Self-administration of cocaine analogs by rats

  Rationale: A novel scheme for the synthesis of cocaine analogs from vinylcarbenoid precursors has made available compounds that have a diverse range of affinities for the DA and 5-HT transporters. These compounds were used to explore the relationship between their biochemical properties and their reinforcing effects. Objectives: The objective was to assess the reinforcing efficacy of selected cocaine analogs and compare the results with their selectivity in binding to DA and 5-HT transporters. Methods: Rats were prepared with chronically indwelling intravenous cannulae and trained to self-administer cocaine on a progressive ratio (PR) schedule. A range of doses of seven cocaine analogs were substituted for cocaine in separate groups of animals. Results: The results demonstrate a wide range of reinforcing efficacies and potencies among the seven selected drugs. Four tropane analogs (WF-11, WF-23, WF-24, WF-55) were found to support self-administration behavior on a PR schedule while three did not (WF-31, WF-54 and WF-60). The DA/5-HT selectivity ratio was found to be a better predictor of self-administration behavior than affinity at the DA transporter alone. Conclusion: These data suggest that drugs with a higher affinity for the DA versus the 5-HT transporter are more likely to be self-administered. Received: 29 October 1998 / Final version: 5 February 1999     

Role of gonadotrophin releasing hormone baseline concentrations in the control of pituitary gonadotrophin and ovarian steroid secretion in the pseudopregnant rat

To study the effect of moderately elevated gonadotrophin releasinghormone (GnRH) baseline concentrations during the luteal andthe follicular phase, pseudopregnant rats were infused s.c withGnRH at several doses for 5 days. These rats were also treatedwith oestradiol or sham-treated during the last 3 days of GnRHtreatment GnRH infusions started on day 7 or day 3 of the lutealphase of the ovulatory cycle; in the rat, the luteal phase orpseudopregnancy lasts about 10 days. Luteinizing hormone (LH)and follicle stimulating hormone (FSH) responses were inducedby i.v. injection of GnRH on day 12 (after expected luteolysis)or on day 8 (before expected luteolysis). In normal rats theLH and FSH responses induced by GnRH on day 12 were higher thanon day 8 (160 and 50% respectively). In GnRH-infused rats theLH and FSH responses were not increased. In these rats the lutealphase was extended (the plasma progesterone concentrations remainedhigh) and the onset of the follicular phase was postponed (plasmaoestrogen concentrations did not increase). Oestradiol increasedthe day 12 LH and FSH responses; this effect of oestradiol wassuppressed by GnRH infusion. On day 8, exogenous oestradiolalso increased the LH and FSH responses, but again the effectof oestradiol was suppressed when the animals were concomitantlyinfused with GnRH. These data may suggest that in the rat, GnRHbaseline concentrations participate in the neuroendocrine systemcontrolling gonadotrophin secretion and hence the ovulatorycycle.     

GABAA receptor mediated elevation of Ca2+ and modulation of gonadotrophin-releasing hormone action in alphaT3-1 gonadotropes

gamma-amino butyric acid (GABA) is the major inhibitory neurotransmitter in the CNS, mediating fast inhibitory synaptic transmission, by activating GABAA receptors. However, these GABA-gated Cl- channels can also be excitatory, causing depolarization, and increasing Ca2+ entry via voltage-operated Ca2+ channels (VOCCs). Evidence exists for excitatory ionotropic GABA receptors in anterior pituitary cells, including gonadotropes, but these have not been directly characterized and their pharmacology remains controversial. Here we have measured the cytosolic Ca2+ concentration ([Ca2+]i) in alphaT3-1 gonadotropes, to test for expression of excitatory GABA receptors. The GABAA agonists, GABA and muscimol, both caused rapid, robust and dose-dependent increases in [Ca2+]i (EC50 values 2.7 and 1 microM), whereas the GABAB agonist, baclofen, did not. The GABAA antagonist, bicuculline, inhibited muscimol's effect, whereas the GABAB antagonist, phaclofen, did not. The neuroactive steroid 5alpha-pregnan-3alpha-ol-11,20-dione (an allosteric activator of GABAA receptors) increased [Ca2+]i, and this effect, like that of muscimol, was inhibited by picrotoxin. The muscimol effect on [Ca2+]i was blocked by the VOCC antagonist, nifedipine, or by Ca2+-free medium. When cells were pretreated with muscimol this increased the spike phase of the [Ca2+]i response to subsequent stimulation with gonadotropin-releasing hormone (GnRH). Similar amplification was seen in muscimol-pretreated cells stimulated with GnRH in Ca2+-free medium, but not when cells were pretreated with muscimol in Ca2+-free medium. The amplification was not, however, GnRH receptor-specific, because the spike response to ionomycin was also increased by muscimol pretreatment. These data provide the first direct evidence for expression of excitatory GABAA receptors, and the first demonstration of acute steroid effects, on GnRH-responsive pituitary cells. They also reveal a novel mechanism by which GABAA activation modulates GnRH action, raising the possibility that this may also influence gonadotrophin secretion from non-immortalized gonadotropes.     

控制性超排卵长、短方案在IVF-ET中的疗效比较

目的:比较促性腺激素释放激素激动剂(GnRHa)长、短方案控制性超排卵在体外受精-胚胎移植(IVF-ET)中的疗效。方法:将2001年7月-2002年4月因双侧输卵管梗阻IVF-ET的患者100人随机分为长方案组(50人)和短方案组(50人)进行超排卵。长方案组从使用促性腺激素(Gn)治疗前1月经周期黄体期(月经21天)使用GnRHa 0.3mg/d,至垂体完全降调节后加用Gn;短方案组从月经周期第2天开始用GnRHa0.1mg/d,同时加用Gn。当患者有3个以上卵泡直径>18mm时肌肉注射人绒毛膜促性腺激素(HCG),36小时后取卵行IVF,取卵48小时后行ET。结果:两组患者平均获卵数、受精率、卵裂率、优质胚胎率、移植胚胎数、临床妊娠率、胚胎种植率及流产率差异无显著性。而两者的Gn使用量有差别,短方案组少于长方案组,两组差异有显著性。两组用Gn第7天雌激素水平不同,短方案组明显高于长方案组,两者差异有显著性。结论:GnRHa长、短方案在IVF-ET中控制性超排卵效果相同,但所需Gn数量不同。     

GnRH analogues as an adjuvant therapy for ovarian cancer patients.

OBJECTIVES: Lowering gonadotropin levels with gonadotropin-releasing hormone (GnRH) analogues in patients with ovarian cancer remains open to debate. The aim of this study was to assess the results of treatment in stage III and stage IV ovarian cancer patients who had surgery supplemented with chemotherapy, radiotherapy, and GnRH analogues. Gonadotropin levels were monitored during treatment. METHODS: The study group comprised 69 patients aged 27-70 years, stratified according to the type of treatment. The overall disease-free, 5-year survival rates and the frequency of remissions were analyzed. Hormonal tests [follicle-stimulating hormone (FSH) and luteinizing hormone (LH)] were performed in 58 patients. Associations were checked between gonadotropin levels, clinical findings, and survival. The results were statistically compared. RESULTS: Statistically significant differences were noted when chemotherapy was supplemented with GnRH analogues and/or radiotherapy. Administration of GnRH analogues resulted in significantly lower levels of LH than of FSH. Levels of FSH were significantly lower in patients surviving at least 5 years or in complete remission at the time of this study. CONCLUSIONS: Combined therapy can produce favorable results in late-stage ovarian cancer, and GnRH analogues have an important role in treatment strategy.     

HEPT类HIV-1逆转录酶抑制剂的研究进展

逆转录酶是设计抗艾滋病药物研究的选择性靶酶,从作用机制、构效关系等方面综述HEPT及其类似物作为HIV-1逆转录酶抑制剂的研究进展.     

苯丙素苷及其类似物的合成研究

利用葡萄糖6位羟基活性较高的特性, 2-(取代)苯乙基-β-D-吡喃葡萄糖苷在低温条件下直接与(取代)肉桂酰氯反应,区域选择性地生成6位酰化的葡萄糖苷,利用此方法很方便的得到了13个苯丙素苷类似物,利用1H NMR 和13C NMR方法确证了他们的结构.     

Tissue Inhibitor of Metalloproteinase-1 Concentrations are Attenuated in Peritoneal Fluid and Sera of Women with Endometriosis and Restored in Sera by Gonadotropin-Releasing Hormone Agonist Therapy

Objective: To establish tissue inhibitor of metalloproteinase-1 (TIMP-1) concentrations in peritoneal fluid (PF) and sera of women with endometriosis and compare them to disease-free controls.

Design: Prospective randomized study.

Setting: Academic medical center.

Patient(s): Women with laparoscopically documented endometriosis and disease-free women of reproductive age.

Intervention(s): Peritoneal fluid and sera were collected, and some women received gonadotropin-releasing hormone agonist (GnRH-a) therapy for endometriosis.

Main Outcome Measure(s): Peritoneal fluid and sera TIMP-1 concentrations were measured with a specific RIA.

Result(s): The TIMP-1 concentrations were significantly lower in PF and sera of women with endometriosis compared with disease-free women. The GnRH-a therapy restored serum TIMP-1 concentrations.

Conclusion(s): Aberrant expression and localization of TIMP-1 may derange the proteolytic milieu of the peritoneal cavity and contribute to the etiology and underlying physiologic sequelae associated with endometriosis. Measurement of TIMP-1 in serum may aid in diagnosing endometriosis and assist with monitoring treatment efficacy in women with this disease.     

629Ac的乏氧细胞毒性

目的研究丝裂霉素C（MMC）衍生物629Ac（5-吖丙啶-3-羟甲基乙酸酯基-1-甲基吲哚-4，7-二酮）的乏氧细胞毒性，为629Ac作为新型辐射增敏剂的应用提供实验和理论依据。方法在有氧和乏氧条件下用MTT法研究MMC和629Ac的IC50（半数抑制浓度）及C1.6（增敏比达1．6的化合物浓度）。结果乏氧条件下629Ac对HepG2细胞的IC50比有氧条件下低；乏氧和有氧条件下，629Ac的IC50比MMC的IC50都小；对于HepG2细胞，MMC具有乏氧选择性辐射增敏作用，其C1.6比629Ac大，且629Ac在有氧条件下也有辐射增敏效应。结论初步研究结果表明，对于HepG2细胞629Ac具有乏氧细胞毒性和辐射增敏效应，并且这些效应都强于MMC。