Estrogen regulation of gene expression in the brain: A possible mechanism altering the response to psychostimulants in female rats

Acute behavioral responses to cocaine are more pronounced in female than in male rats. We have shown that 3 weeks of treatment with 17β-estradiol (E₂) implants significantly enhanced the hyperactivity induced by cocaine in ovariectomized (OVX) rats. The ligand-bound estrogen receptor (ER) functions as a transcription factor to regulate the expression of E-responsive genes. Thus, we hypothesized that estrogen (E) modulates the behavioral response to cocaine via regulation of expression of components of dopamine (DA) and serotonin (5-HT) systems in mesolimbic nuclei important in the response to cocaine as well as the hypothalamus, a brain area known to be E-responsive. Adult female Sprague-Dawley rats were OVX; half of them then received E₂ implant (OVX+E) (n=8/group, two groups). Twenty-seven days later, brain tissue was collected to study E₂ effects on mRNA expression for DA D₁-like (D₁) and D₂-like (D_2S, D_2L, D₃) receptors, DA transporter (DAT), 5-HT_1A, 5-HT_1B, 5-HT_2A, 5-HT_2C receptors, and 5-HT transporter (SERT) as well as ERα and ERβ in amygdala, hypothalamus, nucleus accumbens, midbrain, and ventral tegmental area (VTA). We found that E₂ implants in OVX rats increased mRNA levels for D₁ receptor in hypothalamus, D_2L receptor in midbrain, and D₃ receptor in VTA, and decreased D₃ receptor mRNA levels in midbrain relative to OVX controls. E₂ also increased 5-HT_2C receptor mRNA levels in midbrain and hypothalamus. In addition, E₂ decreased mRNA levels for ERα in amygdala and hypothalamus and ERβ in amygdala. The present study demonstrates that E can regulate mRNA expression for specific DA and 5-HT receptors in a region-specific manner and suggests that such modifications may contribute to the behavioral response to cocaine.