Modulation Of Prolactin Secretion Research Articles

133 Anatomical evidence for kisspeptin and dopaminergic neuron interaction in the diestrous mare

Dopamine (DA), via dopaminergic neurons, modulates prolactin secretion from the pituitary by tonic inhibition of lactotropes. Previously, kisspeptin (Kp) attenuated the prolactin response to the DA antagonist, sulpiride, in diestrous mares and enhanced the prolactin response to sulpiride in estradiol-primed mares. Whether or not Kp can modulate prolactin by acting on DA neurons has yet to be described in horses; therefore, the objective of this study was to determine if Kp and kisspeptin receptor (Kiss1r) co-localize with DA neurons, thus providing evidence for a direct action of Kp on DA neurons. Hypothalami from 4 light-horse diestrous mares, aged 6 to 21, were obtained following euthanasia. Mares were determined to be diestrous based on presence of corpora lutea and progesterone concentrations. Immediately following euthanasia, the carotid artery was perfused with sodium nitrite and 4% paraformaldehyde before decapitation and dissection of hypothalami. Immunofluorescent double labeling of tyrosine hydroxylase (TH) and Kp, as well as TH and Kiss1r, was carried out on paraffin-embedded hypothalamic sections using validated antibodies. Whole slide scans were analyzed for double-labeled cells; percentage of DA neurons colocalized with Kp-ir cell bodies and fibers, as well as percentage of DA neurons colocalized with Kiss1r-ir cells, were calculated and averaged for multiple sectionsper horse from rostral to caudal throughout the hypothalamus. Similarly, percentage and number of Kp or Kiss1r-ir cell bodies co-colocalized with TH-ir cells were calculated for different hypothalamic regions: the arcuate nucleus (Arc), ventromedial nucleus (VMH), and dorsomedial nucleus (DMH), and compared using Kruskall Wallis with Dunn's multiple comparison test. DA neurons were observed lining the third ventricle and spread from the Arc to the DMH, with little to none present in the posterior nucleus. TH and Kp expressing cell bodies co-localized between 8 and 30%, with less in the caudal DMH (P ≤ 0.05) compared with the Arc. Kp fibers synapsed with TH-expressing cell bodies at a low percentage, between 0 and 16%, with less connections in the DMH (P ≤ 0.05) than in the ARC. TH and Kiss1r co-localized between 20 and 65%, with similar distribution throughout the Arc, VMH, and DMH in rostral sections. In caudal hypothalamic sections, co-localization was greater (P ≤ 0.05) in the Arc compared with other areas that express lower or no DA neurons. Co-localization of TH and Kiss1r as well as co-localization and synaptic attachment of Kp on TH positive cells suggests a direct effect of kisspeptin on DA neurons to modulate prolactin release.

The potential implication of neurokinin B in the modulation of prolactin secretion at the pituitary level in cyclic gilts.

Based on the previous studies, neurokinin B (NKB) participation in the modulation of prolactin secretion at the pituitary level can be assumed, but information concerning this topic is largely insufficient. Therefore, in the present study, we aimed: 1) to evaluate changes in the expression of NKB precursor (Tac3) and its receptor (Tacr3) genes as well as the content of NKB and TACR3 proteins in the porcine anterior pituitary throughout the estrous cycle (days 2 - 3, 9 - 10, 12 - 13, 15 - 16, 19 - 20); 2) to determine in vitro the influence of NKB on the expression of Prl, D2r and Trhr genes in the anterior pituitary cells (incubated for 4 h) as well as on prolactin secretion by these cells (incubated for 4 and 24 h) during chosen days of the estrous cycle (9 - 10, 15 - 16, 19 - 20). The experiments have shown alterations in the expression of Tacr3 mRNA and TACR3 protein content, but not in Tac3 mRNA and NKB protein. The treatment with NKB stimulated the expression of Prl (days 15 - 16), D2r (days 9 - 10) and Trhr (days 19 - 20) genes, but its potential to modulate prolactin secretion was observed only following 24-h incubation, specifically inhibition by NKB alone and stimulation by NKB with dopamine on days 19 - 10 of the cycle. These results indicate some implications of NKB in the modulation of prolactin secretion at the pituitary level in cyclic pigs, however further experiments are required to better clarify its role in this process.

The role of neurokinin A and its receptor in the regulation of prolactin secretion by the anterior pituitary of cyclic pigs.

In pigs, plasma prolactin concentration markedly changes during the oestrous cycle and the regulation of its secretion is very complex. The contribution of neurokinins in this process has not been sufficiently delineated. The aim of the study was to examine the effects of neurokinin A (NKA) on prolactin synthesis and secretion in cyclic gilts. The expression of NKA precursor (Ppta) and receptor (Tacr2) genes as well as NKA and TACR proteins content in the porcine pituitaries (days 2-3, 9-10, 12-13, 15-16 and 19-20 of the cycle) was determined. Furthermore, the in vitro influence of NKA on the expression of prolactin (Prl), dopamine receptor (D2r), TRH receptor (Trhr) genes and prolactin secretion by the porcine pituitary cells (days 9-10, 15-16 and 19-20 of the cycle) was assessed. The expression of Ppta and Tacr2 as well as NKA and TACR proteins in the pituitary tissue has been changing throughout the oestrous cycle. NKA affected in vitro the expression of studied genes and prolactin secretion depending on the stage of the cycle, dose of NKA and/or duration of the cell incubation. Altogether, the study indicates that NKA is engaged in the modulation of prolactin secretion in the pig during the oestrous cycle.

GH3 and RC-4BC cell lines are not suitable as in vitro models to study prolactin modulation and AHR responsiveness in rat pituitary

Some environmental contaminants and pharmaceuticals increase the incidence of uterine tumors in toxicological studies with rats. These tumors can result from a hormonal imbalance due to rat-specific disrupted pituitary prolactin regulation, and are therefore of questionable relevance for humans. In this study we compared in vitro prolactin regulation in rat primary pituitary cells to that in pituitary cell lines, GH3 and RC-4BC. Moreover, we assessed the potential effects of aryl hydrocarbon receptor (AHR) activation on prolactin regulation by using two different AHR agonists, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and DELAQ, the N-deethylated minor metabolite of the pharmaceutical laquinimod.In rat primary pituitary cells, known prolactin stimulant thyrotropin-releasing hormone (TRH) marginally increased prolactin secretion (1.2-fold) and gene expression (1.3-fold). In contrast, synthetic dopamine receptor agonist quinpirole, a known inhibitor of prolactin release, significantly inhibited prolactin secretion (2.6-fold) and gene expression (3.6-fold). In GH3 cells, TRH strongly increased prolactin secretion (6.8-fold) and gene expression (30.8-fold), whereas quinpirole did not affect prolactin secretion nor gene expression. In RC-4BC cells, both TRH and quinpirole did not modulate prolactin secretion nor gene expression. Prolactin secretion and gene expression did not significantly change upon exposure to TCDD or DELAQ. However, DELAQ, but not TCDD, attenuated quinpirole-inhibited prolactin gene expression by 51% in primary pituitary cells.This study shows that pituitary prolactin regulation in rat primary pituitary cells in vitro is distinctly different from rat pituitary cell lines GH3 and RC-4BC. Therefore, effects on pituitary prolactin regulation in vitro should best be performed using rat primary pituitary cells. Additionally, AHR ligands may interact with rat pituitary prolactin regulation, but this appears to depend on the ligand and constitutive prolactin secretion. However, interpretation of the in vitro results with respect to occurrence of uterine tumors in rats should take the complex regulation of prolactin release in the pituitary into account as well as the in vivo hypothalamus-pituitary-gonadal (HPG) axis and its feedback loops.

A pharmacogenetic study of patients with schizophrenia from West Siberia gets insight into dopaminergic mechanisms of antipsychotic-induced hyperprolactinemia

BackgroundHyperprolactinemia (HPRL) is a classical side effect of antipsychotic drugs primarily attributed to blockade of dopamine D2 receptors (DRD2s) on the membranes of lactotroph cells within the pituitary gland. Certain antipsychotic drugs, e.g. risperidone, are more likely to induce HPRL because of relative accumulation within the adenohypophysis. Nevertheless, due to competition for pituitary DRD2s by high dopamine levels may limit antipsychotic-induced HPRL. Moreover, the activity of prolactin-producing lactotrophs also depends on other hormones which are regulated by the extra-pituitary activity of dopamine receptors, dopamine transporters, enzymes of neurotransmitter metabolism and other factors. Polymorphic variants in the genes coding for these receptors and proteins can have functional significance and influence on the development of hyperprolactinemia.MethodsA set of 41 SNPs of genes for dopamine receptors DRD1, DRD2, DRD3, DRD4, the dopamine transporter SLC6A3 and dopamine catabolizing enzymes MAOA and MAOB was investigated in a population of 446 Caucasians (221 males/225 females) with a clinical diagnosis of schizophrenia (according to ICD-10: F20) with and without HPRL who were treated with classical and/or atypical antipsychotic drugs. Additive genetic model was tested and the analysis was carried out in the total group and in subgroup stratified by the use of risperidone/paliperidone.ResultsOne statistically significant association between polymorphic variant rs1799836 of MAOB gene and HPRL in men was found in the total group. Furthermore, the rs40184 and rs3863145 variants in SLC6A3 gene appeared to be associated with HPRL in the subgroup of patients using the risperidone/paliperidone, but not with HPRL induced by other antipsychotic drugs.ConclusionsOur results indicate that genetic variants of MAOB and SLC6A3 may have consequences on the modulation of prolactin secretion. A further search for genetic markers associated with the development of antipsychotic-related hyperprolactinemia in schizophrenic patients is needed.

Effect of adrenalectomy on prolactin secretion in primiparous and multiparous lactating rats

The adenohypophysis produces among other hormones prolactin, which plays an important role in reproduction, especially on the mammary glands and lactation of mammals. Prolactin is tonically controlled by tufo-infundibular dopamine, but several studies indicate that prolactin secretion is altered by the action of glucocorticoids and, therefore, is related to stress. However, the exact contribution of corticosteroids in the control of prolactin secretion is poorly understood. On the other hand, it is also known that reproductive experience can modify prolactin secretion by adenohypophysis. Thus, the present study aims to study the hormonal relationships of the hypothalamic-pituitary-adrenal axis, in particular, the glucocorticoid relationship on prolactin secretion as a function of the reproductive experience in females during lactation. The results show that reproductive experience may be a factor modifying the sensitivity of the neuroendocrine response of prolactin secretion to glucocorticoids. However, more studies are needed to understand the possible mechanisms involved, as well as possible modifications in this response as a function of the reproductive status of the females.

P.3.c.006 - Association of polymorphism in the dopamine receptors and transporter genes with hyperprolactinemia in patients with schizophrenia

Association of polymorphism in the dopamine receptors and transporter genes with hyperprolactinemia in patients with schizophrenia D. Osmanova(1), A.S. Boiko(1), O.Y. Fedorenko(1), I.V. Pozhidaev(1), M.B. Freidin(2), E.G. Kornetova(3), S.A. Ivanova(1), B. Wilffert(4), A.J.M. Loonen(5) (1)Mental Health Research Institute- Tomsk NRMC, Laboratory of Molecular Genetics and Biochemistry, Tomsk, Russia (2)Research Institute of Medical Genetics, Tomsk NRMC, Laboratory of Population Genetics, Tomsk, Russia (3)Mental Health Research Institute- Tomsk NRMC, Department of Clinical and Social Psychiatry and Addiction, Tomsk, Russia (4)Groningen Research Institute of Pharmacy, Pharmacotherapy and Clinical Pharmacology, Groningen, The Netherlands (5)Groningen Research Institute of Pharmacy, Pharmacotherapy in Psychiatric Patients, Groningen, The Netherlands Background: Long-term antipsychotic drug use remains the mainstay of treatment for patients with schizophrenia. However, pharmacotherapy with these drugs is complicated by several troublesome side effects, including hyperprolactinemia (HP). Prolactin secretion is persistently inhibited by dopamine, and antipsychotic drugs are believed to increase prolactin release by blocking dopamine receptors in the pituitary gland. Genetic factors play an important role in the development of antipsychotic induced HP [1,2]. Genes coding for dopamine receptors and transporters are considered to be responsible for HP in schizophrenia [3]. The present study aimed to investigate the role of polymorphisms of the dopamine receptors and transporters genes (DRD1, DRD2, SLC6A3) in the pathogenesis of antipsychotic-related HP in patients with schizophrenia. Methods: 431 Russian patients with schizophrenia were examined. The average age of patients was 42.1 ± 1.4 years. Evaluation of serum prolactin level was performed by ELISA using reagents set PRL Test System (USA). Genotyping was carried out on 17 polymorphic variants of the dopamine receptors and transporters genes DRD1 (rs4532, rs936461), DRD2 (rs4245147, rs6279, rs2734842) and SLC6A3 (rs3756450, rs2550956, rs6347, rs2617605, rs3863145, rs250686, rs464049, rs4975646, rs1048953, rs11133767, rs27048, rs40184). The SPSS software was used for statistical analysis. The Hardy-Weinberg equilibrium (HWE) of genotypic frequencies was tested by the chi-square test. Results: We studied the association between HP and a set of SNPs from DRD1, DRD2 receptor genes and neurotransmitter transporter SLC6A3 in patients from Siberia with a clinical diagnosis of schizophrenia who were treated with classical and/or atypical antipsychotic drugs. All patients with schizophrenia were divided into two groups: those with and without HP. Physiological normal results for the serum prolactin levels are less than 20 ng/ml in men, and less than 25 ng/ml in women. Statistically significant result was obtained for polymorphic variant rs2550956 of the gene SLC6A3 (χ2 = 9.992; p = 0.007), which suggests its involvement in the development of HP. The heterozygous genotype TC of rs2550956 was significantly less common in patients with elevated levels of prolactin and it presumably has protective properties (OR 0.54; 95% CI: 0.36–0.81). We did not find any statistically significant associations for other polymorphisms DRD1 (rs4532, rs936461), DRD2 (rs4245147, rs6279, rs2734842) and SLC6A3 (rs3756450, rs6347, rs2617605, rs3863145, rs250686, rs464049, rs4975646, rs1048953, rs11133767, rs27048, rs40184). The group of dopamine receptors is heterogeneous and only some of them participate in the formation of psychotic symptoms and, accordingly, in the antipsychotic action of neuroleptics. The effect of neuroleptics on other groups of dopamine receptors leads to the development of different side effects including extrapyramidal disorders [4], and their role is extremely low in the formation of the actual therapeutic response. Conclusion: Our results indicate that genetic variants of SLC6A3 may have functional consequences on the modulation of prolactin secretion. Neurotransmitter systems are involved in the mechanisms of action of antipsychotic drugs; therefore, a further search for genetic markers associated with the development of antipsychotic-related hyperprolactinemia in schizophrenic patients is needed.

P.3.b.037 - Gene polymorphism of serotonin receptors and drug-induced hyperprolactinemia in schizophrenic patients

Background: Antipsychotics have been used for more than 50 years in the treatment of schizophrenia and many other psychiatric disorders. Schizophrenic patients have to take antipsychotic medication for a long time, often throughout the life [1]. Hyper prolactinemia in these patients is a common and serious side effect of therapy with atypical antipsychotics. Genes coding for serotonin receptors are considered as candidate genes responsible for the particular antipsychotic effects of neuroleptics [2]. The present study aimed to investigate the role of polymorphisms of the serotonin receptors genes (HTR1A, HTR1B, HTR2A, HTR2C, HTR3A, HTR3B, HTR6) in the pathogenesis of antipsychotic-induced hyperprolactinemia in patients with schizophrenia. Methods: 446 Russian patients with schizophrenia were examined, including 225 women and 221 men. The average age of patients was 42.1±1.4 years. Evaluation of serum prolactin performed by ELISA using reagents set PRL Test System (USA). Genotyping was carried out on 29 polymorphic variants of the serotonin receptor genes HTR1A (rs6295, rs1364043, rs10042486, rs1800042, rs749099), HTR1B (rs6298, rs6296, rs130058), HTR2A (rs6311, rs6313, rs6314, rs7997012, rs1928040, rs9316233, rs2224721, rs6312), HTR2C (rs6318, rs5946189, rs569959, rs17326429, rs4911871, rs3813929, rs1801412, rs12858300), HTR3A (rs1062613, rs33940208, rs1176713), HTR3B (rs1176744) and HTR6 (rs1805054). The SPSS software was used for statistical analysis. The Hardy-Weinberg equilibrium (HWE) of genotypic frequencies was tested by the chi-square test. Results: We studied the association between polymorphisms of relevant 5-HT receptor genes and antipsychotic drug-induced hyperprolactinemia in patients with schizophrenia from Siberia. All patients with schizophrenia were divided into two groups: those with and without hyperprolactinemia. Statistically significant results were obtained for polymorphic variants of the genes rs6312 HTR2A (χ2 = 4.685; p = 0.030), rs12858300 HTR2C, rs569959 HTR2C, which suggests the participation of these polymorphic variants in the development of hyperprolactinemia. When men and women were studied separately, only rs569959 HTR2C (χ2 = 6.284; p = 0.043) in men reached the nominal significance threshold. This finding is probably related to the X-bound character of HTR2C (i.e., men are hemizygotes). Also, we found a statistically significant association rs12858300 HTR2C (χ2 = 9.429; p = 0.002) in the female group. We did not find statistically significant association for other polymorphisms HTR1A (rs6295, rs1364043, rs10042486, rs1800042, rs749099), HTR1B (rs6298, rs6296, rs130058), HTR2A (rs6311, rs6313, rs6314, rs7997012, rs1928040, rs9316233, rs2224721), HTR2C (rs6318, rs5946189, rs17326429, rs4911871, rs3813929, rs1801412), HTR3A (rs1062613, rs33940208, rs1176713), HTR3B (rs1176744) and HTR6 (rs1805054). Though hyperprolactinemia is primarily attributed to blockade of DRD2 in the pituitary gland, the secretion of prolactin is also modulated by 5-HT. The involvement of the HTR1A, HTR2A, HTR2C, and HTR3 in the serotonergic-induced prolactin response is well documented. Conclusion: Our results indicate that genetic variants of HTR2C may have functional consequences on the modulation of prolactin secretion. Further search for genetic markers associated with the development of side effects of neuroleptic therapy, will contribute to the development of effective methods of diagnosis, correction and treatment of disease, as well as of adherence of patients with mental disorders to psychotropic therapy.

PROLACTIN АND SEROTONIN

An overview of the results of studies on prolactin (PRL) is given. The molecular and genetic characteristics of PRL and its receptor (PRLR) are presented. The PRLR polymorphism in patients with tumors of the breast is described. Synthesized analogues of human PRL inhibited its peripheral effects. The vegetative nervous system modulate PRL secretion. PRL is a risk factor for breast and prostate cancer. The signaling mechanisms of PRL and its possible clinical use in therapy of breast cancer are characterized.

Excitation of tuberoinfundibular dopamine neurons by oxytocin: crosstalk in the control of lactation.

Milk production in the nursing mother is induced by the hormone prolactin. Its release from the anterior pituitary is generally under tonic inhibition by neuroendocrine tuberoinfundibular dopamine (TIDA) neurons of the arcuate nucleus. Successful nursing, however, requires not only production but also ejection of breast milk. This function is supported by the hormone oxytocin. Here we explored the possibility that interaction between these functionally complementary hormones is mediated by TIDA neurons. First, whole-cell patch-clamp recordings were performed on prepubertal male rat hypothalamic slices, where TIDA neurons can be identified by a robust and rhythmic membrane potential oscillation. Oxytocin induced a switch of this rhythmic activity to tonic discharge through a depolarization involving direct actions on TIDA neurons. The depolarization is sensitive to blockade of the oxytocin receptor and is mediated by a voltage-dependent inward current. This inward current has two components: a canonical transient receptor potential-like conductance in the low-voltage range, and in the high-voltage range, a Ca(2+)-dependent component. Finally, whole-cell and loose-patch recordings were also performed on slices from virgin and lactating female rats to evaluate the relevance of these findings for nursing. In these preparations, oxytocin was found to excite TIDA neurons, identified by their expression of tyrosine hydroxylase. These findings suggest that oxytocin can modulate prolactin secretion by exciting TIDA neurons, and that this may serve as a feedforward inhibition of prolactin release.

Пролактин и серотонин

An overview of the results of studies on prolactin (PRL) is given. The molecular and genetic characteristics of PRL and its receptor (PRLR) are presented. The PRLR polymorphism in patients with tumors of the breast is described. Synthesized analogues of human PRL inhibited its peripheral effects. The vegetative nervous system modulate PRL secretion. PRL is a risk factor for breast and prostate cancer. The signaling mechanisms of PRL and its possible clinical use in therapy of breast cancer are characterized.

374 Night shift work and prolactin in nurses and midwives - preliminary results

ObjectivesNight shift work and exposure to light at night suppress synthesis of melatonin and disrupt circadian rhythm. The pattern of secretion of many hormones, including prolactin, is dependent on circadian...

DRD2 Taq1A Polymorphism Modulates Prolactin Secretion Induced by Atypical Antipsychotics in Healthy Volunteers

Hyperprolactinemia mediated by antagonism of dopaminergic neurotransmission in the pituitary gland is a common adverse effect of antipsychotics. Recent studies have suggested that polymorphisms of dopamine receptors can affect the therapeutic response to antipsychotics. Thus, our aim was to evaluate whether 2 such polymorphisms (DRD2 Taq1A and DRD3 Ser9Gly) modulate prolactin release in healthy volunteers (n = 119) receiving a single dose of quetiapine (25 mg, n = 26), olanzapine (5 mg, n = 57), or risperidone (1 mg, n = 36). The increases in maximum concentration and in area under the curve were calculated from plasma prolactin levels after subtraction of pretreatment levels. Multiple regression analyses revealed that prolactin increases in maximum concentration and in area under the curve depended on drug (quetiapine < olanzapine < risperidone; P < 0.001), sex (women > men; P < 0.001), and Taq1A polymorphism (A1⁺ > A2/A2; P < 0.05). Analysis of the individual drugs revealed that prolactin secretion was modulated by sex and Taq1A polymorphism in olanzapine and risperidone (P < 0.05); however, these factors were not linked to prolactin secretion in quetiapine.

An evaluation of serum prolactin in anxious dogs and response to treatment with selegiline or fluoxetine

Defining objective, reproducible and standardized parameters for the evaluation of patients is one of the main academic focuses of veterinary behaviour medicine. Prolactin, a peptidic neurohormone and a cytokine, whose main regulator is dopamine, seems to be of particular interest in relation to chronically distressed patients. The aim of this clinical study was to assess the correlation between prolactin levels in the blood (prolactinaemia) and chronic anxiety and to evaluate its value in helping to guide the choice of the most appropriate drug in dogs displaying emotional disorders. The inclusion criteria included an EDED score superior or equal to 10 and the absence of any previous treatment or physical condition, which could modify prolactin secretion or emotional reactions. After inclusion, a randomization number was assigned to the dog, with a preselected treatment: fluoxetine (1 mg/kg once a day) or selegiline (0.5 mg/kg once a day). Each dog was evaluated with a complete behaviour examination, a physical examination, EDED score and a blood sample to measure prolactinaemia. The dogs were re-evaluated 4 weeks, 8 weeks and 16 weeks later. The follow-up visits were organised the same way as the inclusion visit, including EDED scoring and prolactinaemia evaluation. A population of 84 dogs was enrolled in study. The analysis of the correlations between prolactinaemia and EDED score show a positive significant correlation. Evaluation of treatment follow up showed a statistically significantly greater improvement with selegiline in the dogs with higher levels of prolactinaemia compared to those with lower levels of prolactin, who were significantly more improved by fluoxetine.

Neurotransmitters Involved in the Opioid Regulation of Prolactin Secretion at the End of Pregnancy in Rats

Using a pharmacological approach, we explored potential mechanisms for the regulation of prolactin secretion by opioid peptides at the end of pregnancy in rats. On day 19 of pregnancy, intracereboventricular administration of the µ-opioid receptor agonist (D-Ala², NMe-Phe⁴, Gly-ol⁵)-enkephalin (DAMGO) or β-endorphin (β-END) induced a dose-related increase in serum prolactin levels 30 min later. Pretreatment with the opioid antagonist naloxone abolished the increase induced by DAMGO injection. At lower doses, DAMGO and β-END did not modify the 3,4-dihydroxyphenylacetic acid/dopamine ratio, but at higher doses, the µ-agonists evoked a significant increase of the dopaminergic activity as compared with saline control. The time course of the effects of β-END (2.5 µg/rat) showed a higher increase in serum prolactin levels at 15 min than at 30 min after treatment. The 3,4-dihydroxyphenylacetic acid/dopamine ratio increased 15 min after β-END administration and was even higher 30 min later. Neither the selective ĸ-agonist U50,488H nor the selective δ-agonist (D-Pen², D-Pen⁵)- enkephalin were able to modify the serum prolactin levels at the doses studied.To evaluate potential neurotransmitters involved in the regulation of prolactin secretion at the end of pregnancy, we combined the administration of serotoninergic or GABAergic antagonists with the opioid agonist DAMGO. The serotonin 5-HT₂ receptor antagonist ketanserin increased the serum prolactin levels and potentiated the effect of DAMGO. The intracerebroventricular administration of SR-95531 did not modify the serum prolactin concentration under basal conditions, but partially prevented the increase induced by DAMGO injection. The intracerebroventricular administration of the GABA_B receptor antagonist phaclofen had no effect on the serum prolactin levels either in naive or DAMGO-treated rats. The present results support the proposal that activation of µ-opioid receptors stimulates prolactin secretion at the end of pregnancy. Although the exact mechanisms by which the opioid system modulates prolactin secretion at the end of pregnancy are unclear, these results suggest an interaction of the opioidergic system with serotoninergic and GABAergic systems, without ruling out a direct or indirect action on dopaminergic neurons. In conclusion, the opioid system may regulate prolactin secretion at the end of pregnancy through either stimulatory (present results) or inhibitory actions previously described.

Short Communication

Gluten Exorphins are opioid peptides identified in enzymatic digests of gluten. The effects of Gluten Exorphins are still largely unknown. It has been shown that Gluten Exorphin B5 (Tyr-Gly-Gly-Trp-Leu) stimulates Prolactin secretion in male rats. In this study, we have evaluated the Prolactin response to Gluten Exorphin B4, another exorphin whose structure (Tyr-Gly-Gly-Trp) is identical to that of the NH(2)-terminal sequence of Gluten Exorphin B5. To this aim, five groups of male rats were given the following intravenous treatments: vehicle, Gluten Exorphin B5 3 mg kg<PRE>-1</PRE> body weight, Gluten Exorphin B4 at the doses of 3, 6 and 9 mg kg<PRE>-1</PRE> body weight. At the dose of 3 mg kg<PRE>-1</PRE> body weight, Gluten Exorphin B5 induced a significant increase in Prolactin levels. Gluten Exorphin B4 could not modify Prolactin secretion, even when administered at doses three times higher than those effective for Gluten Exorphin B5. The present study: (1) indicates that Gluten Exorphin B4 does not modify Prolactin secretion in male rats; (2) confirms the ability of Gluten Exorphin B5 to exert a stimulatory action on Prolactin release; (3) suggests that the presence of the carboxy-terminal leucine in Gluten Exorphin B5 is essential for its action on Prolactin secretion.

Prolactin release during the estradiol-induced LH surge in ewes: modulation by progesterone but no evidence for prolactin-releasing peptide involvement.

An estradiol-induced prolactin surge accompanies the LH surge in several species, including sheep. However, the neural mechanisms underlying this surge remain poorly understood. A first study on estradiol- and progesterone-treated ovariectomized ewes examined whether the prolactin surge, like the LH surge, is sensitive to progesterone. Our data clearly showed that the estradiol-induced prolactin surge in the ewe is blocked by continuous exposure to progesterone and, importantly, that this blockade is overcome by pretreatment with the progesterone receptor antagonist, RU486. In a second study, we established that the generation of the prolactin surge is not dependent on the co-secretion of a prolactin-releasing peptide in the hypophyseal portal blood or cerebrospinal fluid. The neuronal pathways targeted by estradiol and progesterone to modulate prolactin secretion at the time of the LH surge remain to be identified. Importantly, it has not been established whether there is any overlap in the neuronal systems generating the gonadotropin-releasing hormone and prolactin surges.

The regulatory action of estrogen and vasoactive intestinal peptide on prolactin secretion in sea bream ( Sparus aurata, L.)

The effect of estradiol-17β (E 2) implants on the in vitro secretion of prolactin (PRL) and its modulation by vasoactive intestinal peptide (VIP) in a marine teleost, sea bream ( Sparus aurata L.), was determined. Experiments were conducted during winter and spring. During winter, fish ( n=130, body weight 50–70 g) were randomly divided into 2 groups; control and E 2 treated (10 mg/kg, wet weight). Fish were sacrificed after 7 days treatment and in vitro pituitary cultures in Ringer bicarbonate supplemented with increasing doses (0–200 nM) of VIP were carried out for 18 h. Culture medium was analysed by PAGE and secreted PRL quantified by densitometry. Fish treated with E 2 secreted significantly more PRL ( P<0.05) in vitro than control fish. In E 2 primed fish VIP caused a dose-dependent inhibition of PRL secretion in vitro. VIP had no detectable effect on the secretion of PRL from control pituitaries. Treatment with E 2 had a different effect during spring; PRL secretion was significantly decreased ( P<0.01) compared with the control fish. Anatomical evidence of abundant VIP immunoreactive nerve fibres in neurohypophysial (NH) tissue penetrating the rostral pars distalis provide further evidence supporting an action for VIP in the regulation of PRL cells. In conclusion, the responsiveness of PRL in the pituitary gland varied with season. Moreover, in the sea bream VIP appears to modulate PRL secretion from E 2 primed pituitary glands.

Influence of time of day on hypothalamic monoaminergic activity in early pregnancy: effect of a previous reproductive experience

Several dopamine-related neurochemical and behavioral responses are influenced by the time of day. The light–dark shift is a major zeitgeber for various functionally important hypothalamic monoaminergic systems. However, these influences are modulated by reproductive state and by reproductive experience (RE) in females. Early pregnancy in rodents generates diurnal and nocturnal prolactin surges that are reduced in intensity in a second pregnancy. Dopamine (DA) is a major inhibitory factor of prolactin synthesis and secretion. Other neurotransmitters such as serotonin (5HT) and norepinephrine (NE) can modulate prolactin secretion as well. Previous works have demonstrated that RE induces changes in central concentrations of both dopamine and serotonin. In addition, RE modulates the responses of both dopaminergic and serotoninergic nerve terminals. The present investigation was designed to examine the possible effects of RE on hypothalamic concentrations of DA, NE, 5HT and their major metabolites homovanillic acid (HVA), 3-4-dihydroxyphenyl acetic acid (DOPAC), 3-methoxy mandelic acid (VMA) and 5-hydroxyindole 3-acetic acid (5HIAA), respectively. These parameters were measured in pregnant rats during the light–dark shift and the prolactin surges. Primi- and multigravid rats were sacrificed on the 7th–8th day of pregnancy between 1700 and 1900 h (light–dark shift and diurnal prolactin surge) or 0200 and 0400 h (nocturnal prolactin surge), and hypothalamic concentrations of DA, NE and 5HT and their metabolites were measured by high performance liquid chromatography coupled to an electrochemical detector (HPLC-ED). Trunk blood was collected and serum prolactin measured by radioimmunoassay. The prolactin surge was confirmed and multigravid rats showed significantly lower serum prolactin levels as compared to primigravid rats between 0200 and 0400 h. During the light–dark shift DA and NE concentrations increased while DOPAC/DA, HVA/DA and 5HIAA/5HT ratios decreased in multigravid rats compared to primigravid rats. Except for 5HIAA/5HT, these differences were not observed during the prolactin nocturnal surge. These results suggest that a previous reproductive experience induces central functional changes during pregnancy which are expressed differently according to the time of day.

Short-term modulation of prolactin secretion by melatonin in anestrous ewes following dopamine- and opiate receptor blockade.

This study tested the hypothesis that the dopaminergic and opioidergic systems are not involved in the short-term stimulatory action of melatonin (MLT) on the secretion of prolactin in anestrous ewes. Thus, MLT should stimulate prolactin release after blockade of either dopamine (DA) or opiate receptors with specific antagonists at the level of the pituitary gland and central nervous system (CNS), respectively. During afternoon intracerebroventricular (icv.) infusion of MLT, the mean plasma prolactin concentration increased significantly (P < 0.001) as compared with the concentrations noted before and during the infusion of the vehicle (veh.). As a result of subcutaneous (s.c.) injection of sulpiride (SULP, DA antagonist), an increase in plasma prolactin concentration was observed, followed by a gradual decrease during the icv. infusion of the vehicle. MLT infused icv. significantly increased (P < 0.001) the secretion of prolactin in SULP + MLT-treated ewes, as compared with the concentration of prolactin noted during infusion of the vehicle in SULP + veh.-treated ewes. Naloxone (NAL, opioid antagonist) infused icv. did not significantly affect the secretion of prolactin, however, a significant (P < 0.01) increase in the concentration was observed after the infusion. In MLT + NAL-treated ewes, the plasma prolactin concentration increased significantly (P < 0.001) during the infusion, as compared with the concentration noted before and that in NAL-alone infused ewes. These results demonstrate that melatonin stimulates prolactin release after the pharmacological exclusion of the dopaminergic input with the DA antagonist sulpiride and also despite the presence of DA activity in the hypothalamus after NAL treatment. Secondly, endogenous opioid peptides are not a major component of this melatonin action.