Sexual Differentiation and Substance Use: A Mini-Review.

The organizational/activational hypothesis suggests that gonadal steroid hormones like testosterone (T) and estradiol (E2) are important at 2 different times during the lifespan when they perform 2 different functions. First steroids "organize" brain structures early in life and during puberty, and in adults these same hormones "activate" sexually dimorphic behaviors. This hypothesis has been tested and proven valid for a large number of behaviors (learning, memory, social, and sexual behaviors). Sex differences in drug addiction are well established both for humans and animal models. Previous research in this field has focused primarily on cocaine self-administration by rats. Traditionally, observed sex differences have been explained by the sex-specific concentrations of gonadal hormones present at the time of the drug-related behavior. Studies with gonadectomized rodents establishes an activational role for E2 that facilitates vulnerability in females, and when E2 is combined with progesterone, addiction is attenuated. Literature on organizational actions of steroids is sparse but predicts that T, after it is aromatized to E2, changes aspects of the neural reward system. Here we summarize these data and propose that sex chromosome complement also plays a role in determining sex-specific drug-taking behavior. Future research is needed to disentangle the effects of hormones and sex chromosome complement, and we propose the four core genotype mouse model as an effective tool for answering these questions.