environment, and the extent of place preference is an indirect measure of cocaine reward. They found that female mice that were trained during estrus cycles formed stronger preference for the cocaine-paired environment than that of males and females that were trained during diestrus. Looking into the brain, they found that the activity of VTA dopamine neurons - a key component of the brain reward circuit - was enhanced in females during estrus, and this drove molecular changes in the reward circuit that ultimately enabled stronger cocaine reward. These findings suggest that the activity and dynamics of the brain reward circuit underlies sex-specific cocaine reward processing.