Across all stages of drug use and abuse, women exhibit heightened responsiveness and hence greater vulnerability to the properties of addictive drugs. This is especially true regarding the increased susceptibility women exhibit towards drug relapse. In women, maximal vulnerability peaks during the follicular phase of the menstrual cycle when estrogen levels are at their highest. These findings have been recapitulated in female rodents, where estradiol heightens multiple measures of drug responsiveness and abuse. The mechanisms by which estradiol mediates enhanced vulnerability to drug relapse are completely unknown. The two PIs of this proposal have been independently studying the neurological underpinnings of relapse, and the mechanisms by which estrogens affect neuronal activity. Now working together, we have generated a unifying theory, whereby estradiol activation of estrogen receptor ? (ER?), localized to the surface membrane of medium spiny neurons of the nucleus accumbens shell (NAcSh), activates metabotropic glutamate receptor 1a (mGluR1a) signaling. Activation of ER?/mGluR1a signaling by estradiol is hypothesized to in turn promote mGluR5-induced relapse, a process mediated through the long-term depression of NAcSh afferents from the infralimbic cortex. To test this theory, the studies outlined in this proposal will utilize a recently developed mouse model of estradiol facilitation of drug relapse, taking advantage of electrophysiological, optogenetic and viral technologies. Collectively, these studies will provide a foundation to better understand and develop novel therapeutic approaches to treat drug relapse in women.