Compared with men, women show enhanced responses to drugs of abuse, and consequently are thought to be more vulnerable to addiction. The ovarian hormone estradiol has emerged as a key facilitator in the heightened development of addiction in females. These actions of estradiol appear mediated by estrogen receptor (ER) activation of metabotropic glutamate receptor type 5 (mGluR5). However, the downstream effectors of this ER/mGluR5 signaling pathway are unknown. Here we investigate whether cannabinoid 1 receptor (CB1R) activation is a part of the mechanism whereby estradiol influences behavioral and synaptic correlates of addiction. Following repeated cocaine administration, estradiol-treated ovariectomized rats exhibited both sensitized locomotor responses and decreases in the dendritic spine density of nucleus accumbens core medium-spiny neurons in comparison to oil-treated controls. Both effects of estradiol were blocked by AM251, a CB1R inverse agonist. These results indicate that part of the signaling mechanism through which estradiol impacts behavioral and synaptic correlates of addiction in female rats requires activation of CB1Rs.