Increase In Plasma Prolactin Levels Research Articles

Suppressive Effects of Neuromedin U Receptor 2-Selective Peptide Agonists on Appetite and Prolactin Secretion in Mice.

Neuromedin U receptor 2 (NMUR2), which is expressed in the central nervous system (CNS) including the hypothalamus, has been noted as a therapeutic target against obesity. We previously reported that intranasal administration of CPN-219, a NMUR2-selective hexapeptide agonist, suppresses body weight gain in mice; however, there is no detailed information regarding its CNS effects. Recently, in addition to appetite suppression, stress responses and regulation of prolactin (PRL) secretion have also attracted attention. NMUR2 expressed in the hypothalamic tuberoinfundibular dopaminergic neurons has emerged as an alternative target for treating hyperprolactinemia. Here, CPN-219 decreased food intake up to 24 h after administration at a dose of 200 nmol, resulting in body weight gain suppression, although grooming and anxiety-like behaviors were transiently induced. Interestingly, the restraint stress-induced increase in plasma PRL levels was significantly suppressed at a lower dose of 20 nmol, indicating the potential for drug development as an anti-PRL agent of NMUR2-selective agonists.

Clinical Practice Guidelines for management of Sexual Disorders in Elderly.

Clinical Practice Guidelines for management of Sexual Disorders in Elderly.

TANTRA O YOGA. ESTUDIOS CLÍNICOS, 1ª PARTE: YOGA

Varios estudios clínicos muestran cómo los ejercicios de las tradiciones védicas, como el yoga, o budistas theravada o mahayana así como las prácticas tántricas tienen un impacto psicobiológico significativo. Este estudio busca el correlato neurofisiológico de las prácticas llamadas meditaciones tántricas y no-tántricas mediante una revisión sistemática cualitativa de los datos recolectados. Primero se verificaron los resultados de las no-tántricas, luego se recolectaron los datos de las tántricas, se las comparó y presentamos el resultado dividido en tres partes. En esta primera parte se encontró que las no-tántricas crean una mejor respuesta de relajación con actividad parasimpática incrementada e inhibición del sistema simpático, que induce un estado hipometabólico de descanso profundo donde el practicante permanece despierto y su atención, en «alerta tónica» con los síntomas correspondientes a ese estado hipometabólico -hipotonía, disminución del consumo de oxígeno, de la tasa cardíaca y de la concentración de lactato en sangre-, modificación del normal funcionamiento endócrino, aumentos en la concentración de fenilalanina en los meditadores avanzados, en los niveles de prolactina plasmática, un incremento de cinco veces en los niveles plasmáticos de arginina vasopresina, mientras que la hormona estimulante de la tiroides disminuye de forma crónica y aguda. Esta investigación abre el camino para desarrollar estudios clínicos longitudinales, para confirmar los efectos benéficos a largo plazo de las prácticas y establecer mecanismos para contrarrestar los secundarios indeseados mostrados aquí. AbstractSeveral clinical studies show how exercises in Vedic traditions, such as Yoga, or Theravada or Mahayana Buddhisms as well as tantric practices have a significant psychobiological impact. This study seeks the neurophysiological correlate of the practices called tantric and non-tantric meditations through a qualitative systematic review of the data collected. First the non-tantric meditations results were checked, then the tantric meditations data was collected, finally both were compared and we hereby report the results arranged in three sections. In this first section, it was found that non-tantric meditations create a better relaxation response with increased parasympathetic activity and inhibition of the sympathetic system, which induces a deep rest hypometabolic state where the practitioner remains awake and their attention, in "tonic alertness" with the symptoms corresponding to such hypometabolic state -hypotonia, decreased oxygen consumption, heart rate and blood lactate concentration- change in normal endocrine function, increased phenylalanine concentration in advanced meditators, increased plasma prolactin levels, a five-fold increase in arginine vasopressin plasma levels, while thyroid stimulating hormone decreases chronically and acutely. This research opens the door to conduct longitudinal clinical studies, to confirm the long-term beneficial effects of practices and establish mechanisms to counteract the unwanted side-effects herein presented.

Catechol-O-methyltransferase gene variants may associate with negative symptom response and plasma concentrations of prolactin in schizophrenia after amisulpride treatment

Catechol-O-methyltransferase (COMT) enzyme is involved in the pathogenesis of psychotic symptoms and may be associated with a therapeutic response to antipsychotic drugs. The aim of this study was to examine the relationship between COMT variants, plasma prolactin level, and the therapeutic effectiveness of amisulpride treatment in patients with schizophrenia. A 12-week naturalistic study of amisulpride treatment was carried out in 185 Han Chinese patients with schizophrenia. The patients were screened for 14 single-nucleotide polymorphisms of the COMT gene. The Positive and Negative Syndrome Scale (PANSS) was used to assess the improvement of psychopathological symptoms from the baseline to the end point in each subject. For better presentation of time-course changes in response status, a mixed model for repeated-measures (MMRM) analysis of symptom improvement during the 12-week treatment period was conducted. The change in plasma prolactin level after amisulpride treatment was also examined (n=51). No significant differences in the genotype frequencies of the COMT variants investigated were observed between responders and non-responders. Moreover, an MMRM analysis of psychopathological symptom improvement during the 12-week treatment course showed that it depended significantly on COMT variants (rs4680, rs4633, and rs6267), particularly regarding changes in negative symptoms. The increase in plasma prolactin levels observed was influenced by the COMT rs4680 variant and was positively correlated with a reduction in PANSS negative scores. Our results suggest that variation of the COMT gene is associated with treatment response regarding negative symptoms and prolactin changes after amisulpride treatment in patients with schizophrenia.

QIP on baseline prolactin monitoring in psychiatric inpatients on antipsychotics

Mental health patients suffer higher rates of mortality and morbidity due to physical health problems. A number of antipsychotics are associated with significant increases in plasma prolactin levels and the risk of hyperprolactinaemia. The importance of physical health monitoring is increasingly recognised and commissioned for in mental health services. In the context of greater focus on physical health monitoring in mental health settings, this project set out to assess and improve compliance with guidance on baseline prolactin level testing of inpatients on antipsychotics.

Dopamine receptor D2 deficiency reduces mouse pup ultrasonic vocalizations and maternal responsiveness

Dopamine signalling facilitates motivated behaviours, and the D2 dopamine receptor (D2R) is important in mother-infant interactions. D2R antagonists disrupt maternal behaviour and, in isolated rat pups, reduce ultrasonic vocalizations (USVs) that promote maternal interaction. Here, we examined the effects of genetic D2R signalling deficiency on pup-dam interaction with Drd2 knockout (D2R KO) mice. Using heterozygous (HET) cross littermates, the effect of pup genotype on isolation-induced USVs was quantified. Independent of parental genotype, D2R-deficient pups emitted fewer USVs than wild type (WT) littermates in a gene dose-dependent manner. Using reciprocal D2R KO-WT crosses, we examined how parental genotype affects pup USVs. Heterozygous pups from D2R KO dams produced fewer USVs than HET pups from WT dams. Also, exposure to USV-emitting pups increased plasma prolactin levels in WT dams but not in D2R KO dams, and KO dams showed delayed pup retrieval and nest building. These findings indicate the importance of the interaction between pup and dam genotypes on behaviour and further support the role of D2R signalling in maternal care.

An endogenous dopaminergic tone acting on dopamine D3 receptors may be involved in diurnal changes of tuberoinfundibular dopaminergic neuron activity and prolactin secretion in estrogen-primed ovariectomized rats

The diurnal rhythm of tuberoinfundibular dopaminergic (TIDA) neuron activity, i.e., high in the morning and low in the afternoon, is prerequisite for the afternoon prolactin (PRL) surge in proestrous and estrogen-primed ovariectomized (OVX) female rats. Whether dopamine acts via D(3) receptors in regulating the rhythmic TIDA neuron activity and PRL secretion in estrogen-primed OVX (OVX+E(2)) rats is the focus of this study. Intracerebroventricular (icv) injection of a D(3) receptor agonist, PD128907 (0.1-10 μg/3 μl), in the morning significantly reduced the basal activity of TIDA neurons and increased plasma PRL level. The effects of PD128907 were reversed by co-administration of U99194A, a D(3) receptor antagonist, but not by raclopride, a D(2) receptor antagonist. To determine whether endogenous dopamine acts on D(3) receptors involved in the diurnal changes of the activities, we used both U99194A, a D(3) receptor antagonist, and an antisense oligodeoxynucleotide (ODN) against D(3) receptor mRNA in the study. U99194A (0.1 μg/3 μl, icv) given at 1200 h significantly reversed the lowered TIDA neuron activity and the afternoon PRL surge at 1500 h. Moreover, OVX+E(2) rats pretreated with the antisense ODN (10 μg/3 μl, icv) for 2 days had the same effects as the D(3) receptor antagonist on TIDA neuron activity and the PRL surge. The same treatment with sense ODN had no effect. In conclusion, an endogenous DA tone may act on D(3) receptors to inhibit TIDA neuron activity and in turn stimulate the PRL surge in the afternoon of OVX+E(2) rats.

Activity of Hypothalamic Dopaminergic Neurones During the Day of Oestrus: Involvement in Prolactin Secretion

A secretory surge of prolactin occurs on the afternoon of oestrus in cycling rats. Pituitary prolactin is inhibited by dopamine. We evaluated the activity of the neuroendocrine dopaminergic neurones during oestrus and dioestrus, as determined by dopaminergic activity in the median eminence and neurointermediate lobe of the pituitary, as well as Fos-related antigen expression in tyrosine hydroxylase (TH)-immunoreactive (ir) neurones of the arcuate nucleus (ARC) and periventricular nucleus (Pe). During oestrus, the 4-dihydroxyphenylacetic acid/dopamine ratio in the median eminence decreased at 16.00 h, coinciding with the increase in plasma prolactin levels. Similarly, the expression of Fos-related antigen in TH-ir neurones of Pe and rostral-, dorsomedial- and caudal-ARC also decreased at 16.00 h. On dioestrus, 4-dihydroxyphenylacetic acid/dopamine ratio in the median eminence and Fos-related antigen expression in TH-ir neurones of Pe and rostral-ARC decreased at 18.00 h, whereas prolactin levels were unaltered. No variation in dopaminergic activity was found in the neurointermediate lobe of the pituitary on either oestrus or dioestrus. The number of TH-ir neurones in the ARC and parameters of dopaminergic activity were found to be generally lower on oestrus compared to dioestrus. The transitory decrease in the activity of neuroendocrine dopaminergic neurones temporally associated with the prolactin surge on the afternoon of oestrus suggests a role for dopamine in the generation of the oestrous prolactin surge.

Paliperidone Extended Release

Paliperidone, the major active metabolite of the atypical antipsychotic risperidone, is available in an oral extended-release (ER) formulation (Invega(R)) and is indicated for the acute and maintenance treatment of schizophrenia in adults in the US and the EU. Once-daily paliperidone ER provides stable plasma drug concentrations over a 24-hour period and may be initiated at therapeutically effective dosages without the need for titration. Paliperidone ER 3-12 mg/day improved Positive and Negative Syndrome Scale (PANSS) total scores (primary endpoint) from baseline to study end to a significantly greater extent than placebo in 6-week, double-blind trials in patients with acute symptoms of schizophrenia. The significant improvement in PANSS total score was seen after 4 days of treatment in some trials and paliperidone ER was effective against both positive and negative symptoms of the disease. End of treatment clinical response rates were significantly higher in paliperidone ER recipients than in those who received placebo. The efficacy of paliperidone ER was maintained with longer-term treatment (up to 52 weeks) in open-label extensions of placebo-controlled trials. When compared with quetiapine, paliperidone ER was associated with significantly greater improvements in PANSS total scores from baseline at 2 weeks (primary endpoint) in patients with acute schizophrenia, and at 6 weeks. The two drugs did not significantly differ in terms of clinical response rates. In the only trial to evaluate paliperidone ER for the prevention of symptom recurrence, paliperidone ER recipients had a significantly longer time to recurrence than did placebo recipients, as well as significantly less deterioration of symptom severity. In a 6-month, open-label trial in patients with non-acute schizophrenia, PANSS total scores, PANSS subscale scores and all five Marder factor scores did not significantly differ between paliperidone ER and olanzapine, but were significantly reduced from baseline at endpoint in both treatment groups. In adults with non-acute schizophrenia who were previously unsuccessfully treated with other oral antipsychotics and switched to paliperidone ER, PANSS total scores, PANSS subscale scores and all five Marder factor scores were significantly decreased from baseline at week 26 or endpoint. Paliperidone ER was generally well tolerated during short- and longer-term use and had a tolerability profile generally similar to that of its parent drug, risperidone. There were no unexpected tolerability findings during treatment of up to 52 weeks in duration. Paliperidone ER appeared to have little pro-arrhythmic potential and little effect on plasma glucose, lipid or insulin levels, but increased plasma prolactin levels over both short- and longer-term treatment periods. Clinically significant gains in bodyweight were seen in 15% of patients treated with paliperidone ER during the extension phase of placebo-controlled trials. Pooled analyses revealed that extrapyramidal symptoms occurred in approximately a quarter of the patients treated with higher doses of paliperidone ER (9 and 12 mg/day) in 6-week trials, and in 25% of paliperidone ER (mean dosage 10 mg/day) recipients during the 52-week extension phases. Although additional active comparator trials would be of interest, paliperidone ER is a useful option in the treatment and prevention of the acute symptoms of schizophrenia and may also be of use in patients with non-acute disease, including those previously unsuccessfully treated with other oral antipsychotics.

Endocrine and Neurochemical Effects of 3,4-Methylenedioxymethamphetamine and Its Stereoisomers in Rhesus Monkeys

3,4-Methylenedioxymethamphetamine (MDMA) is an amphetamine derivative that elicits complex biological effects in humans. One plausible mechanism for this phenomenon is that racemic MDMA is composed of two stereoisomers that exhibit qualitatively different pharmacological effects. In support of this, studies have shown that R(-)-MDMA tends to have hallucinogen-like effects, whereas S(+)-MDMA tends to have psychomotor stimulant-like effects. However, relatively little is known about whether these stereoisomers engender different endocrine and neurochemical effects. In the present study, the endocrine and neurochemical effects of each stereoisomer and the racemate were assessed in four rhesus monkeys after intravenous delivery at doses (1-3 mg/kg) that approximated voluntary self-administration by rhesus monkeys and human recreational users. Specifically, fluorescence-based enzyme-linked immunosorbent assay was used to assess plasma prolactin concentrations, and in vivo microdialysis was used to assess extracellular dopamine and serotonin concentrations in the dorsal striatum. R(-)-MDMA, but not S(+)-MDMA, significantly increased plasma prolactin levels and the effects of S,R(+/-)-MDMA were intermediate to each of its component stereoisomers. Although S(+)-MDMA did not alter prolactin levels, it did significantly increase extracellular serotonin concentrations. In addition, S(+)-MDMA, but not R(-)-MDMA, significantly increased dopamine concentrations. Furthermore, as in the prolactin experiment, the effects of the racemate were intermediate to each of the stereoisomers. These studies demonstrate the stereoisomers of MDMA engender qualitatively different endocrine and neurochemical effects, strengthening the inference that differences in these stereoisomers might be the mechanism producing the complex biological effects of the racemic mixture of MDMA in humans.

Melperone, an aytpical antipsychotic drug with clozapine‐like effect on plasma prolactin: contrast with typical neuroleptics

To evaluate the effect of melperone, a butyrophenone with atypical antipsychotic properties, on plasma prolactin (PRL) concentrations compared with clozapine and typical neuroleptics. Analysis of pre- and post-treatment PRL levels collected prospectively per protocol in a non-randomized study of 26 melperone-, 76 clozapine-, and 66 neuroleptic-treated patients with schizophrenia or schizoaffective disorder. Cross-sectional analysis of a larger sample of patients with PRL data was also performed. For males, post-treatment PRL levels were significantly higher in the typical neuroleptic group compared with the melperone (p = 0.0001) and clozapine (p = 0.0001) groups, with no significant difference between clozapine and melperone. For females, post-treatment PRL levels were significantly higher in the melperone group as compared to the clozapine group (p = 0.004). There were too few typical neuroleptic-treated females to permit analysis of this sample. However, the cross-sectional analysis of PRL data confirmed the results for melperone- and clozapine-treated females, and showed higher PRL levels in typical neuroleptic-treated females as compared with those who received melperone and clozapine. Melperone did not significantly increase PRL levels in male patients. However, melperone and typical neuroleptics caused increase in PRL levels in females. Further study of melperone's effects on PRL concentration is warranted.

Differences in Prepuberal Neonatally Estrogenized or Androgenized Male Rats

The main objective of this work was to analyze the different effects produced in prepuberal male rats by neonatal androgenization or estrogenization. For this purpose male Wistar rats were injected on day one of life with 500 micrograms of estradiol benzoate (estrogenized animals), 500 micrograms of testosterone propionate (androgenized animals) or olive oil (control animals) and decapitated on day 15. At the moment of decapitation estrogenized animals showed decreases in body, testes, prostate and adrenal weights, increases in pituitary, seminal vesicles and epididymis weights, an increase in prolactin plasma levels and a decrease in those of androgens. Androgenized animals showed only decreased testes and epididymis weights and androgen plasma levels. These results evidence the presence of important qualitative differences in prepuberal neonatally estrogenized or androgenized rats, especially in the accessory sex organs.

Effects of oestrogen-induced hyperprolactinemia on the rat prostate.

Exposure of intact rats to increasing doses of oestradiol-17 beta in the presence of a constant amount of exogenous androgen caused a dose-related increase in the concentration of zinc in the lateral lobes and a decrease in the levels of ventral lobe prolactin binding. These changes occurred concomitantly with a dose-dependent increase in plasma prolactin levels, and could not be obtained in hypophysectomized rats given the same steroid treatment. In the intact animals a dose-dependent decrease in the responsiveness of the prostaglandin E1-dependent adenylyl cyclase in the ventral lobe was observed, an effect which has earlier been shown to be prolactin mediated. The results indicate that oestrogen has indirect effects on specific parameters of prostate function by inducing a relative hyperprolactinemia. This model may be useful in studying effects of chronically and physiologically elevated levels of endogenous prolactin on the rat prostate.

Characteristics of prolactin-releasing response to salsolinol (SAL) and thyrotropin-releasing hormone (TRH) in ruminants

The secretion of prolactin (PRL) is stimulated by thyrotropin-releasing hormone (TRH), and inhibited by dopamine (DA). However, we have recently demonstrated that salsolinol (SAL), a DA-derived endogenous compound, is able to stimulate the release of PRL in ruminants. The aims of the present study were to compare the characteristics of the PRL-releasing response to SAL and TRH, and examine the relation between the effects that SAL and DA exert on the secretion of PRL in ruminants in vivo and in vitro. Three consecutive intravenous (i.v.) injections of SAL (5 mg/kg body weight (b.w.): 19.2 μmol/kg b.w.) or TRH (1 μg/kg b.w.: 2.8 nmol/kg b.w.) at 2-h intervals increased plasma PRL levels after each injection in goats ( P < 0.05); however, the responses to SAL were different from those to TRH. There were no significant differences in each peak value between the groups. The rate of decrease in PRL levels following the peak was attenuated in SAL-treated compare to TRH-treated animals ( P < 0.05). PRL-releasing responses to SAL were similar to those to sulpiride (a DA receptor antagonist, 0.1 mg/kg b.w.: 293.3 nmol/kg b.w.). In cultured bovine anterior pituitary (AP) cells, TRH (10 −8 M) significantly increased the release of PRL following both 15- and 30-min incubation periods ( P < 0.05), but SAL (10 −6 M) did not increase the release during the same periods. DA (10 −6 M) completely blocked the TRH-induced release of PRL for a 2-h incubation period in the AP cells ( P < 0.05). Sulpiride (10 −6 M) reversed this inhibitory effect but SAL (10 −6 M) did not have any influence on the action of DA. These results show that the mechanism(s) by which SAL releases PRL is different from the mechanism of action of TRH. Furthermore, they also show that the secretion of PRL is under the inhibitory control of DA, and SAL does not antagonize the DA receptor's action.

Profile of paliperidone extended release: review of efficacy and safety data

Paliperidone, an active metabolite of risperidone, is the most recent second-generation antipsychotic to become available on the market. This article addresses the pharmacology, clinical efficacy and tolerability of paliperidone. A comprehensive review of studies on MEDLINE using terms, such as paliperidone, 9-hydroxy risperidone, efficacy and tolerability, was conducted. Paliperidone, a 9-hydroxy derivative of risperidone is an antagonist at the dopamine and serotonin receptor sites. As paliperidone is an active metabolite of the parent compound risperidone, it is not metabolized hepatically, has minimal drug–drug interactions and is largely excreted unchanged by the kidneys. It follows linear pharmacokinetics. Evidence from short- and long-term trials supports the efficacy and tolerability of paliperidone extended release (ER) in the treatment of schizophrenia. Randomized, double-blind, placebo-controlled, multicenter studies have demonstrated both paliperidone 6 and 12 mg result in symptom improvement, increase in time of first recurrence of psychotic symptoms as well as significant improvements in personal and social performance. Studies demonstrated increases in plasma prolactin levels and extrapyramidal symptoms with paliperidone ER treatment compared with placebo. Changes in blood glucose and lipid levels with paliperidone ER were comparable to placebo. Overall, paliperidone is an efficacious, well-tolerated addition to the treatment armamentarium for schizophrenia.

Efficacy and Safety of Paliperidone Extended-Release Tablets: Results of a 6-Week, Randomized, Placebo-Controlled Study

Paliperidone extended-release tablet (paliperidone ER; Invega, Janssen L.P., Titusville, New Jersey) is an oral psychotropic for schizophrenia treatment. Efficacy and safety of once-daily paliperidone ER (6 and 12 mg) were assessed versus placebo in 444 patients with acute schizophrenia in a 6-week, multicenter, double-blind, randomized, parallel-group study. An olanzapine (10 mg) treatment arm was included to confirm trial validity. Both doses of paliperidone ER demonstrated significant improvement in Positive and Negative Syndrome Scale (PANSS) total score (p < or = .006) and certain PANSS Marder factor scores compared with placebo (p < or = .025); PANSS total score also improved in the olanzapine treatment arm. Paliperidone ER 6 mg (p < or = .008), but not 12 mg, was associated with significant improvements in personal and social performance. The incidence of treatment-emergent adverse events (AEs) for paliperidone ER 6 mg was comparable with placebo and slightly greater with paliperidone ER 12 mg. Changes in blood glucose and lipid levels with paliperidone ER were comparable with placebo. Two patients treated with paliperidone ER experienced glucose-related AEs. Body-weight increases of 1-2 kg were observed with paliperidone ER. Although there were increases in plasma prolactin levels with paliperidone ER treatment, the incidence of prolactin-related AEs was < or =1%. In this study, paliperidone ER, particularly the 6-mg dose, was effective and well tolerated, and provides a valuable new treatment option for schizophrenia.

Preprothyrotropin-releasing hormone178–199 affects tyrosine hydroxylase biosynthesis in hypothalamic neurons

ProThyrotropin-releasing hormone (proTRH) is a prohormone widely distributed in many areas of the brain. After biosynthesis, proTRH is subjected to post-translational processing to generate TRH and seven non-TRH peptides. Among these non-TRH sequences, we found previously that preproTRH178-199 could regulate the secretion of prolactin in suckled rats by their pups. Dopamine (DA), the main regulator of prolactin secretion, is produced in dopaminergic tyrosine hydroxylase (TH)-positive neurons in the hypothalamic arcuate nucleus (ARC). In this study we investigated whether prolactin release during the estrous sexual cycle is regulated by preproTRH178-199 through its effect on DA neurons of the ARC. We observed that biotinylated preproTRH178-199 bound to neurons in the ARC; this was higher during proestrus than during diestrus. Binding of preproTRH178-199 to DA neurons was seen only during proestrus in the ARC. Using primary neuronal hypothalamic cultures we found that preproTRH178-199 peptide decreased TH levels in a dose-responsive manner, whereas intra-ARC administration of preproTRH178-199 induced a 20-fold increase in plasma prolactin levels. Together, these results suggest a potential role for preproTRH178-199 in regulating dopaminergic neurons involved in the inhibition of pituitary prolactin release.

Physiologic Role for Prolactin Releasing Peptide

Prolactin (PRL) releasing peptide (PrRP) is produced in A1 and A2 catecholaminergic neurons of the ventrolateral medulla and nucleus tractus solitarius (NTS), respectively. PrRP-positive neurons in NTS project to the hypothalamic paraventricular and arcuate nuclei. I.c.v. administration of PrRP in conscious rats results in increased circulating PRL levels. We have developed an siRNA plasmid, which when injected bilaterally into the NTS results in significant diminution of immunoreactive PrRP content in the hypothalamus. We hypothesized that this would also impair the animal’s neuroendocrine response to restraint stress. Plasmid containing our PrRP siRNA or a control plasmid (scrambled siRNA) were injected bilaterally into the NTS of adult male rats bearing an indwelling jugular vein cannula. 18 hr later two blood samples (0 and 5 min) were withdrawn from the jugular cannula of conscious, unrestrained animals. They were then subjected to 10 min immobilization stress and additional blood samples taken during the stress (10 min) and at the end of the immobilization (15 min). The rats were then returned to their cages and two more blood samples taken at 20 and 30 min. There were no significant differences in plasma PRL levels between treatment groups before restraint (0 and 5 min). A significant, 10 fold increase in plasma PRL levels was observed in the control animals, while only a 4 fold increase in PRL was observed in siRNA treated rats. Plasma PRL levels were significantly lower in siRNA treated rats versus controls at 15, 20 and 30 min. These data demonstrate the efficacy of our plasmid based siRNA delivery system and suggest that PrRP, produced in neurons of the NTS which project to neuroendocrine centers in the hypothalamus, is an important mediator of stress related PRL secretion in the rat. Supported by NIH HL066023.

Experimental allergic encephalomyelitis in pituitary-grafted Lewis rats.

Treatment of susceptible rats with dopaminergic agonists that reduce prolactin release decreases both severity and duration of clinical signs of experimental allergic encephalomyelitis (EAE). To assess to what extent the presence of an ectopic pituitary (that produces an increase in plasma prolactin levels mainly derived from the ectopic gland) affects EAE, 39 male Lewis rats were submitted to pituitary grafting from littermate donors. Another group of 38 rats was sham-operated by implanting a muscle fragment similar in size to the pituitary graft. All rats received subcutaneous (s.c.) injections of complete Freund's adjuvant (CFA) plus spinal cord homogenate (SCH) and were monitored daily for clinical signs of EAE. Animals were killed by decapitation on days 1, 4, 7, 11 or 15 after immunization and plasma was collected for prolactin RIA. In a second experiment, 48 rats were immunized by s.c. injection of a mixture of SCH and CFA, and then received daily s.c. injections of bromocriptine (1 mg/kg) or saline. Groups of 8 animals were killed on days 8, 11 or 15 after immunization and plasma prolactin was measured. Only sham-operated rats exhibited clinical signs of the disease when assessed on day 15 after immunization. A progressive decrease in plasma prolactin levels was observed in pituitary-grafted rats, attaining a minimum 15 days after immunization, whereas plasma prolactin levels were increased during the course of the disease in sham-operated rats. Plasma prolactin levels were higher in pituitary-grafted rats than in sham-operated rats 1 day after immunization, but lower on days 7, 11 and 15 after immunogen injection. Further supporting a correlation of suppressed prolactin levels with absence of clinical signs of EAE, rats that were administered the dopaminergic agonist bromocriptine showed very low plasma prolactin levels and did not exhibit any clinical sign of EAE. These results indicate that low circulating prolactin levels coincide with absence of clinical signs of EAE in Lewis rats.

Rapid re-enlargement of a macroprolactinoma after initial shrinkage in a young woman treated with bromocriptine

We report the case of a macroprolactinoma in a 32-year-old woman, who presented with secondary amenorrhea, galactorrhea, increased plasma prolactin level (3259 ng/ml), headache and bi-temporal visual field defect. Magnetic resonance imaging showed a large pituitary tumor. The patient responded well to bromocriptine (7.5 mg/day) with improvement of clinical symptoms and normalization of plasma prolactin within a few weeks. After 4 months of treatment, tumor size was also reduced markedly. During continued treatment at the same dose of bromocriptine the plasma prolactin level remained normal, but after 8 months of treatment the patient suddenly complained of worsening of her visual fields, and magnetic resonance imaging indicated re-enlargement of the tumor. Bromocriptine was discontinued and transsphenoidal pituitary surgery was performed. After surgery the visual field defect improved, but postoperative plasma prolactin level (1104 ng/ml) and magnetic resonance imaging indicated a residual tumor. Postoperative treatment with quinagolide (0.15 mg/day) resulted in disappearance of all clinical symptoms, normalization of prolactin level and a reduction in size of the residual tumor. This case demonstrates that a dissociation of the inhibitory effect of bromocriptine on tumor size and prolactin level may rarely develop during the course of drug treatment in a patient with macroprolactinoma.