Long-Term Treatment with Estradiol Induces Reversible Alterations in Tuberoinfundibular Dopaminergic Neurons: a Decreased Responsiveness to Prolactin

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Abstract
Previous studies have demonstrated that short-term (3–5 days) treatment with estradiol increases the rate of turnover and synthesis of dopamine (DA) in terminals of tuberoinfundibular (TI) neurons in the median eminence by virtue of the ability of this hormone to increase circulating concentrations of prolactin. The present studies were undertaken to examine the long-term effects of estradiol on serum prolactin concentrations and TIDA neuronal activity (estimated by the rate of DOPA accumulation in the median eminence after the administration of a decarboxylase inhibitor). Female rats, ovariectomized for 2 weeks, were implanted subcutaneously with silastic capsules containing estradiol benzoate and sacrificed 6,12 and 18 days after capsule implantation. Serum prolactin concentrations were markedly increased at 6,12 and 18 days whereas the rate of DOPA accumulation was increased at 6 days but not at 12 days, and was decreased at 18 days. The concentration of DA in the median eminence was reduced at 6 days and further reduced at 12 and 18 days. The low rate of DOPA accumulation in the median eminence despite the high circulating concentrations of prolactin suggests that long-term estradiol treatment reduces the ability of TIDA neurons to respond to prolactin. This was confirmed by the finding that direct intracerebroventricular (icv) injections of prolactin increased the rate of DOPA accumulation in the median eminence of sham-implanted rats but not in 18 day estradiol-treated rats. To determine if the effects of estradiol were reversible, ovariectomized rats were implanted with estradiol-containing capsules for 18 days. The capsules were then removed and the animals sacrificed at various times up to 18 days later. The elevated serum concentrations of prolactin returned to control values within 18 days after removing the capsules, and the reduced DA concentrations in the median eminence increased but were still less than control after 18 days. On the other hand, the rate of DOPA accumulation in the median eminence increased progressively after removing the capsules reaching values greater than control by 18 days. These results suggest that there may be a rebound increase in the sensitivity of TIDA neurons to prolactin in rats that had the estradiol capsules removed. This was substantiated by the fact that icv prolactin caused a greater increase in the rate of DOPA accumulation in the postestradiol group of rats. These results suggest that long-term estradiol treatment reduces the activity of TI DA neurons, in part by attenuating their responsiveness to prolactin, and that termination of estradiol treatment results in a rebound increase in the sensitivity of TIDA neurons to prolactin. The decreased responsiveness of TIDA neurons induced by estradiol does not appear to be a consequence of elevated levels of circulating prolactin induced by this treatment, since chronic treatment with haloperidol for either 11 or 22 days induced similar elevations of circulating prolactin with an associated increase in the rate of DOPA accumulation in the median eminence. The results of these studies suggest that estradiol exerts a direct action on some component of the prolactin feedback mechanism so as to decrease the responsiveness of TIDA neurons to prolactin.