吗啡依赖和戒断对大鼠杏仁核神经甾体和氨基酸递质水平的影响

目的研究吗啡依赖和戒断时大鼠杏仁核中神经甾体和氨基酸递质水平的变化。方法连续7天给予大鼠盐酸吗啡建立吗啡依赖模型。使用纳洛酮(2mg/kg)催促戒断,观察戒断症状并进行评分。将大鼠断头处死后,剥离大脑并分离出杏仁核,用液-液萃取和固相萃取法提取游离型和结合型神经甾体。神经甾体(包括脱氢表雄酮、孕烯醇酮、别孕烯醇酮、脱氢表雄酮硫酸酯和孕烯醇酮硫酸酯)的含量使用高效液相色谱-质谱法测定。甘氨酸、谷氨酸和γ-氨基丁酸的含量采用柱前OPA衍生-电化学检测-高效液相色谱法测定。结果与盐水对照组相比,吗啡依赖大鼠杏仁核中的脱氢表雄酮水平降低33 %(P<0·01)。与戒断对照组比较,吗啡戒断大鼠杏仁核中的孕烯醇酮和别孕烯醇酮水平分别升高45 %和42 %(P<0·05) ,γ-氨基丁酸水平降低18 %(P<0·01)。与吗啡依赖组比较,吗啡戒断组大鼠杏仁核中的孕烯醇酮和孕烯醇酮硫酸酯水平分别升高60 %和40 %(P<0·05) ,甘氨酸水平降低14 %(P<0·05)。结论吗啡依赖大鼠杏仁核中的脱氢表雄酮可能参与吗啡依赖的形成而与吗啡戒断症状的表达无关。其他神经甾体(包括孕烯醇酮、别孕烯醇酮和孕烯醇酮硫酸酯)则可能参与吗啡的戒断而与依赖的形成无关。纳洛酮催促戒断时,大鼠杏仁核中抑制性氨基酸递质的合成和释放受到抑制。表明大鼠杏仁核中的各种神经甾体和氨基酸递质在吗啡依赖和戒断时发生了不同的变化。     

小鼠吗啡依赖纳洛酮催促戒断跳跃反应模型的建立

目的建立稳定的小鼠吗啡依赖纳洛酮催促戒断跳跃反应模型。方法小鼠连续皮下注射吗啡,以纳洛酮催促戒断跳跃反应为指标,调整吗啡给予天数(5,6,7,10d)、吗啡累积剂量(360,560,640,945,1100,1105,1200mg/kg)、每日给予吗啡的频数[一天二次(bid),一天三次(tid)]、纳洛酮催促紧前给予吗啡与否、以及纳洛酮剂量(10,20mg/kg),建立四个造模方案包括八个子方案。结果方案A、B2、C2吗啡组小鼠跳跃反应率未达100%;方案B1、C1、D2、D3、D4吗啡组小鼠跳跃次数变异系数较大。方案D1采用小鼠连续皮下注射倍增剂量的吗啡,tid×6d,每日每次剂量分别为5,10,20,40,80,160mg/kg;第7天皮下注射吗啡160mg/kg,3h后腹腔注射纳洛酮10mg/kg,吗啡组小鼠可产生显著的跳跃反应,与对照组比较差异有显著性(P<0.01),且变异系数小(CV为0.22),该方案吗啡依赖小鼠跳跃反应次数适度,离散度小。结论选用方案D1可建立稳定的小鼠戒断跳跃反应模型。     

Effects of haloperidol and amisulpride on motor and cognitive skill learning in healthy volunteers

Buprenorphine is a mu opioid partial agonist currently used as an analgesic, and being developed for the treatment of opioid dependence. The purpose of this study was to determine the abuse liability of parenteral buprenorphine in volunteers maintained on daily sublingual (SL) buprenorphine (8 mg). In a residential laboratory, eight volunteers underwent pharmacologic challenges two times per week. Medication challenges were 16 h after the daily dose of buprenorphine, and consisted of double-blind IM injections of buprenorphine (4, 8, 16 mg), the prototypic mu opioid agonist hydromorphone (9 and 18 mg), or saline. Assessments consisted of physiologic monitoring, subjects’ self-reports, and a trained observer’s ratings of drug effects, and were collected for 0.5 h before and 2.0 h following injection. Supplemental doses of IM buprenorphine produced opioid agonist-like effects, indicating some abuse potential of parenteral buprenorphine in buprenorphine-maintained patients. There was incomplete cross-tolerance to the effects of hydromorphone, suggesting that higher maintenance doses of buprenorphine may be needed to maximize clinical efficacy. However, there was a lack of graded dose-effects for hydromorphone, suggesting that buprenorphine’s combination of partial agonist effects and high affinity for opioid receptors may limit the magnitude of effects of supplemental full agonists. Finally, participants tolerated cumulative doses of maintenance buprenorphine plus challenge buprenorphine without adverse effects, suggesting higher doses of buprenorphine can be safely administered to opioid dependent patients. Received: 22 February 1996/Final version: 23 August 1996     

Stimulus functions of drugs and the assessment of abuse liability

The development of a unifying framework for conceptualizing the commonalities in various forms of substance abuse must encompass the data base focused upon the stimulus functions of drugs. In the first instance, for example, the research on drug self-administration has provided convincing evidence of a remarkable concordance between laboratory animals and human substance abusers in the reinforcing stimulus functions of a range of chemical agents. The recognition of these cross-species and cross-drug generalities has radically changed conceptualizations of substance abuse from a reactive to a more active process and has encouraged the kind of functional analysis of drug-seeking and drug-taking that has proven productive and useful in the study of other behavioral interactions. In this regard as well, recent refinements in the analysis of the discriminative stimulus functions of drugs have provided a more comprehensive basis for characterizing a chemical agent's spectrum of action and evaluating its abuse liability. While the correlation between the discriminative stimulus functions and the reinforcing stimulus functions is remarkably high for some drug classes, there are notable exceptions. Finally, the assessment of abuse liability requires an analysis of the eliciting stimulus functions of drugs as reflected by the physiological and behavioral changes, both acute and chronic, that follow drug administration. The methods used to evaluate both physiological dependence and behavioral toxicity in relationship to sensory and motor effects for a range of abused drugs have depended heavily upon an assessment of the eliciting stimulus functions of such compounds.     

山莨菪碱治疗麻醉剂依赖性

阿片成瘾者２５０例（男性２２２例，女性２８例，年龄３０±ｓ５ａ）应用山莨菪碱０．５－２ｍｇ／（ｋｇ·ｄ），分２－３次加入１０％葡萄糖２５０ｍＬ或５％葡萄糖生理盐水５００ｍＬ静脉滴注；东莨菪碱０．０２－０．０３ｍｇ／ｋｇ加入１０％葡萄糖２５０ｍＬ静脉滴注１次，必要时对重患者追加１次，疗程５－７ｄ。结果戒断症状均有改善（Ｐ＜０．０１），２７例需加用羟丁酸钠。不良反应轻，可作为阿片瘾者的脱瘾药物。＊Ｐ＜０．０１。碱确能解除阿片药物戒断症状。其对阿片戒断症状缓解时间在治疗４－５ｄ后，强烈觅药渴求也随之逐渐消失。１５０例（６０％）要求进食，１７５例（７０％）仍需借助安眠药睡眠。另６５例（２６％）戒断症状阵发性发作，每次持续０．５－１ｈ，症状轻重不一，轻者流泪、全身弥漫性疼痛，重者焦躁不安、心中猫抓虫咬样难受，甚至想自残，可配合艾司唑仑３－４ｍｇ／ｄ，ｐｏ或氯硝西泮６－１０ｍｇ／ｄ，ｐｏ；也可用氯硝西泮１－２ｍｇ／次，ｉｍ，每日２－３次；针刺胃俞、脾俞、中脘、足三里、印堂、太阳、百会、内关、合谷、命门、夹脊和肾俞穴位，根据临床症状任选其中３－５个穴位进行治疗或心理治疗能快速减轻患者戒断症状。治程中２７例（１０．８％）重?     

Acute subcortical stroke and early serotonergic modification: a IDAP study

The intensity dependence of the auditory-evoked potentials (IDAP) is inversely related to serotonergic tone. Depression is frequently observed after stroke, associated with cognitive impairment and increased mortality. Aim of this study was to investigate the serotonergic tone in acute stroke patients by IDAP. Consecutive patients with an acute stroke admitted in our stroke unit were evaluated using clinical and instrumental examinations and compared with healthy controls. The IDAP was calculated as the linear amplitude/stimulus intensity function (ASF) slope, by measuring the peak-to-peak amplitude of Nl-P2 on four blocks of different stimulus intensities. Twenty patients were enrolled; 11 had a right brain infarction; nine had depressive symptoms (DS). The ASF slope of the auditory-evoked potentials was markedly increased in stroke patients compared with controls ( P  = 0.021). Stroke patients with DS had a significant steeper ASF slope than controls ( P  = 0.017). There was no statistical difference in ASF slope between stroke patients without DS and controls. Post-stroke depression pathophysiology is still debated. Our study suggests that in acute stroke patients with DS, there is a direct involvement of the serotonergic system, regardless the degree of disability and the site of the lesion.