The possible role of 2-hydroxyestradiol in the development of estrogen-induced striatal dopamine receptor hypersensitivity.

In the present study, we have confirmed the existence of a biphasic response in striatal dopamine receptor sensitivity following the administration of estradiol benzoate (EB). This biphasic response consists of a hyposensitive phase 24 h after the last injection of EB, followed by a hypersensitive phase 72 h after the last injection of EB. In contrast to this, the administration of 2-hydroxyestradiol (2-OHE2), a catechol metabolite of estrogen, resulted in a striatal dopamine receptor hypersensitivity at both 24 and 72 h after the last injection of 2-OHE2. Studies on the in vivo metabolism of [3H]estradiol to its [3H]catechol metabolites indicated that the administration of piperonyl butoxide (PBO; a microsomal enzyme inhibitor) significantly decreased the level of [3H]catechol metabolites of [3H]estradiol in the striatum and in the medial basal hypothalamus. In addition, PBO administration resulted in about a 7-fold decrease in the ability of estradiol to induce a striatal dopamine receptor hypersensitivity. These data indicate that the biphasic response in striatal dopamine receptor sensitivity following estrogen, may be mediated by separate molecular mechanisms. The association of the hypersensitive phase with pharmacological doses and/or treatment paradigms, the development of a similar hypersensitivity following the administration of the 2-OHE2 metabolite of estrogen and the attenuation of the estrogen-induced striatal dopamine receptor hypersensitivity in PBO pretreated animals all suggest that this striatal dopamine receptor hypersensitivity may be mediated, at least in part, by the catecholestrogens.