Down-Regulation by 17<i>β</i>-Estradiol of D₂Dopamine Receptors in the MtTF₄Pituitary Tumor*

Abstract

We have recently reported that 17 beta-estradiol (E2) paradoxically inhibits the growth of the rat MtTF4 pituitary tumor which has been induced by estrogen administration. While looking for a molecular explanation for these divergent effects, we observed that E2 treatment resulted in a marked decrease of D2 dopamine receptors (RDA) in the tumor but not in normal pituitary glands. Herein, we characterize further the effect of E2 on RDA concentration in the tumor. Three weeks after a sc injection of a MtTF4 -cell suspension, adult male Fischer rats were treated, or not, either with E2 or with various other steroids. The number of dopamine-binding sites (Bmax) was determined on crude membranes by Scatchard analyses with the dopamine antagonist [3H]spiroperidol. Only one kind of binding site was observed, and the affinity constant for [3H]spiroperidol was not significantly modified by any of the various treatments used. The decrease of Bmax after 8 days of treatment was dose dependent and was maximal with 5-micrograms daily doses of E2. With 10 micrograms E, daily, Bmax decreased exponentially with the duration of the treatment; t 1/2 was approximately 5 days. Treatment for 8 days with progesterone (50 micrograms/day), dihydrotestosterone (50 micrograms/day) or 17 alpha-estradiol (10 micrograms/day), known to be inactive on tumor growth, did not alter Bmax, whereas diethylstilbestrol (10 micrograms/day) or dexamethasone (50 micrograms/day), which inhibit tumor growth, were as efficient as E2 in decreasing Bmax. In conclusion, the number of dopamine-binding sites in the membranes of MtTF4 tumor is decreased by E2 in a time- and dose-dependent fashion. Circumstantial evidence suggests that this decrease is due to a loss of RDA per cell rather than the loss of RDA-bearing cells. The relationship between the control of dopamine-binding sites and cell growth is not clear; however, this model may be useful for the elucidation of the mechanism by which E2 modulates cell membrane properties.