安定身体依赖性小鼠肝微粒体酶水平和血浆安定浓度的研究

用掺食法递增安定剂量56 d致小白鼠身体依赖性,肝微粒体蛋白及细胞色素P_(450)含量均显著增加,高于进食安定7 d组,分别为313.0±s 30.56及261.17±s 23.04 mg·g~(-1)肝,P<0.05及3.96±s 0.07和2.60±s 0.52 nmol·mg~1蛋白,P<0.01。戒断后血浆安定浓度随戒断时间延长逐渐降低,而去甲基安定浓度急剧下降,于戒断后24 h达最低水平,以后逐渐回升。而进食安定7 d组的安定及去甲基安定浓度均逐渐下降,二者间无显著性差异。     

安定身体依赖性小鼠脑内单胺类递质的研究

本研究以掺食法递增安定剂量，喂食５６ｄ，形成身体依赖性模型，观察对小鼠自主运动的影响。戒断后小鼠自主活动增加，２４ｈ时戒断组自主流动显著高于对照组（Ｐ＜０．０１），并测定戒断后小鼠脑内单胺类递质水平，去早肾上腺素（ＮＥ）变化不明显；多巴胺（ＤＡ）在戒断后２４ｈ达２．３５ｕｇ·ｇ－１±ｓ０．４０ｕｇ·ｇ－１脑组织，明显高于喂食安定７ｄ组（１．９３ｕｇ·ｇ－１±ｓ０．２５ｕｇ·ｇ－１）（Ｐ＜０．０５）．５－羟色胺（５—ＨＴ）下降．至２４ｈ时达最低点，而其代谢物５－羟吲哚乙酸（５－ＨＩＡＡ）则升高，与５－ＨＴ变化呈负相关（ｒ＝－０７８８０）     

清风胶囊对吗啡依赖大鼠戒断后焦虑行为的影响

目的:评价清风胶囊对吗啡依赖大鼠戒断后焦虑行为的影响作用。方法:采用剂量递增法给大鼠腹腔注射(ip)盐酸吗啡,按吸毒成瘾-戒断-再成瘾-再戒断程序建立吗啡依赖大鼠模型,利用高架十字迷宫实验评价大鼠的焦虑水平。结果:经纳洛酮催促戒断后,各造模组大鼠进入开放臂次数百分比(OE%)和在开放臂停留时间百分比(OT%)较对照组显著降低(P<0.05,P<0.01),表明模型大鼠呈现明显的焦虑症状。给予药物治疗后,地西泮组(1mg·kg-1)、清风胶囊高剂量组(2g·kg-1)OE%和OT%、清风胶囊中剂量组(1g·kg-1)OE%、清风胶囊低剂量组(0.5g·kg-1)OT%较吗啡模型组显著升高(P<0.05,P<0.01),各组大鼠总进臂次数(OE+CE)和总进臂时间(OT+CT)差异均无显著性(P(0.05),表明清风胶囊和地西泮能显著增加大鼠进入开放臂次数的百分比和在开放臂停留时间的百分比,而对总的运动能力无明显影响。结论:清风胶囊对吗啡依赖大鼠戒断后焦虑症状有明显的治疗效果。     

酒精依赖大鼠戒断行为与血浆ACTH、皮质醇含量变化的观察

目的·· :研究慢性酒精刺激和戒断大鼠血浆促肾上腺皮质激素(ACTH)、皮质醇与其相关行为变化的关系 ,同时观察纳洛酮翻转作用。方法·· :给大鼠自由饮酒28d ,观察对照组、饮酒组及纳洛酮治疗组的戒断症状、游泳时间 ;利用放射免疫分析法检测血浆中ACTH、皮质醇水平。结果·· :饮酒组戒断2 -48h戒断症状评分均明显比对照组高,以戒断6h评分最高(16.5±s3.12,P<0.01),其游泳时间在戒断6h为22.8min±s4.2min ,与对照组比显著延长(P<0.01) ;饮酒28d及戒断后血浆皮质醇水平渐升高,在戒断6h达最高(17.03ng·ml-1±s3.9ng·ml-1) ,至72h时降至正常水平 ;而血浆ACTH水平在饮酒28d及戒断后4h、24h显著降低 ,48h、72h逐渐恢复正常水平。纳洛酮治疗组与饮酒组比 ,戒断症状评分明显降低 ,游泳时间显著缩短 ,血浆皮质醇水平亦明显降低 ;但ACTH水平与饮酒组比较无显著性差异。结论·· :慢性酒精刺激及戒断导致垂体 -肾上腺轴功能紊乱 ,纳洛酮能阻止皮质醇的升高 ,减轻酒精戒断症状。     

海洛因依赖者自然戒断后免疫学动态变化

目的 :研究海洛因依赖者自然戒断后 3个月内不同时点的免疫系统及相关激素水平的变化。方法 :2 5例海洛因依赖者在戒断后 4 8h、30d、6 0d、90d测查IL - 1β、IL - 6和sIL - 2R ,IgA、IgG和IgM ,补体C3、C4以及COR和PRL水平的变化 ,并与 15例正常受试者进行比较。结果 :与正常对照组比较 ,海洛因依赖者的IL - 1β在自然戒断后 4 8h较低 ,此后各时点与正常对照组比较无显著性差异 ;IL - 6在自然戒断后各时点均保持在较低水平 ;sIL - 2R则在自然戒断后各时点均保持在较高水平 ;IgA ,IgM在自然戒断后各时点均保持在较低水平 ,补体C3、C4在自然戒断后 4 8h检测值较低 ,90d恢复至正常 ;COR在自然戒断后 6 0d内各时点检测值均较高 ,PRL在戒断 4 8h内检测值较低 ,COR和PRL在戒断 90d后恢复至正常水平。结论 :海洛因依赖者免疫系统及内分泌系统会发生某些改变 ,自然戒断后 ,有些改变会很快恢复正常 ,但有些则会持续超过 3个月。     

大鼠吗啡依赖戒断后焦虑模型的建立和评价

目的:利用高架十字迷宫建立大鼠吗啡戒断后焦虑模型。方法:342只大鼠按给药总时间的不同,随机分为7、10、14d3大组。每大组各114只,按戒断时间的不同再分设戒断0、24、48、72、96、120、144h、丁螺环酮治疗、生理盐水对照共9小组。采用剂量递增法给药,建立吗啡依赖模型后自然戒断,用高架十字迷宫观察各组大鼠焦虑行为。结果:(1)7d大组,戒断后48h表现出焦虑症状,与生理盐水组比较,其OE、OT、OE%、OT%4项指标均下降(P<0.05)。(2)10d大组,与生理盐水组比较,戒断后48、72、96h均表现出焦虑症状(P<0.05),其中又以72h组最为显著,OE、OT、OE%均明显下降(P<0.01);丁螺环酮治疗组与戒断72h组比较,其OE、OT、OT%均增高(P<0.05),OE%显著增高(P<0.01)。(3)14d给药组,与10d给药组相类似,典型的焦虑症状也出现在戒断后72h,与生理盐水组比较,OE、OT、OT%均明显降低(P<0.01),OE%降低(P<0.05);丁螺环酮组与戒断72h组比较,OE%、OT、OT%均明显增高(P<0.01),OE增高(P<0.05)。结论:吗啡持续给药7、10、14d大鼠通过自然戒断均能成功建立吗啡戒断后焦虑模型,但以10d、戒断72h为最佳。该模型可较为客观和准确地反映吗啡依赖戒断后焦虑行为。     

河豚毒素对大鼠和小鼠纳洛酮催促吗啡戒断症状的影响

通过建立吗啡 (Mor)依赖大鼠及小鼠模型 ,观察河豚毒素 (TTX ,大鼠 0 .0 0 3～ 0 .1μg·kg- 1·d- 1,im ,5d ;小鼠 0 .0 2～ 0 .2 μg·kg- 1·d- 1,ip ,2d)对纳洛酮 (Nal)催促戒断症状的预防及治疗作用 .结果表明TTX抑制戒断后大鼠体重丢失 ;明显抑制Mor依赖小鼠Nal催促后的跳台反应 ,并促进催促后小鼠体重的恢复 .证实TTX可显著抑制Mor依赖大鼠和小鼠Nal激发的戒断反应 ,其效果与可乐定相近 .在防治戒断症状的有效剂量范围内 ,TTX不影响麻醉大鼠的血压 ,呼吸和心率 ,也不影响尼古丁诱发的神经反射活动 ,对痛觉反应和中枢神经系统无明显抑制作用 .     

益安口服液用于海洛因依赖者脱毒Ⅳ期临床评价

目的·· :评价益安口服液治疗海洛因依赖的戒断症状及稽延性戒断症状的效果及不良反应。方法··:固定疗程、固定剂量的多中心Ⅳ期临床开放实验。海洛因中度依赖者单纯使用益安口服液 ;重度依赖者 ,前3d与美沙酮联合用药。疗程为10d。稽延性戒断症状的治疗于脱毒后d10开始 ,疗程30d ;稽延性戒断症状于用药后每5d测评一次。结果··:单独使用益安口服液组 (495例 )和与美沙酮联合组 (75例 )用药后每日戒断症状总分与各自用药前比较 ,差异有显著性(P<0.01) ;稽延性戒断症状治疗组 (109例 )每次测评稽延性症状总分与用药前相比明显下降 ,差异有显著性 (P<0.01)。益安口服液的不良反应主要有口干、腹泻、食欲不振、恶心等胃肠道反应 ,一般表现较轻 ,药物减量即可缓解。结论·· :益安口服液能有效地控制海洛因依赖者的戒断症状 ;治疗稽延性戒断症状效果肯定 ;不良反应小 ,是一安全的戒毒中药制剂     

吗啡依赖大鼠戒断期额叶联络皮层脑电活动的分析

目的:探察吗啡依赖大鼠戒断期额叶联络皮层脑电活动的特征性改变。方法:将20只SD大鼠随机分为生理盐水对照组和吗啡模型组(n=10),对照组皮下注射生理盐水,模型组采用剂量递增法皮下注射吗啡,连续7 d,建立吗啡依赖大鼠条件性位置偏爱(conditioned place preference,CPP)模型。比较各组大鼠戒断期CPP测试的变化及戒断症状的评分情况;记录戒断期大鼠额叶联络皮层的脑电活动。结果:与对照组相比,模型组大鼠戒断d3、d5在白箱内停留时间明显延长(P<0.01);戒断症状评分在戒断d1-d3明显增加(P<0.01)。与对照组相比,模型组大鼠戒断d3脑电活动出现α波及β波明显减少,δ波显著增多(P<0.01),θ波变化无显著性差异。结论:吗啡依赖大鼠急性戒断期额叶联络皮层脑电活动存在特征性改变。     

粉防己碱对大鼠吗啡戒断反应的影响

目的:研究钙拮抗剂粉防己碱 (Tet)对大鼠吗啡戒断反应的影响。方法··:以剂量递增法形成吗啡依赖模型 ,用纳洛酮催促戒断 ,戒断症状按柳田知司评分法给予评分。结果··:吗啡阳性组戒断症状分值为26.5±s7.1;Tet(30mg·kg-1) +吗啡组和Tet(60mg·kg-1) +吗啡组的戒断症状分值分别为 :11.7±s4.6、6.6±s4.3 ,与吗啡阳性组相比有极显著性差异 (P<0.001)。结论··:Tet能抑制吗啡大鼠依赖的戒断症状。     

苯巴比妥致大鼠身体依赖性实验

本文采用苯巴比妥掺食法，连续给药８０ｄ，造成大鼠身体依赖性模型。自然戒断后第１４ｈ，开始出现戒断症状，并逐渐加重，第１６ｈ出现震颤、抽搐等症状，第２４ｈ出现阵发自发性惊厥，部分大鼠因惊厥而死亡。第６２ｈ症状完全自然消退。与苯巴比妥等药效剂量的安定可以部分抑制戒断症状。用荧光法对大鼠脑内的单胺类递质的测定表明：５—ＨＴ、５—ＨＩＡＡ，ＮＡ和ＤＡ的含量在依赖状态或是戒断后第７２ｈ与对照组比较，无明显的差异。用放射受体法测定苯巴比妥依赖及戒断状态大鼠脑内ＧＡＢＡ的含量，结果表明：二者ＧＡＢＡ值明显地低于空白对照组，安定替代组大鼠脑内ＧＡＢＡ含量亦显著地低于对照组。     

Neuropsychiatric aspects of sedative drug withdrawal

The withdrawal syndromes after discontinuance of alcohol, barbiturates, benzodiazepines and other sedative drugs, such as chloral and paraldehyde, are all similar. The severity of a withdrawal reaction is largely determined by the daily dose, the duration of administration and the rate of fall of the drug levels after withdrawal, as well as the propensity of the individual patient. The time course of a withdrawal reaction is determined by the drug's clearance. Alcohol has a half-life of a few hours; withdrawal symptoms may develop within 6–8 hours of abstinence and convulsions in 12–48 hours. After discontinuance of short- or medium-acting barbiturates (half-life 8–40 hours) symptoms may develop in 1–3 days, followed by convulsions and delirium after 3–8 days. Symptoms and seizures may develop in the 1–10 days after withdrawal of benezodiazepines. In patients with no prior history of epilepsy the types of seizures most commonly induced by drug withdrawal are generalized convulsions, but partial seizures are not uncommon if there is a focal cerebral lesion, or a previous history of partial seizures. Paroxysmal activity and photosensitivity may occur after barbiturate withdrawal in non-epileptics, more commonly in severe withdrawal reactions. Similar EEG changes may be seen after alcohol and benzodiazepine withdrawal, but photosensitivity does not appear to have been shown to be a feature of the benzodiazepine withdrawal syndrome.     

Lack of tolerance or withdrawal effects in mice after chronic administration of the non-sedating anxiolytic, CGS 9896

CGS 9896, a non-sedating anxiolytic, was compared to diazepam with respect to the development of tolerance and withdrawal. Both compounds were administered daily to mice at various doses (3, 10 or 30 mg/kg) for periods of up to 4 weeks. Measures of sedation/muscle relaxation, motor activity and anticonvulsant effects were then assessed. When administered acutely, CGS 9896 increased motor activity, had no effect on traction reflex, and elevated the threshold for PTZ-induced convulsions. After chronic administration of CGS 9896, no changes in these parameters were observed compared to the effects seen after acute treatment. Acute administration of diazepam reduced motor activity, impaired traction reflex and increased PTZ-induced convulsion threshold. Tolerance developed to the effects of diazepam in all three measures. Following a four week dosing period with 30 mg/kg of either CGS 9896 or diazepam, the drugs were withdrawn and similar behavioral measures obtained at various withdrawal intervals up to 15 days. In separate groups of mice, precipitated withdrawal was also assessed by the administration of the benzodiazepine agonist, CGS 8216. No effects were observed after any period of withdrawal from CGS 9896. By contrast, withdrawal from diazepam resulted in significant alterations of motor activity and convulsion threshold. These results indicate that CGS 9896 is likely to be free of undesirable tolerance and withdrawal effects typically associated with the benzodiazepines.     

海洛因和吗啡对猴的致依赖性比较

本文用吗啡依赖猴作对比,对恒河猴海洛因依赖形成的时间、累计剂量、催促实验戒断反应的量 -效、时 -效变化及自然戒断反应出现的时 -效关系等进行了研究。结果表明 :海洛因sc恒河猴,起始剂量为2.5mg·kg-1 ,tid ,每2d递增1.25mg·kg-1,日剂量达11.25mg·kg-1 后,改为每日递增1.25mg·kg-1,日剂量达到20mg·kg-1 时,维持该剂量到用药时间为3mon。给药d5,当海洛因累计剂量为17.5mg·kg-1 时,催促实验中,猴出现明显的戒断症状,以后随给药剂量的增加,戒断反应呈显著的量 -效、时 -效变化,反应强度在给药头10d内增加最快,以后呈缓慢上升的趋势。注射满3mon,突然停药,可出现明显的戒断症状,其时 -效关系与吗啡组基本一致。与吗啡组相比,在依赖形成初期,海洛因具有形成依赖时间短,用药量少,戒断反应程度严重,戒断症状稍有不同,有兴奋表现等特点。海洛因组Emax=100分,ED50 =20.9mg·kg-1;吗啡组Emax=104.2分,ED50 =80.7mg·kg-1,二者的等效剂量比为1∶3.9。自然戒断实验中,二组均达最大反应强度,且戒断反应程度基本相近。     

Chronic diazepam treatment: Effect of dose on development of tolerance and incidence of withdrawal in an animal test of anxiety

The effect of the treatment dose of diazepam was assessed on the rate of development of tolerance to diazepam's effects on rat behaviour in the elevated plus-maze test of anxiety. Tolerance developed more rapidly when treatment was with the higher dose: after 14 days when rats were given 2·5 mg/kg/day, but not until 21 days when they were given 1 mg/kg/day. When rats were tested undrugged 36 h after the last of 14 daily doses of diazepam (2·5 mg/kg) they showed behavioural changes indicating increased anxiety. Rats tested at this time with a lower dose of diazepam (1 mg/kg) also showed changes indicating increased anxiety compared with the control scores. This indicates that a more gradual tapering of doses would be necessary to avoid withdrawal responses.     

Interoceptive stimuli produced by cocaine are blocked during diazepam withdrawal

Rats were trained to select one lever after an intraperitoneal (ip) injection of cocaine (10 mg/kg), and an alternate lever after saline injection under a FR10 schedule of food reinforcement. Following chronic administration of cocaine (20 mg/kg/8hr), but not diazepam (80 mg/kg/8hr) for 7 days, the dose-effect curve for the generalization of cocaine shifted twofold to the right. Subsequently, in the rats receiving chronic diazepam, RO 15-1788, a drug known to precipitate diazepam withdrawal, failed to substitute for cocaine: however, the discriminability of cocaine (5 mg/kg) was reduced from 83% to 13% selection of cocaine-appropriate lever after 72 hr following the last diazepam, injection. These data suggest that chronic administration of cocaine, but not diazepam, produced tolerance to the discriminative stimulus properties of cocaine, and following chronic diazepam administration and withdrawal, the stimulus properties of cocaine are antagonized.     

Genetic differences in the development of physical dependence upon diazepam in Lewis and Fischer 344 inbred rat strains.

The purpose of the present study was to investigate physical dependence upon diazepam systematically in two inbred strains of rats, Lewis (LEW) and Fischer 344 (F344). Rats were chronically fed food containing diazepam on an escalating drug dosage schedule, from 1 and 2 to 12 mg/g of food, over a period of 30 days. During treatment, the growth curve in LEW and F344 rats was suppressed compared with the respective controls. Motor incoordination was evaluated by a rotarod performance test. The ranking of the motor incoordination during the final concentration of diazepam was as follows: F344 greater than LEW. After substitution of normal food for the diazepam-admixed food, various signs of diazepam withdrawal occurred 16-120 h later. These signs included vocalization, irritability, muscle rigidity, ear-twitching, Straub's tail, piloerection, fascicular twitch, tremor, convulsion, and death. The incidences of vocalization, ear-twitching, piloerection, and tremor in F344 were significantly higher than those in LEW rats. Furthermore, two of six F344 rats showed spontaneous convulsions and one rat died of convulsions. Overall withdrawal scores were significantly greater in F344 (16.0) than in LEW (6.3) rats. These results suggest that diazepam withdrawal severity is strongly influenced by genetic factors, and F344 rats are highly susceptible to dependence upon benzodiazepines.     

Reduction of diazepam serum half life and reversal of coma by activated charcoal in a patient with severe liver disease

We report a case of prolonged coma (7 days) which arose as a complication of the treatment of alcohol withdrawal seizures and delirium with intravenous phenobarbital and diazepam. In an attempt to enhance the elimination of diazepam and its active metabolites, as well as phenobarbital, 40 grams activated charcoal was given every 4 hours (6 doses). Coma was completely reversed within 12 hours; serum half life (t1/2) of diazepam was reduced from 195 to 18 hours during charcoal administration. We postulate that higher free (unbound) diazepam concentrations secondary to hypoalbuminemia, occurring as a result of liver disease, may have increased the depth of our patient's coma, but paradoxically, by making more drug available for diffusion across the gastrointestinal membrane barrier, may have enhanced the ability of activated charcoal to adsorb diazepam and, therefore, decrease its t1/2.     

Diazepam prevents progression of kindled alcohol withdrawal behaviour

The purpose of the present experiment was to study the kindling hypothesis of alcohol withdrawal stating that exposure to repeated episodes of alcohol withdrawal results in an increased severity of subsequent withdrawal reactions. Two groups of male Wistar rats were subjected to 13 episodes of 2 days severe alcohol intoxication and 5 days alcohol withdrawal. Animals in the control group (n=80) developed clinical withdrawal signs following each intoxication episode. In the diazepam group (n=80) the withdrawal reactions during episodes 1–9 were blocked by intraperitoneal diazepam administration (0–30 mg/kg) 8, 11 and 15 h into withdrawal. During episode 10–13 diazepam treatment was terminated and convulsive withdrawal behaviour was observed 9–15 h after last alcohol dose. The probability of seizure activity during these four withdrawal episodes was calculated as 0.239 and 0.066 in the control and the diazepam groups, respectively. Based on Monte Carlo simulation techniques, this difference was found to be statistically significant (P<0.05). No differences in the non-convulsive alcohol withdrawal symptoms tremor, hyperactivity and rigidity were detected between controls and diazepam animals after diazepam treatment. It was concluded that the increased convulsive behaviour in the control group was caused by cumulated kindling-like cerebral alterations during the previous repeated alcohol withdrawal phases.