In the present study, we tested whether 17beta-estradiol (E2)-induced PRL sensitivity to somatostatin-14 (SRIF) involves selective up-regulation of discrete somatostatin receptor subtypes (ssts) in primary cultures of female rat pituitary cells. The efficacy of the endogenous peptide SRIF to inhibit GH and PRL secretion and cAMP accumulation was compared with those of octreotide (OCT), BIM-23052, BIM-23056, and BIM-23268, which have been reported to be relatively selective for rat sst2, sst3, and sst5. Experiments were performed in steroid-depleted media supplemented or not with 1 nM E2 for 96 h. SRIF, OCT, and BIM-23052 inhibited cAMP accumulation and GH release independently of E2. In contrast, all three agonists affected PRL release in E2-treated cultures only. Inhibition of cAMP accumulation by SRIF, OCT, and BIM-23052 was enhanced by exposure of cells to E2. The rank of potency of the agonists, OCT = SRIF > BIM-23052, was similar for GH and PRL inhibition. BIM-23268 was a weak agonist on GH, but not on PRL, secretion. BIM-23056 had no effect on the release of either hormone, but slightly inhibited cAMP formation in E2-treated cells. To verify whether SRIF receptor gene expression correlated with these observations, messenger RNA (mRNA) transcripts corresponding to the five ssts were measured by quantitative RT-PCR in the presence or absence of E2. Control cells expressed predominantly sst2 and sst3 transcripts; sst1 mRNA was present in moderate amounts, whereas sst4 and sst5 were only weakly expressed. E2 had a differential effect on distinct ssts; it increased mRNA concentrations corresponding to sst2 and sst3, and decreased that of sst1. These results indicate that sst2 and sst3 receptors are the major somatostatin receptors expressed in the female rat pituitary, and that both of them are positively regulated by estradiol. However, the capacity of lactotropes to respond to SRIF after exposure to E2 seems to depend more upon E2-induced up-regulation of the sst2 than of the sst3 receptor subtype.
Met-enkephalin and b-endorphin induced a partial reversion of the dopamine inhibition of prolactin release from pituitary cells of lactating rats in primary culture. This effect of opiate peptides was dose-dependent with an EC50 of 40f8 nM and 4 5 + 7 nM and maximal blockade of dopamine inhibition of 60% and 68% for Met-enkephalin and /]-endorphin, respectively. Naloxone antagonized the effect of Met-enkephalin with an EC50 of 22_$12 nM. Furthermore, this Met-enkephalin effect on dopamine inhibition of prolactin secretion appeared non-competitive since it reduced maximal inhibition without affecting the apparent affinity of dopamine. Finally, it should be noted that the two opiate peptides had no effect on spontaneous prolactin release.In electrophysiological experiments, local ejection of dopamine on tested cells induced an hyperpolarization concomitant with an increase of the membrane conductance. Ejection of Met-enkephalin or /&endorphin alone did not modify the electrical properties of the cells (resting potential, membrane conductance and excitability). In contrast, both peptides blocked in a reversible manner the dopamine-induced electrical responses. These effects were antagonized by naloxone. However, this interaction of opiate peptides with dopamine electrical response was not observed on all cells tested. We conclude that the blocking effect of opiates on dopamine-induced hyperpolarization may account, at least in part, for the ability of these peptides to interact with dopamine inhibition of prolactin release.Prolactin (PRL) release is under a tonic inhibitory control by dopamine (DA) (1). Opiates have been shown to interact with DA inhibition of PRL secretion both at the hypothalamic (2-4) and pituitary level (5 -8). I n the anterior pituitary, morphine and opiate peptides had no effect on the spontaneous PRL release (9, 10) but reversed inhibition of secretion induced by DA. Although this was not observed under all experimental conditions (1 l), this effect seems to involve a specific opiate receptor since it has been shown to be blocked by opiate antagonists ( 5 , 6, 8). In addition, spccific opiate binding sites have been described in anterior pituitary membranes (12, 13), although they could not be fully characterized because of the important contamination of endogenous B-endorphin-like peptides (14).Recently, it has been shown that DA induced a hyperpolarizing response due to a n increased potassium conductance on human (1 S), bovine (16) and rat lactotrophs ( I 7). During this response spontaneous calcium action potentials were suppressed (17). DA was also shown to affect calcium and potassium fluxes in those cells (18). These phenomena are likely to be implicated in the mechanism o f action of DA on PRL release since, in addition to cyclic AMP (CAMP) production (19-22) and modulation of phosphatidylinositol phosphate breakdown (23-26), regulation of PRL secretion is dependent on calcium entry into lactotrophs (27,28).An effect of morphinomimetic peptides on the DA hyperpolarization of ...
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