Estrogen Receptor β in the Nucleus Accumbens Regulates the Rewarding Properties of Cocaine in Female Mice

Background:Females are more vulnerable to developing cocaine addiction compared with males, a phenomenon that may be regulated by the steroid hormone 17β-estradiol. 17β-Estradiol enhances cocaine reward as measured by the conditioned place preference test. It is currently not known which estrogen receptor is involved or the neuroanatomical locations in which estrogen receptors act to enhance cocaine responses. The purpose of this study was to determine if the estrogen receptors ERα and ERβ regulate cocaine conditioned place preference in mice and whether they act in the nucleus accumbens, a brain region critically involved in the development of cocaine abuse. Methods:Ovariectomized mice were treated with 17β-estradiol or agonists selective for ERα or ERβ and tested for cocaine conditioned place preference and for c-fos expression in the nucleus accumbens. Female mice with intact ovaries were also tested for cocaine conditioned place preference after RNA interference-mediated knockdown of ERα or ERβ in the nucleus accumbens. Results:We found that mice treated with 17β-estradiol or an ERβ agonist exhibited increased cocaine conditioned place preference, while knockdown of ERβ, but not ERα, in the nucleus accumbens of females with intact ovaries abrogated cocaine conditioned place preference. Acute treatment with 17β-estradiol or an ERβ agonist induced expression of the immediate-early gene c-fos in the nucleus accumbens, whereas the ERα agonist did not. Conclusions:These data indicate that ERβ in the nucleus accumbens regulates the development of cocaine conditioned place preference in female mice. 17β-Estradiol may activate neurons in the nucleus accumbens via ERβ. We speculate that this might increase the saliency of cocaine cues that predict drug reward.