Clinical and preclinical studies indicate gender differences in the prevalence of cocaine dependence, response to treatment and in relapse that are unrelated to differences in the pharmacokinetics of the drug. Our long term goal is to understand the neurobiological mechanisms that contribute to gender differences in drug addiction. Identifying the mechanisms that mediate differences in vulnerability to drugs of abuse may lead to effective therapeutic strategies for the treatment and prevention of addiction and relapse. Animal studies show sex differences in cocaine-induced behavioral sensitization, characterized by an increase in locomotor activity upon repeated cocaine exposure. Sensitization involves long-term adaptations in neural circuitry that mirror the increase in drug craving in addicts, promoting its use to study motivational components of addictive behavior. In females, estrogen potentiates behavioral sensitization by mechanisms still unclear. Data from recent neuroimaging studies implicate frontal cortical areas in drug craving. Moreover, we have shown that opioid modulation of cocaine-induced sensitization in females is different from that observed in males and varies with estrogen plasma levels. A decrease in mu opioid receptor density in the nucleus accumbens was also observed. It is hypothesized that estrogen facilitates cocaine sensitization by: (1) amplifying mu opioid signaling in the nucleus accumbens. (2) potentiating the metabolic response of frontal cortical neurons to cocaine. Changes in neural activity in cocaine-sensitized male and female rats as well as in ovariectomized rats with and without estrogen will be ascertained in the prefrontal cortex and anterior cingulate by functional magnetic resonance imaging (fMRI). Endogenous mu ligands and receptors in the nucleus accumbens will be studied by in situ hybridization, immunohistochemistry, autoradiography and mu-ligand induced 35S yGTP binding and by pharmacological manipulations and behavioral testing. The use of behavioral, pharmacological and neurochemical data together with fMRI will provide us with an integrated approach to examine the effects of cocaine, and its correlation with gonadal hormonal status, on neural substrates of the female. The proposed research is unique since/t is the first time that conscious awake animals will be used to identify sites in the brain that respond to repeated cocaine administration.