17β-estradiol is necessary for extinction of cocaine seeking in female rats.

Human and preclinical models of addiction demonstrate that gonadal hormones modulate acquisition of drug seeking. Little is known, however, about the effects of these hormones on extinction of drug-seeking behavior. Here, we investigated how 17β-estradiol (E₂) affects expression and extinction of cocaine seeking in female rats. Using a conditioned place preference (CPP) paradigm, ovariectomized rats were maintained throughout conditioning with 2 d of E₂ treatment followed by 2 d of vehicle treatment, or were injected with E₂ daily. Hormone injections were paired or explicitly unpaired with place conditioning sessions. Expression of a cocaine CPP was of equal magnitude regardless of conditioning protocol, suggesting that E₂ levels during conditioning did not affect subsequent CPP expression. During extinction, daily E₂ administration initially enhanced expression of the cocaine CPP, but resulted in significantly faster extinction compared to controls. Whereas E₂-treated rats were extinguished within 8 d, vehicle-treated rats maintained CPP expression for more than a month, indicative of perseveration. To determine whether E₂ could rescue extinction in these rats, half were given daily E₂ treatment and half were given vehicle. E₂-treated rats showed rapid extinction, whereas vehicle-treated rats continued to perseverate. These data demonstrate for the first time that E₂ is necessary for extinction of cocaine seeking in female rats, and that it promotes rapid extinction when administered daily. Clinically, these findings suggest that monitoring and maintaining optimal E₂ levels during exposure therapy would facilitate therapeutic interventions for female cocaine addicts.