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 17beta-estradiol (E(2)) 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 E(2) implant (OVX+E) (n=8/group, two groups). Twenty-seven days later, brain tissue was collected to study E(2) effects on mRNA expression for DA D(1)-like (D(1)) and D(2)-like (D(2S), D(2L), D(3)) 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 ERalpha and ERbeta in amygdala, hypothalamus, nucleus accumbens, midbrain, and ventral tegmental area (VTA). We found that E(2) implants in OVX rats increased mRNA levels for D(1) receptor in hypothalamus, D(2L) receptor in midbrain, and D(3) receptor in VTA, and decreased D(3) receptor mRNA levels in midbrain relative to OVX controls. E(2) also increased 5-HT(2C) receptor mRNA levels in midbrain and hypothalamus. In addition, E(2) decreased mRNA levels for ERalpha in amygdala and hypothalamus and ERbeta 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.