In vivo Regulation of Prolactin Gene Expression in the Male Rat: Role of Sex Steroids and Dopamine

The influence of sex steroids and the dopaminergic system on the in vivo modulation of prolactin (PRL) mRNA levels was investigated by quantitative in situ hybridization in the male rat anterior pituitary gland. In situ hybridization was performed using a [³⁵S]-labeled cDNA probe encoding PRL. Orchiectomy performed 14 days earlier did not modify PRL mRNA levels. In orchiectomized rats treatment with the dopaminergic agonist bromocriptine for 14 days decreased PRL mRNA levels by 30%, while in intact animals the same treatment did not induce any changes in PRL mRNA levels. Administration of the dopamine D₂ receptor antagonist haloperidol in both intact and orchiectomized rats induced a 4-fold increase in mRNA levels. Administration of dihydrotestosterone to orchiectomized animals which had been treated or not with haloperidol or bromocriptine did not modify PRL mRNA levels. In orchiectomized animals administration of 17ß-estradiol (0.25 μg twice daily) for 14 days caused a 4-fold increase in amounts of PRL mRNA. Administration of bromocriptine to 17ß-estradiol-treated animals induced a 15% decrease of PRL mRNA levels compared to those obtained by 17ß-estradiol administered alone. The concomitant administration of 17ß-estradiol and haloperidol resulted in a 50% increase in PRL mRNA levels compared to those measured in animals treated with haloperidol alone. The present results clearly demonstrate that in vivo estrogen as well as dopamine-mediated mechanisms play a regulatory role in PRL mRNA levels in the male rat.     

Hyperprolactinemia inhibits natural killer (NK) cell functionin vivo and its bromocriptine treatment not only corrects it but makes it more efficient

We studied NK cell function in eight patients with pathological hyperprolactinemia by measuring⁵¹Cr release by K562 cells exposed to their mononuclear cells and found it decreased compared to normal controls (P<0.01). Bromocriptine (BrC) treatment corrected NK function but also made it more efficient at 12:1 than at 25:1 or 50:1 effector:target ratios (ANOVA;P=0.01). The study of NK cell function in agarose revealed that its decrease in hyperprolactinemia is due to their low active binding to target cells, active killing, and recycling capacity. BrC tended to correct them but also increased recycling capacity to levels higher than those of controls (P<0.05). Sequential studies in three hyperprolactinemic patients before and after BrC showed correction of NK function within 1 week but its increased efficiency at the 12:1 effector:target ratio required 8 weeks. We conclude that hyperprolactinemia decreases NK cell function. BrC corrects this by decreasing prolactin levels but also makes NK function more efficient by increasing the capacity of NK cells to recycle after killing.     

The Parkinson-Control study: a 1-year randomized, double-blind trial comparing piribedil (150 mg/day) with bromocriptine (25 mg/day) in early combination with levodopa in Parkinson's disease.

Dopamine agonists have been recommended as early treatment for Parkinson's disease (PD), alone or combined with levodopa. Piribedil is a non-ergot selective D(2)/D(3) agonist with alpha(2) antagonist properties shown to be effective in the treatment of PD. This 12-month international, randomized, double-blind trial aimed to assess the efficacy of piribedil 150 mg versus bromocriptine 25 mg, in early combination with levodopa in Stage I to III PD patients. Motor efficacy was assessed using the Unified Parkinson's Disease Rating Scale (UPDRS III, Items 18-31) as improvement from baseline. Response rate was defined as a 30% improvement. Among the 425 randomly assigned patients, 178 were also included in a substudy on cognitive follow-up evaluated by a dysexecutive syndrome oriented battery. A relevant improvement in UPDRS III over the 12-month study duration was observed both in the piribedil and bromocriptine groups (-7.9 +/- 9.7 points from baseline versus -8.0 +/- 9.5; not significant [n.s.]) with a response rate of 58.4% and 55.3% (n.s.), respectively. Piribedil and bromocriptine resulted in similar improvement on all UPDRS III subscores. Piribedil patients required less levodopa dose increase than those on bromocriptine. Cognitive performance remained generally unchanged in both groups, with a significant effect of piribedil limited to the Wisconsin Card Sorting Test. An overall good tolerability of piribedil was observed. Early combination of piribedil 150 mg with levodopa resulted in significant long-term improvement of all motor symptoms in PD patients insufficiently controlled by levodopa alone. Taking into account both efficacy and acceptability in the long-term, piribedil proved in this bromocriptine controlled study to be an effective and safe treatment for PD.     

Maintained pregnancy levels of oestrogen afford complete protection from post-partum exacerbation of collagen-induced arthritis.

Pregnancy is known to influence the course of rheumatoid arthritis (RA) in women, as well as type II collagen-induced arthritis (CIA) in DBA/1 mice. A characteristic feature is the remission during gestation and the exacerbation of the diseases during the post-partum period. In the case of CIA in DBA 1 mice, two hormonal changes have been assumed to be critical for the induction of the post-partum flare: (i) the fall in steroid hormone levels from those present during pregnancy; and (ii) surges of prolactin (PRL) release at and after delivery. Our results show that treatment with oestradiol during a short period immediately after parturition protects the mouse from a post-partum flare of the disease, and that treatment with bromocriptine, a drug known to inhibit the endogenous PRL release, has a significant though less marked effect. Studies of lactating (i.e. animals with physiological stimulation of endogenous PRL release) and non-lactating arthritic mice revealed no clear-cut differences, indicating that PRL is of minor importance for the induction of the post-partum flare. Some steroids other than oestradiol, which may be implicated in the exacerbation of arthritis, namely progesterone and hydrocortisone, had no clinical effect. Analyses of agalactosyl IgG levels in mice with CIA, and anti-collagen II antibodies in sera collected at the end of the experiments revealed no significant differences between the oestradiol and the control groups. The successful oestradiol treatment of the mice indicates that the drop in endogenous oestradiol levels prior to delivery ends the oestrogen-mediated protection against arthritis during pregnancy.     

Memantine,amantadine, and L-deprenyl potentiate the action of L-DOPA in monoamine-depleted rats

Summary Some treatments used for Parkinson's disease attenuate locomotor depression in rats treated with reserpine and -methyl-p-tyrosine. In the present study memantine (2.5, 5.0mg/kg), amantadine (10, 20mg/kg) (both uncompetitive NMDA antagonists), and L-deprenyl (1.0, 5.0 mg/kg; MAO-B inhibitor) were tested for possible synergistic interactions with the dopamine agonists: bromocriptine (2.5, 5.0mg/kg) and L-DOPA (50, 100mg/kg, + benserazide, 100 mg/kg). At higher doses, memantine (10 mg/kg), amantadine (40 mg/kg), bromocriptine (5 and 10mg/kg) and L-DOPA (100, 200mg/kg) but not L-deprenyl (up to 10 mg/kg) produced a pronounced increase in locomotor activity when given alone. The combination of memantine, amantadine and L-deprenyl with bromocriptine did not result in synergism of action and, at best, an additive effect was seen. On the other hand the combination of these agents with L-DOPA produced a pronounced synergistic effect. Hence, the clinical observation that coadministration of L-DOPA with either memantine or amantadine results in enhancement of their action is also reflected in an animal model of Parkinson's disease. Such a combination therapy should allow the use of lower doses of both drugs which may reduce the occurrence of side effects and may also be predicted to have additional benefits related to the neuroprotective properties of memantine, amantadine, and L-deprenyl.     

INCREASED LEVELS OF PROLACTIN DURING,BUT NOT AFTER,THE IMMUNISATION WITH RAT COLLAGEN II ENHANCES THE COURSE OF ARTHRITIS IN DBA/1 MICE

In addition to its well known effects on reproductive organs and lactation the pituitary hormone prolactin (PRL) also influences immune functions. The present investigation was performed in order to clarify the regulatory role of prolactin in autoimmune disease by using the collagen II arthritis model. Groups of virgin female DBA/1 mice were subjected to different short-term treatment protocols (5-10 days) with rat PRL and the drugs bromocriptine (inhibits prolactine secretion) and haloperidol (enhances prolactin secretion). Treatments were performed at different stages of disease development, and effects on clinical scores, anti-collagen II antibody titres as well as agalactosyl IgG levels were recorded. The effects of the treatment protocols on serum PRL levels were assessed by using a radioimmunoassay (RIA) system. Although the accumulated results of the present study indicate that PRL does not fulfil a major role in the regulation of collagen II arthritis, some interesting observations were made. High levels of PRL (PRL injections) made the arthritis worse only if treatment was performed during the induction stage of the disease. Bromocriptine treatment during the immunisation period did not significantly affect the course of arthritis, but treatment at later stages tended to cause exacerbation (significant at the onset period only). These results indicate that PRL has different effects during early and late stages of the development of collagen 11-induced arthritis.     

以重度ED为首发症状的垂体泌乳素瘤4例报告

目的:以重度ED为首发症状的垂体泌乳素瘤易误诊,分析该病所致重度ED的特点,以提高诊治水平。方法:回顾4例以重度ED(IIEF-5评分5～7分)为首发临床症状、经MRI检查确诊的垂体泌乳素瘤,结合文献诊治特点进行分析。结果:4例因垂体泌乳素瘤引起的重度ED误诊时间长达2年,血清泌乳素(PRL)均为正常高值的10倍以上,开始应用PDE5抑制剂无效,3例行单鼻孔-蝶窦-垂体瘤全切除术,术后24个月随访:1例PRL正常,IIEF-5 19分,2例PRL分别降至600和768 IU/L,IIEF-5均为15分,此时再服用PDE5抑制剂获得满意效果;1例口服溴隐亭保守治疗,12个月后随访PRL正常,IIEF-5>21分。结论:检测血PRL和脑MRI检查可以确诊以重度ED为首发临床症状的垂体泌乳素瘤,在PRL极高的情况下,单纯应用PDE5抑制剂无效,通过手术或药物降低PRL后,ED症状可改善,若改善不明显,此时再应用PDE5抑制剂将会收到满意的效果。     

控制性超促排卵中溢乳症的临床处理分析

目的探讨不同临床处理对体外授精-胚胎移植(in vitro fertilization and embryo transfer,IVF-ET)中伴溢乳症的不孕症患者妊娠结局的影响。方法选择在邢台不孕不育专科医院生殖中心接受IVF-ET的不孕症患者358例,其中伴溢乳症296例,无溢乳症及基础血清催乳素(prolactin,PRL)正常的62例。按有无溢乳症、高PRL血症及其处理方法分为5组,A组为溢乳症不伴有高PRL血症,应用甲磺酸溴隐亭治疗;B组为溢乳症伴有高PRL血症,应用甲磺酸溴隐亭治疗;C组为溢乳症不伴有高PRL血症,应用中药治疗;D组为溢乳症不伴有高PRL血症,未给予药物治疗;E组为无溢乳症及基础血清PRL正常。比较5组不孕症患者外源性促性腺激素(gonadotropin,Gn)启动日PRL水平、注射绒毛膜促性腺激素(chorionic gonadotrophin,HCG)日PRL水平、获卵数、可用胚胎数、临床妊娠率。结果 5组不孕症患者比较,A组临床妊娠率最低(P0.05);在Gn启动日和注射HCG日,A组PRL水平低于其他4组(P0.05)。结论不孕症患者无高PRL血症的溢乳症状无需进行治疗,为改善症状,中药治疗可作为很好的尝试。     

The relevance to clinical care of recent research in neurobiology

Progress continues to be made in clarifying neurobiological factors in alcoholism and other chemical dependencies. Research in animal behavioral genetics and human genetics has revealed substantial genetic predispositions for some cases of alcoholism. Studies of neurotransmitters suggest that some alcoholics may have antecedent deficiencies in one or more important neurochemical systems. Cocaine dependence is considered to be related to biphasic change in sopaminergic neurons and receptor systems. Condensation products such as salsolinol, tetrahydropapaveroline, and beta carbolines can alter alcoholic preference and motivate heavy ethanol consumption in animals. However, hypothesized theoretical mechanisms underlying such increased drinking with infusions of condensation products are unclear and may require revision. New pharmacological treatments stemming from advances in neurobiological research have been applied successfully to treatment of withdrawal states, but none have been demonstrated to be appropriate for long-term maintenance of abstinence.