Estrogen modulation of adrenoceptor responsiveness in the female rat pineal gland: differential expression of intracellular estrogen receptors.

The effect of different doses of 17beta-estradiol (E2) on the pineal response to beta-adrenoceptor stimulation in female rats was examined. Pinealocytes from 21-day-old ovariectomized rats were exposed to different estrogen doses and treated with beta-adrenergic agonists. Estrogen treatment produced a dose-dependent, biphasic response to beta-adrenoceptor-induced accumulation of cAMP. This effect was inhibitory at estrogen doses up to 0.1 nM and fitted to a negative exponential curve, while at doses from 0.1 to 100 nM the effect was stimulatory and fitted to a standard positive hyperbola. For in vivo studies, ovariectomized rats were treated with equivalent estrogen concentrations plus a single dose of progesterone (250 microg per rat), and their pineals exposed in vitro to beta-adrenergic agonists. Low doses of E2 (0.1-100 ng per rat) reduced both pineal cAMP accumulation and N-acetyltransferase activity after beta-adrenoceptor stimulation, while a high dose (10 microg per rat) induced the opposite response. Apparently, the final estrogen target was the pineal beta-adrenergic receptor, as a low dose of E2 (which had diminished cAMP accumulation after beta-adrenoceptor stimulation) also reduced its maximal binding capacity (Bmax) and its dissociation constant (Kd). We also found that the female rat pineal gland contains two different ER subtypes, alpha and beta, which respond to estrogen exposure with nucleocytoplasmic shuttling. These results indicate that, in the female rat, estrogen directly modulates pineal sensitivity to adrenergic stimulation in a complex, dose-dependent manner that may be related to differential expression and activity of two estrogen receptor subtypes within pineal cells.