Cocaine withdrawal-induced anxiety in females: impact of circulating estrogen and potential use of delta-opioid receptor agonists for treatment.

Sex differences in cocaine addiction warrants further research focused on examining the growing population of female cocaine addicts. As demonstrated in both clinical and preclinical research, females are more susceptible to drug relapse with anxiety being a contributing factor. In support of this, a recent clinical study from our laboratory highlights the importance of menstrual cycle phase and anxiety at treatment admission for cocaine addiction on treatment retention. In support of these trends in the clinical population, the purpose of the present study was to design an animal model to directly test the role of circulating hormone levels during cocaine withdrawal. To directly measure the influence of estrogen on anxiety-like behavior during early stages of withdrawal, both ovariectomized and intact female rodent models were employed. The elevated-plus maze and elevated-zero maze were used to assess anxiety-like behavior. Recent evidence in male rodents highlights a potential role for the delta opioid-receptor (DOR) system in the modulation of cocaine withdrawal-induced anxiety. In addition to the evaluation of hormonal effects, a potential anxiolytic specific for DOR was tested for its efficacy in females withdrawn from cocaine. Our results support the use of DOR agonists as a potential anxiolytic in females and highlight the importance of estrogen and other circulating hormones during all phases of cocaine addiction.