Hypothalamic neurotransmitter function in experimentally induced hyperprolactinemia

Abstract

It is known that animals or patients bearing a prolactin (PRL)-secreting tumor (PST) do not suppress PRL levels after administration of indirectly acting dopamine agonists, namely nomifensine (Nom), and are not responsive to the PRL releasing effect of antidopaminergic drugs and opioid peptides. Since the action of these drugs is mediated through the tuberoinfundibular dopaminergic (TIDA) system, these findings have been taken to indicate that animals and humans bearing prolactinomas have a defective TIDA function. Alternatively, PRL unresponsiveness to these drugs could be due to hyperfunction of TIDA system for the feedback action of high PRL levels. To clarify whether hypo- or hyperfunction of the TIDA system was responsible for such behaviour, we tested the effect of a synthetic opioid peptide (FK 33–824), a DA receptor antagonist, domperidone (Dom), and of Nom on PRL secretion in two experimental models of non-tumoral hyperprolactinemia, i.e. rats bearing ectopic pituitaries since 3 days (TP rats), or treated with ovine PRL (oPRL 250 μg, twice daily for 3 days), in which existence of an increased TIDA function has been demonstrated. FK 33–824 (0.5 mg/kg i.p.) increased significantly plasma PRL levels in control rats but failed to do so in TP rats and it elicited a significantly lower PRL response than in controls in rats treated with oPRL. In both experimental models, a PRL secretagogue, e.g. 5-hydroxytryptophan (50 mg/kg i.p.), elicited the same response as in controls, indicating that the pituitayr PRL pool was preserved. Kinetic characteristics of opioid binding sites in the hypothalamus of hyperprolactinemic rats did not differ from those of controls, and also hypothalamic Met-enkephalin concentrations were similar to those of controls. These findings would exclude a defect of endogenous opioid neurotransmission as responsible for the impaired PRL stimulation by the enkephalin analog. Supporting this were the findings that oPRL-treated rats exhibited a growth hormone response to FK 33–824 and a rise in plasma luteinizing hormone after naloxone (5 mg/kg s.c.) similar to those present in controls. These data indicate that the defective PRL responsiveness to opioids has to be attributed to the impairment of a neurotransmitter e.g. DA, functionally located at a site ‘downstream’ from opioid receptors. As already shown for oPRL-treated rats, TP rats exhibited a faster turnover rate of DA in the median eminence of the hypothalamus. In keeping with the idea that the hypothalamic dopaminergic system was involoved in the defective PRL responsiveness to opioids, Dom (50 μg/kg i.p.) induced aignificantly lower increase of PRL levels in TP and oPRL-injected rats than in controls. All these data demonstrate that opioid peptides and DA receptor antagonists are unable to discriminate the functional state of TIDA system. In fact, they fail to elicit a rise in plasma PRL in hyperprolactinemic states related to either TIDA hypo- (PST rats and humans) or hyperfunction (TP and oPRL-treated rats). In contrast to FK 33–824 and Dom, Nom (10 mg/kg i.p.), a drug which fails to lower PRL secretion in animals and patients with prolactinoma, did suppress plasma PRL levels of oPRL-treated rats as those of controls. The latter data indicate that indirectly acting DA agonists can discriminate the functional state of TIDA system; they fail to lower PRL secretion only when TIDA function is defective.