Estradiol-induced conditioned place preference may require actions at estrogen receptors in the nucleus accumbens

Intrinsic rewarding effects of estradiol (E(2)) may underlie some of the sex differences that emerge postpuberty for the prevalence of drug use and behavioral responses to drugs, but the effects and mechanisms of E(2) for reward have not been well characterized. Conditioned place preference (CPP), as measured by the time spent on the nonpreferred/drug-associated side of the chamber, was utilized as a functional assay to investigate the effects and mechanisms of E(2) in the nucleus accumbens for reward. To determine whether intracellular estrogen receptors (ERs) are important for E(2)-induced CPP, rats were administered E(2) (10 microg; subcutaneously (s.c.)), which produced CPP in each experiment, and/or ER blockers, such as tamoxifen (Experiment 1), ICI 182,780 (Experiment 2), or antisense oligonucleotides targeted to ERs (Experiment 3). Experiment 1: E(2) significantly increased the time spent on the originally nonpreferred side of the chamber. Coadministration of tamoxifen (10 mg/kg; s.c.) attenuated effects of E(2) to produce a CPP, but tamoxifen alone, increased time spent on the nonpreferred side. Experiment 2: coadministration of ICI 182,780 (10 microg/microl) to the nucleus accumbens attenuated effects of E(2) to enhance CPP and did not produce a CPP when administered alone. Experiment 3: coadministration of s.c. E(2) with ER antisense oligonucleotides to the nucleus accumbens significantly decreased time spent on the nonpreferred side and expression of ERs in the nucleus accumbens compared to scrambled antisense oligonucleotides or saline vehicle administration. Thus, E(2)'s rewarding effects may involve actions at ERs in the nucleus accumbens.