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 17 beta-estradiol (E-2) 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 E-2 treatment followed by 2 d of vehicle treatment, or were injected with E-2 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 E-2 levels during conditioning did not affect subsequent CPP expression. During extinction, daily E-2 administration initially enhanced expression of the cocaine CPP, but resulted in significantly faster extinction compared to controls. Whereas E-2-treated rats were extinguished within 8 d, vehicle-treated rats maintained CPP expression for more than a month, indicative of perseveration. To determine whether E-2 could rescue extinction in these rats, half were given daily E-2 treatment and half were given vehicle. E-2-treated rats showed rapid extinction, whereas vehicle-treated rats continued to perseverate. These data demonstrate for the first time that E-2 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.