Dopaminergic Mechanisms Involved in Prolactin Release after Mifepristone and Naloxone Treatment during Late Pregnancy in the Rat

Soaje, Marta; Valdéz, Susana R.; Bregonzio, Claudia; Penissi, Alicia Beatriz; Deis, R. P.

doi:10.1159/000096825

Cited by 20 publications

(21 citation statements)

References 119 publications

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“…Moreover, it seems that naloxone treatment activates these neurons as well, suggesting an additional pathway by which endogenous opioids may regulate prolactin secretion. Although, at the end of pregnancy there is no evidence of the participation of this neuronal system to control prolactin secretion, the results above may support our recent study [12] which demonstrates that during late pregnancy, naloxone treatment has no direct effect on dopaminergic neurons, either in control oil-treated rats or in mifepristone-pretreated rats. Thus, endogenous opioids may inhibit prolactin secretion during late pregnancy through a nondopaminergic neuronal system without involvement of a direct effect on neuronal DA activity and probably with the participation of as yet undetermined prolactin-releasing factors unmasked by naloxone treatment.…”

Section: Introductionsupporting

confidence: 64%

“…In fact, we have recently demonstrated that mifepristone treatment to rats on day 19 of pregnancy induced a fall in the DOPAC/DA ratio in MBH, a diminution of the expression of TH measured in protein extracts of MBH as well as a decrease in the intensity of TH immunoreactivity in the arcuate nuclei, periventricular nuclei and the nerve terminals of the median eminence [12]. These results complement and confirm previous work showing that progesterone increases hypothalamic dopaminergic tone and TH expression [24, 25].…”

Section: Discussionmentioning

confidence: 99%

“…The effect of mifepristone was enhanced by the administration of the opioid antagonist naloxone, suggesting an inhibitory-neuromodulatory role of the opioid system at the end of pregnancy [8, 9]. Furthermore, we have recently showed that mifepristone is able to inhibit the hypothalamic dopaminergic neuronal system in terms of dopaminergic transmission and tyrosine hydroxylase(TH) expression [12], thus lowering the inhibitory dopaminergic tone upon prolactin secretion.…”

Section: Introductionmentioning

confidence: 99%

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Pituitary Changes Involved in Prolactin Secretion Induced by Mifepristone and Naloxone during Late Pregnancy

Gabutti

Ezquer²,

Deis³

et al. 2008

Neuroendocrinology

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Background/Aims: The antiprogesterone mifepristone facilitates prolactin release, an effect enhanced by administration of the opioid antagonist naloxone. The present study explores ultrastructural changes in lactotropes after mifepristone and naloxone administration, correlating them with the expression of pituitary prolactin. Methods/Results: Rats were sacrificed at 18:00 h on day 19 of pregnancy. Prolactin immunoelectron microscopy of lactotropes from control rats showed characteristics of quiescent cells with numerous small and spherical secretory granules. Naloxone administration did not modify lactotrope morphology or prolactin expression in terms of mRNA or protein abundances. Mifepristone treatment induced lactotrope activation with development of the rough endoplasmic reticulum and Golgi complex with prolactin immunoreactive small newly formed and large mature secretory granules. Mifepristone increased prolactin mRNA and protein expression. Naloxone administration to mifepristone-treated rats potentiated lactotrope activation compared with mifepristone alone showing exocytotic images of prolactin granules and some cells with evident signs of involution. Conclusions: (1) Blockade of progesterone action by mifepristone activated the lactotrope, increased significantly prolactin mRNA and protein expression and prepared the pituitary for naloxone action. (2) The high serum prolactin levels induced by mifepristone and naloxone may regulate negatively lactotrope activity as suggested by the presence of regressing cells neighboring the actively secreting cells.

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Section: Introductionsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pituitary Changes Involved in Prolactin Secretion Induced by Mifepristone and Naloxone during Late Pregnancy

Gabutti

Ezquer²,

Deis³

et al. 2008

Neuroendocrinology

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“…Indeed, oestradiol preferentially upregulates PR-B as compared to PR-A expression in the hypothalamus (54) and the increased PR-B to PR-A ratio may contribute to the progesterone stimulatory effect. Although sparsely explored, a stimulatory effect for progesterone during late pregnancy is suggested by the ability of RU486 treatment to decrease TH protein levels in the medial basal hypothalamus (55). In contrast to its stimulatory action, progesterone can also have an inhibitory effect on the tuberoinfundibular dopaminergic neurons with a decrease in TH activity, TH phosphorylation levels and TH mRNA levels in tuberoinfundibular dopamine neurons observed on the evening of prooestrus, but RU486 treatment on pro-oestrus had no effect on the progesterone induced suppression of TH mRNA levels (6,(8)(9)(10).…”

Section: Discussionmentioning

confidence: 99%

Differential and Interactive Effects of Ligand-Bound Progesterone Receptor A and B Isoforms on Tyrosine Hydroxylase Promoter Activity.

Jensik¹,

Arbogast²

2010

Posters I

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The classical progesterone receptors (PRs) are expressed in some hypothalamic dopaminergic and brainstem noradrenergic neurons. Progesterone influences prolactin and luteinising hormone release from the anterior pituitary gland, in part by regulating the activity of these catecholaminergic neurons. The aim of this study was to determine the effects of PRs on tyrosine hydroxylase (TH) promoter activity. When CAD, SK-N-SH and CV-1 cells were transfected with TH promoter constructs and PR-A or PR-B expression vectors, progesterone treatment caused three-to six-fold increases in TH-9.0kb promoter activity in PR-B expressing cells, but a modest increase or no change in PR-A expressing cells. Using CAD cells, deletional analysis mapped the site of PR action to the −1403 to −1304 bp region of the TH promoter. Mutational analysis of putative regulatory sequences in this region indicated multiple DNA elements are required for complete PR-B transactivation. Electrophoretic mobility shift assays were unable to demonstrate direct PR-B binding to TH promoter DNA sequences. However, chromatin immunoprecipitation (ChIP) analysis indicated PR-B was recruited to the TH promoter. Two different PR-B DNA binding domain mutants had opposite effects on PR-B mediated TH promoter activation. A GS to AA mutation located in the p-box of the first zinc finger of PR-B inhibited progesterone transactivation of the TH promoter, whereas a C to A mutation in the zinc finger increased transactivation. PR-A was able to inhibit PR-B transactivation in a dose-dependent manner, although the degree of PR-A inhibition was dependent on the TH promoter deletion construct. These data indicate that ligand-bound PR-B is recruited to DNA elements in the TH promoter and acts as a transcriptional activator of the TH gene and that changes in the ratio of PR-A to PR-B may affect the ability of progesterone to increase TH expression.

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“…The spontaneous fall in P 4 provoked by luteolysis at the end of pregnancy, or induced by ovariectomy, luteectomy or prostaglandin F2α (PGF2α)-induced luteolysis triggers a surge of PRL 12–24 h later that has been extensively studied in our laboratory [5,23,24,25,26,27], but little information is available on the changes in hypothalamic PRL regulatory mechanisms after the P 4 decline, in particular whether this decline produces changes in TH, ER, P 4 (PR), PRLR and some proteins involved in PRL signaling (STAT5 and SOCS family members) expression, all factors that may play a role in triggering PRL release. With the aim of investigating if the P 4 fall induces changes in hypothalamic dopaminergic activity and in the expression of receptors that regulate the dopaminergic neurons, we have determined the expression of TH, receptors for PRL (long form, PRLR long ), estrogen (ER) α and β, P 4 (PRA and B), STAT5a, STAT5b, SOCS1, SOCS3 and CIS, and DA and its metabolite DOPAC contents in the mediobasal hypothalamus (MBH) on day 20 of pregnancy, 24 h after PGF2α-induced luteolysis.…”

Section: Introductionmentioning

confidence: 99%

Effect of Progesterone Withdrawal on Hypothalamic Mechanisms Related to Prolactin Release in Late Pregnant Rats

et al. 2011

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Background/Aims: Progesterone (P₄) fall provoked by spontaneous or prostaglandin F2α (PGF2α)-induced luteolysis in late pregnant rats triggers a prolactin (PRL) surge 12–24 h later. Methods: To investigate the hypothalamic mechanism mediating this response, we determined expression of tyrosine hydroxylase (TH), PRL receptors (long form, PRLR_long), estrogen-α (ERα) and ERβ, P₄ (PR) A and B receptors, and STAT5a, STAT5b, suppressors of cytokine signaling 1 (SOCS1), SOCS3 and CIS at mRNA (by semiquantitative and real-time RT-PCR) and protein (by Western blot only for TH, ERα and PRs) levels, and dopamine and DOPAC (by high-performance liquid chromatography) contents in the mediobasal hypothalamus (MBH) 24 h after luteolysis induced by a PGF2α analogue (cloprostenol, 25 µg/rat s.c. at 8 and 12 h on day 19 of pregnancy). Results: PGF2α treatment decreased circulating P₄ and estradiol and increased PRL and the estradiol/P₄ ratio. MBH DOPAC and DOPAC/dopamine ratio fell, indicating decreased dopaminergic transmission. PRLR_long, PRB and ERα mRNA increased. ERα and PR proteins were not modified. However, TH protein and mRNA did not change. PRA, the small PR isoform, was much more abundant than PRB, the isoform considered to mediate P₄ genomic actions. STAT5a, SOCS1 and SOCS3 mRNA were also increased. Conclusion: The P₄ fall induced by PGF2α treatment induces PRL release through diminution in MBH dopaminergic transmission without change in TH expression. The increased PRLR along with elevated circulating PRL may be responsible for maintaining high TH expression through activation of short-loop feedback mechanisms, counteracting the effect of the fall in circulating P₄. In parallel, SOCS expression contributes to limit PRL signaling.

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Dopaminergic Mechanisms Involved in Prolactin Release after Mifepristone and Naloxone Treatment during Late Pregnancy in the Rat

Cited by 20 publications

References 119 publications

Pituitary Changes Involved in Prolactin Secretion Induced by Mifepristone and Naloxone during Late Pregnancy

Pituitary Changes Involved in Prolactin Secretion Induced by Mifepristone and Naloxone during Late Pregnancy

Differential and Interactive Effects of Ligand-Bound Progesterone Receptor A and B Isoforms on Tyrosine Hydroxylase Promoter Activity.

Effect of Progesterone Withdrawal on Hypothalamic Mechanisms Related to Prolactin Release in Late Pregnant Rats

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