青藤碱对吗啡依赖小鼠位置偏爱效应的影响

目的 :利用条件性位置偏爱实验研究中药成分青藤碱对小鼠吗啡奖赏效应的影响。方法 :实验采用有倾向性程序。吗啡 (9mg· kg-1,sc,每日 1次 ,5 d)引起小鼠显著的位置偏爱效应。在训练阶段每天 sc吗啡前3 0 min预先给予青藤碱 (1 0 ,3 0和 60 mg· kg-1,ip)可剂量依赖性地抑制吗啡引起的小鼠位置偏爱效应。结果 :提示预先给予青藤碱能消除吗啡产生的条件性位置偏爱。     

左旋四氢巴马汀对可卡因条件性位置偏爱的影响

目的 :探讨不同剂量的左旋四氢巴马汀 (1 THP)对可卡因引起的条件性位置偏爱的影响以及自身是否引起条件性位置偏爱。方法 :采用倾向性实验程序 ,(1)♂SD大鼠ip可卡因 (10mg·kg- 1 )训练 8d ,d9测定大鼠对伴药侧的偏爱效应及测试前 30min注射不同剂量的 1 THP(0 6 2 5 - 5mg·kg- 1 )观察其对该效应的影响 ;(2 )测量注射 1 THP2 4h及 4 8h后的作用效应 ;(3)♂SD大鼠ipl-THP(1 2 5mg·kg- 1 及 5mg·kg- 1 )训练 8d ,d9测定大鼠对伴药侧产生的偏爱效应。结果 :10mg·kg- 1 可卡因可以诱导大鼠对伴药盒产生显著的条件性位置偏爱 ;测试前分别注射 2 5mg·kg- 1 和 5mg kg- 1 的l-THP可不同程度地降低可卡因诱导的条件性位置偏爱效应的表达 ,且 2 5mg·kg- 1 的l-THP 2 4h后效应仍比较显著。两个剂量的l-THP均不能诱导大鼠形成条件性位置偏爱。结论 :l-THP对可卡因的强化效应有抑制作用 ,且自身不引起条件性位置偏爱     

多巴胺D_1受体参与吗啡介导的小鸡条件性位置偏爱的表达

目的 :利用条件性位置偏爱模型探求吗啡对小鸡的奖赏作用及其相关的多巴胺机制。方法 :ip 2mg·kg-1吗啡对小鸡进行 4次条件化训练后进行条件性位置偏爱测试 ,测试前 15min分别ip生理盐水、0 .2 5mg·kg-1多巴胺D1受体拮抗剂SCH2 3390或者等剂量的多巴胺D2 受体拮抗剂雷氯必利 (raclopride) ,观察其干预效果。结果 :吗啡诱导出小鸡的条件性位置偏爱 (P <0 .0 1) ,条件性位置偏爱的表达被SCH2 3390阻断 (P <0 .0 5 ) ,而不受雷氯必利的影响 (P >0 0 5 )。结论 :吗啡的奖赏作用在鸟类中也有体现 ,小鸡可以成为研究药物成瘾的合适的模型。多巴胺D1受体可能参与对吗啡药物渴求的形成。     

奥丹西隆对小鼠吗啡条件性位置偏爱效应的影响

目的 :探讨 5 -HT3 型受体特异性拮抗剂奥丹西隆对吗啡诱导的条件性位置偏爱 (CPP)效应的影响。方法 :建立小鼠吗啡CPP模型 ,观察奥丹西隆对CPP的影响。结果 :吗啡 (5mg·kg-1,sc)可诱导小鼠对伴药箱产生显著的CPP ;测试前 30min注射奥丹西隆 (0 0 1- 1mg·kg-1,sc)不影响小鼠已形成的对吗啡的位置偏爱 ;而训练阶段于每次注射吗啡同时注射奥丹西隆 (0 0 1- 0 1mg·kg-1,ip)可拮抗小鼠对吗啡的CPP效应 ,但较大剂量奥丹西隆 (1mg·kg-1,ip)则不影响其效应 ,而且此剂量单独给药亦表现出自身的CPP潜力。结论 :一定剂量的奥丹西隆可拮抗小鼠对吗啡的偏爱效应的获得 ,但不影响其表达 ,提示该类药物有治疗阿片类依赖的潜力。     

大鼠多巴胺D_1受体介导二氢埃托啡位置偏爱效应(英文)

目的:研究不同的多巴胺(DA)受体拮抗剂对二氢埃托啡(DHE)奖赏效应的影响,方法:采用条件性位置偏爱模型评价DHE的奖赏效应,DA受体拮抗剂采取外周给药或直接到伏隔核内,结果:DHE(0.05、0.5和5.0μg·kg~(-1),sc)产生位置偏爱效应,氟哌啶醇、Sch-23390 sc或直接注射到伏隔核都能抑制DHE(0.5μg·kg~(-1),sc)的偏爱效应;而l-舒必利和螺哌隆在这两种给药途径下都不影响DHE的偏爱效应,结论:伏隔核中D_1受体(而不是D_2受体)在DHE偏爱效应中起关键作用。     

粉防己碱对小鼠吗啡位置偏爱效应的影响(英文)

利用条件性位置偏爱实验研究钙拮抗剂粉防己碱对小鼠吗啡奖赏效应的影响 .实验采用有倾向性程序 .吗啡 ( 5mg· kg-1,sc,每日 1次 ,5d)引起小鼠显著的位置偏爱效应 .在训练阶段每天 sc吗啡前 30 min预先给予粉防己碱 ( 1 0 ,2 0和 40 mg·kg-1,ip)可剂量依赖性地抑制吗啡引起的小鼠位置偏爱效应 .而粉防己碱 ( 1 0 ,2 0和 40 mg· kg-1,ip)只在测试前 30 min给药 1次 ,不影响吗啡已形成的小鼠位置偏爱 .结果说明粉防己碱能有效地抑制吗啡偏爱效应的获得 ,但不影响其表达 .     

氟西汀和帕罗西汀对甲基苯丙胺条件性位置偏爱效应的作用

目的··:探讨5 -羟色胺选择性重摄取抑制剂 (SSRI)氟西汀和帕罗西汀对甲基苯丙胺 (MA)诱导的条件性位置偏爱效应(CPP)的影响。方法·· :采用倾向性实验程序。♂Wistar大鼠腹腔注射MA(0.5mg·kg-1)并训练8d ,d9测定大鼠对伴药盒的偏爱效应及测试前30min注射不同剂量 (2.5 -10.0mg·kg-1)氟西汀和帕罗西汀对该效应的影响。结果··:0.5mg·kg-1 的MA可以诱导大鼠对伴药盒产生显著的条件性位置偏爱 ;测试前注射氟西汀和帕罗西汀均可剂量依赖性地降低MA诱导的条件性位置偏爱效应的表达。结论··:氟西汀和帕罗西汀对MA的强化效应有抑制作用 ,提示该类药物有治疗甲基苯丙胺精神依赖性的潜力     

钩藤碱对大鼠苯丙胺条件性位置偏爱效应的影响

目的:观察钩藤碱对大鼠苯丙胺条件性位置偏爱效应的影响及钩藤碱的奖赏效应或厌恶效应.方法:连续给予苯丙胺(2 mg/kg,sc,每日1次)4 d,引起大鼠产生显著的条件性位置偏爱效应,建立苯丙胺位置偏爱模型.钩藤碱低、中、高剂量(10、20、60 mg/kg) 苯丙胺组在训练阶段第2天sc苯丙胺12 h后分别按剂量ip给予钩藤碱,氯胺酮 苯丙胺组在训练阶段第3天sc苯丙胺之前15 min给予氯胺酮(15 mg/kg,ip),均连续3 d.钩藤碱 生理盐水组连续给予钩藤碱(60 mg/kg,ip,每日1次)4 d.结果:钩藤碱各剂量组和阳性药氯胺酮组大鼠在伴药箱的逗留时间均明显缩短,钩藤碱三剂量组随剂量的增加其作用相应增强.钩藤碱 生理盐水组大鼠不形成条件性位置偏爱.结论:预先给予钩藤碱能在一定程度上消除苯丙胺诱导的条件性位置偏爱效应,而钩藤碱本身未显示精神依赖性潜力.     

孕酮对吗啡精神依赖大鼠海马和纹状体中阿片受体水平的影响

目的观察孕酮对于吗啡所致奖赏效应及海马和纹状体μ受体水平的影响。方法32只SD大鼠随机分为空白对照组、吗啡组、孕酮组和孕酮加吗啡组,并建立吗啡条件性位置偏爱(CPP)模型,采用免疫组化法测定大鼠海马和纹状体中μ受体的水平。结果与空白对照组比较,5 mg.kg-1吗啡可诱导大鼠产生稳定的CPP效应(P<0.01),15 mg.kg-1孕酮本身不产生CPP效应,但能抑制吗啡的CPP效应。与空白对照组比较,吗啡CPP形成时,海马和纹状体中μ受体的数量降低(均为P<0.01)。与吗啡组比较,合用15 mg.kg-1孕酮可使纹状体中μ受体的数量升高(P<0.05),而在海马中未见变化。结论孕酮可以有效抑制吗啡CPP效应,其机制可能与其逆转吗啡诱导的纹状体中μ受体水平的变化有关。     

左旋四氢巴马汀抑制甲基苯丙胺引起的条件性位置偏爱的表达

本文采用大鼠条件性位置偏爱实验方法,通过观察左旋四氢巴马汀（1-THP）对甲基苯丙胺（MA）所引起的条件性位置偏爱效应的影响,评价其对MA奖赏效应的抑制作用。结果表明,1-THP在不影响大鼠活动性的剂量（1,5mg/kg）下,可显著抑制0.5mg/kgMA所产生的条件性位置偏爱效应的表达（P<0.01）。提示1-THP可能在抑制甲基苯丙胺奖赏效应方面发挥作用。     

Estradiol-induced conditioned place preference may require actions at estrogen receptors in the nucleus accumbens.

Intrinsic rewarding effects of estradiol (E(2)) may underlie some of the sex differences that emerge postpuberty for the prevalence of drug use and behavioral responses to drugs, but the effects and mechanisms of E(2) for reward have not been well characterized. Conditioned place preference (CPP), as measured by the time spent on the nonpreferred/drug-associated side of the chamber, was utilized as a functional assay to investigate the effects and mechanisms of E(2) in the nucleus accumbens for reward. To determine whether intracellular estrogen receptors (ERs) are important for E(2)-induced CPP, rats were administered E(2) (10 microg; subcutaneously (s.c.)), which produced CPP in each experiment, and/or ER blockers, such as tamoxifen (Experiment 1), ICI 182,780 (Experiment 2), or antisense oligonucleotides targeted to ERs (Experiment 3). Experiment 1: E(2) significantly increased the time spent on the originally nonpreferred side of the chamber. Coadministration of tamoxifen (10 mg/kg; s.c.) attenuated effects of E(2) to produce a CPP, but tamoxifen alone, increased time spent on the nonpreferred side. Experiment 2: coadministration of ICI 182,780 (10 microg/microl) to the nucleus accumbens attenuated effects of E(2) to enhance CPP and did not produce a CPP when administered alone. Experiment 3: coadministration of s.c. E(2) with ER antisense oligonucleotides to the nucleus accumbens significantly decreased time spent on the nonpreferred side and expression of ERs in the nucleus accumbens compared to scrambled antisense oligonucleotides or saline vehicle administration. Thus, E(2)'s rewarding effects may involve actions at ERs in the nucleus accumbens.     

Uncoupling of 5-HT1A receptors in the brain by estrogens: regional variations in antagonism by ICI 182,780

Previously we have shown that 17beta-estradiol (in vivo and in vitro) rapidly decreases the function of serotonin(1A) (5-HT(1A)) receptors, allowing us to hypothesize that 17beta-estradiol accomplished this via activation of a membrane estrogen receptor. Hippocampus and frontal cortex obtained from ovariectomized rats were incubated with 17beta-estradiol or bovine serum albumin (BSA)-estradiol in the presence or absence of the estrogen receptor (ER) antagonist ICI 182,780. Membranes were prepared to measure R(+)8-OH-DPAT-stimulated [(35)S]GTPgammaS binding (a measure of 5-HT(1A) receptor coupling and function). In both hippocampus and frontal cortex, 17beta-estradiol and BSA-estradiol (50 nM) decreased R(+)8-OH-DPAT-stimulated [(35)S]GTPgammaS binding. ICI 182,780 blocked the effect of both the estrogens in hippocampus, but only the effect of 17beta-estradiol in frontal cortex. Due to the inability of ICI 182,780 to block the effects of BSA-estradiol in frontal cortex, similar experiments were performed using the selective estrogen receptor modulator tamoxifen as the agonist. Tamoxifen (100 nM and 1 microM) decreased R(+)8-OH-DPAT-stimulated [(35)S]GTPgammaS binding. ICI 182,780 (1 microM) blocked the ability of tamoxifen to decrease 5-HT(1A) receptor coupling in the hippocampus, but not in the frontal cortex. Taken together, these data support the existence of a pharmacologically distinct ER in hippocampus vs. frontal cortex that might be responsible for rapid uncoupling of 5-HT(1A) receptors.     

甲基苯丙胺诱导的小鼠条件性位置偏爱及多巴胺D_3受体的调制作用

目的:研究甲基苯丙胺(MA)对小鼠条件性位置偏爱(CPP)形成和复吸的影响,同时探讨多巴胺D3受体在此过程中的作用。方法:采用CPP系统,以多巴胺D3受体基因敲除(D3RKO)小鼠及具有相同遗传背景的野生型(WT)小鼠为对象,腹腔注射(ip)不同剂量(2mg·kg-1、5mg·kg-1、10mg·kg-1)甲基苯丙胺,观察给药前后小鼠CPP形成和复吸的行为改变,采用SPSS13.0统计软件包对实验数据进行单因素方差分析和独立样本t检验,以P<0.05为检验水准。结果:甲基苯丙胺2mg·kg-1不能使WT小鼠产生CPP效应,但能使D3RKO小鼠产生CPP效应,CPP消退后再次给药激发均无复吸效应;甲基苯丙胺5mg·kg-1能使WT和D3RKO小鼠均产生CPP效应,消退后再次给药激发,WT小鼠无复吸效应,而D3RKO小鼠出现复吸效应;甲基苯丙胺10mg·kg-1能使D3RKO小鼠产生CPP效应,无复吸效应,而WT小鼠未产生CPP效应。结论:甲基苯丙胺诱导下,D3RKO小鼠较野生型小鼠更容易形成CPP效应,也更容易发生复吸,提示多巴胺D3受体在甲基苯丙胺成瘾中发挥了一定作用,可能对甲基苯丙胺诱导的依赖和复吸具有抑制作用。     

Pure Antiestrogens and Breast Cancer

Summary

Tamoxifen, which is the most commonly used drug for treatment of breast cancer, has both estrogen agonist and antagonist actions. Pure antiestrogens are devoid of any estrogen agonist effects. ICI182,780 (fulvestrant) (Faslodex) and ICI164,384 are competitive inhibitors of estrogen by binding to the estrogen receptor (ER). Preclinical and clinical studies show that fulvestrant and ICI164,384 are more potent than tamoxifen in inhibiting the growth of breast cancer cells. They are devoid of any estrogen-agonist action on the uterus and vagina but lack the beneficial effects of tamoxifen on the bone and serum lipid profile. Fulvestrant is the first pure antiestrogen to complete phase III clinical trials. Such studies have shown that fulvestrant is at least as good as anastrozole in the treatment of post-menopausal women with advanced breast cancer who had relapsed or progressed on prior endocrine therapy. The drug was well tolerated and only minor side-effects were reported. Its potential role in the adjuvant setting will be determined by its adverse effects on bone mass and serum lipids. EM-800 and EM-652 are the most potent pure antiestrogens and EM-652 has the highest affinity of all antiestrogens to ER. They have no stimulatory effects on the uterus or vagina. It seems reasonable to expect that pure antiestrogens will be good alternatives to tamoxifen and aromatase inhibitors in the treatment of breast cancer.     

Pure antiestrogens and breast cancer

Tamoxifen, which is the most commonly used drug for treatment of breast cancer, has both estrogen agonist and antagonist actions. Pure antiestrogens are devoid of any estrogen agonist effects. ICI 182,780 (fulvestrant) (Faslodex) and ICI 164,384 are competitive inhibitors of estrogen by binding to the estrogen receptor (ER). Preclinical and clinical studies show that fulvestrant and ICI 164,384 are more potent than tamoxifen in inhibiting the growth of breast cancer cells. They are devoid of any estrogen-agonist action on the uterus and vagina but lack the beneficial effects of tamoxifen on the bone and serum lipid profile. Fulvestrant is the first pure antiestrogen to complete phase III clinical trials. Such studies have shown that fulvestrant is at least as good as anastrozole in the treatment of post-menopausal women with advanced breast cancer who had relapsed or progressed on prior endocrine therapy. The drug was well tolerated and only minor side-effects were reported. Its potential role in the adjuvant setting will be determined by its adverse effects on bone mass and serum lipids. EM-800 and EM-652 are the most potent pure antiestrogens and EM-652 has the highest affinity of all antiestrogens to ER. They have no stimulatory effects on the uterus or vagina. It seems reasonable to expect that pure antiestrogens will be good alternatives to tamoxifen and aromatase inhibitors in the treatment of breast cancer.     

Role of the NO/sGC/PKG signaling pathway of hippocampal CA1 in morphine-induced reward memory

Although evidence suggests that the nitric oxide(NO)/soluble guanylyl cyclase(sGC)/cGMP dependent protein kinase(PKG) signaling pathway in the hippocampal CA1 region plays a key role in memory processing,it remains unclear whether this signaling cascade is involved in drug-induced reward memory.In this study,we investigated the role of the NO/sGC/PKG signaling pathway in the CA1 on morphine-induced reward memory using a conditioned place preference(CPP) paradigm.We found that rats receiving an intraperitoneal(ip) injection of 4 mg·kg-1 morphine exhibited CPP,whereas rats treated with only 0.2 mg·kg-1 morphine failed to produce CPP.Intra-CA1 injection of the neuronal NO synthase(nNOS) inhibitor 7-NI,the sGC inhibitor ODQ or the PKG inhibitor Rp-8-Br-PET-cGMPS had no effect on the acquisition of CPP by 4 mg·kg-1 morphine.Intra-CA1 injection of 7-NI blocked the consolidation of CPP induced by 4 mg·kg-1 morphine,and this amnesic effect of 7-NI was mimicked by ODQ and Rp-8-Br-PET-cGMPS.Intra-CA1 injection of the NOS substrate L-arg or the sGC activator YC-1 with an ineffective dose of morphine(2 mg·kg-1,ip) elicited CPP.This response induced by L-arg or YC-1 was reversed by pre-microinjection of Rp-8-Br-PET-cGMPS in the CA1.These results indicated that the activation of the NO/sGC/PKG signaling pathway in the CA1 is necessary for the consolidation of morphine-related memory.     

Testosterone reduces cumulative burying in female Wistar rats with minimal participation of estradiol

Testosterone exerts anxiolytic effects, but the participation of its aromatase metabolic product estradiol is controversial. Therefore, we used the defensive burying paradigm in female Wistar rats to explore testosterone's (1.0 mg/rat, s.c.) interactions with picrotoxin (a noncompetitive γ-aminobutyric acid-A receptor [GABA_A] antagonist; 1.0 mg/kg, i.p.), formestane (an aromatase inhibitor; 3.0 mg/rat, s.c.), and tamoxifen (an estrogen receptor-β antagonist; 1.0 mg/kg, s.c.). Serum levels of testosterone, estradiol, and progesterone were determined in the same rats. Burying latency and locomotion did not significantly change. Systemic testosterone administration enhanced serum testosterone and estradiol levels and reduced defensive burying. This reduction in total burying was blocked by pretreatment with picrotoxin and tamoxifen, but not formestane. We conclude that testosterone produced anxiolytic-like effects in female rats that were mediated by actions at the GABA_A receptor, with participation of the estradiol receptor-β, rather than estradiol aromatization.     

Faslodex(TM) for the treatment of breast cancer

Faslodex(TM) (fulvestrant), also known as ICI 182780, is the first in a new class of selective estrogen receptor down-regulators (SERDs), which target and degrade the estrogen receptor (ER), and has been developed for the treatment of advanced breast cancer. Up to now application of tamoxifen, a partial estrogen antagonist, has been the "gold standard" in breast cancer therapy in postmenopausal women. However, breast tumors become resistant to tamoxifen after a while, leading to progression of the cancer. Also, the risk of the development of endometrial carcinoma is one of the disadvantages in treatment with tamoxifen. Therefore "pure" antiestrogens with high affinity to the estrogen receptor, but without agonistic activity, have been developed in the last few years. Summarizing all data from in vitro and in vivo studies and clinical trials, the antiestrogen Faslodex(TM) (AstraZeneca, Cheshire, U.K.) appears to be a very promising new agent for the treatment of advanced and early breast cancer. (c) 2001 Prous Science. All rights reserved.