Effect of hypophysectomy and subsequent prolactin administration on hypothalamic 5-hydroxytryptamine synthesis in ovariectomized rats

Increased levels of PRL whether of natural or experimentally induced cause result in an increased turnover of the putative PRL-inhibiting factor dopamine (DA) within tuberoinfundibular neurons, suggesting that PRL can regulate its own release via a short loop feedback mechanism. Although it is known that activation of the hypothalamic 5-hydroxytryptamine (5HT) system stimulates PRL release, the possibility that PRL could alter metabolism or release of this amine within the hypothalamus has not been examined. In the first experiment, bilaterally ovariectomized adult Sprague-Dawley rats were divided into three groups: hypophysectomized rats (HYPOX), HYPOX rats injected sc with 0.5 mg kg^-1 ovine PRL (oPRL) at 1000 h and 1800 h on the day before killing the rats (HYPOX + PRL), and rats without further surgical manipulation (controls: NON-HYPOX). Three weeks after surgical manipulation, the rats were injected iv with 100 mg kg^-1 NSD-1015 and killed 15 or 30 min later. 5-Hydroxytryptophan accumulation was measured by HPLC with electrochemical detection as an index for the rate of 5HT synthesis. The rate of 5HT synthesis was increased in the median eminence (ME) and mediobasal hypothalamus (MBH) but not anterior hypothalamus of HYPOX rats in comparison to the rate of synthesis of this amine in these areas of control rats. This effect was reversed in the ME and MBH of HYPOX + PRL rats. If 5HT stimulation of PRL release were achieved by 5HT inhibition of the tuberoinfundibular DA system as has been proposed previously, then it is also conceivable that the PRL short loop feedback on hypothalamic 5HT synthesis as suggested by the results of the first experiment is mediated via this DA system. To test this hypothesis in the second experiment, adult Sprague-Dawley rats were injected at 1000 h and 1800 h on the day before their killing with 0.5 mg kg^-1 oPRL; 0.5 mg kg^-1 oPRL, and 10 mg kg^-1 pimozide (PIM) a DA receptor antagonist; 10 mg kg^-1 PIM; or, on the day of their killing, with 1 mg kg^-1 apomorphine (APO), a DA receptor agonist. An additional group of ovariectomized-HYPOX as well as a group of ovariectomized-NON-HYPOX rats were also included in this experiment. On the day of the experiment the rats were injected iv with 100 mg kg^-1 NSD-1015 and killed 30 min later. 5-Hydroxytryptophan accumulation was measured by HPLC with electrochemical detection as an index of the rate of 5HT synthesis. PIM inhibition of DA receptors in HYPOX + PRL rats negated the effect of PRL to inhibit the increased rate of 5HT synthesis in the ME and MBH of HYPOX rats. Similar results were observed in HYPOX rats treated with PIM but not PRL. APO administration led to a decrease in the rate in 5HT synthesis of HYPOX rats similar to that observed in HYPOX + PRL rats. In the third experiment, the minimal effective dose for the inhibitory effect of APO on 5HT synthesis in the ME and MBH was characterized. These observations depict an inverse relationship between the level of circulating PRL and 5HT synthesis in the ME and MBH of ovariectomized rats, suggesting that hypothalamic 5HT stimulation of PRL release involves a reciprocal, short loop feedback mechanism. This feedback mechanism apparently involves an intermediary DA component.