Sex differences in vulnerability to addiction.

This article reviews evidence for sex differences in vulnerability to addiction with an emphasis on the neural mechanisms underlying these differences. Sex differences in the way that the gonadal hormone, estradiol, interacts with the ascending telencephalic dopamine system results in sex differences in motivated behaviors, including drug-seeking. In rodents, repeated psychostimulant exposure enhances incentive sensitization to a greater extent in females than males. Estradiol increases females' motivation to attain psychostimulants and enhances the value of drug related cues, which ultimately increases their susceptibility towards spontaneous relapse. This, along with females' dampened ability to alter decisions regarding risky behaviors, enhances their vulnerability for escalation of drug use. In males, recent evidence suggests that estradiol may be protective against susceptibility towards drug-preference. Sex differences in the actions of estradiol are reviewed to provide a foundation for understanding how future research might enhance understanding of the mechanisms of sex differences in addiction-related behaviors, which are dependent on estradiol receptor (ER) subtype and the region of the brain they are acting in. A comprehensive review of the distribution of ERα, ERβ, and GPER1 throughout the rodent brain are provided along with a discussion of the possible ways in which these patterns differentially regulate drug-taking between the sexes. The article concludes with a brief discussion of the actions of gonadal hormones on the circuitry of the stress system, including the hypothalamic pituitary adrenal axis and regulation of corticotropin-releasing factor. Sex differences in the stress system can also contribute to females' enhanced vulnerability towards addiction.