一针吗啡会改变你的一生吗?

在现实生活和临床工作中,我们常常可以观察到这样一种现象:酒香可以勾起酒精成瘾者强烈的饮酒欲望和冲动,白花花的粉末状物质或注射针头可以唤起吸毒病人对海洛因急迫的用药想法和渴求。这种对成瘾性物质需求敏感性的增加,实际上就是滥用药物动机的增强,即药物滥用动机敏化(motivation sensitization)。在动物上,则表现为对药物诱导的行为反应性明显增强(如海洛因、吗啡诱导大、小鼠的高活动性),即行为敏化(behavioral sensitization)。行为敏化与药物成瘾的某些特征(如强迫性用药、觅药行为),尤其是,与长时间停药后的复吸行为密切相关,是药物成瘾动物的重要行为特征之一。因此,作为研究药物成瘾神经生物学机制的一种动物模型,行为敏化已日益受到人们的关注。本课题组率先建立了单针吗啡诱导的小鼠行为敏化模型,发现吗啡预处理后,存在3～4 d的孵育阶段,可以促进短暂的药理作用向长时程的行为效应转化。单针吗啡给药所诱导的小鼠外在行为的改变具有持续时间长(至少21 d)、行为反应明显、重复性和稳定性较好的特点。在此模型基础上,进一步探讨单针吗啡诱导小鼠行为敏化的神经生物学机制,研究结果表明单针吗啡诱导小鼠行为敏化的形成涉及到新的基因转录、新的蛋白合成,以及组蛋白乙酰化修饰的改变。单针吗啡诱导行为敏化的形成过程中包括两个期:易损期和稳定期。Hsp70在单针吗啡诱导行为敏化形成过程中的易损期内发挥了至关重要的作用。基于本课题组已取得的实验数据和相关研究资料,我们提出了一个崭新的观点,即"分子伴侣介导阿片成瘾(molecular chaperone-mediated opioid addic-tion)"理论。介导神经/行为可塑性可能是分子伴侣Hsp70一个新的生理功能。当然,分子伴侣介导短暂药理作用(单针给药)与长时程行为改变(行为敏化)的分子药理学机制还有待进一步研究。     

成瘾药物行为敏化及机制

反复、间断给予依赖性药物(如吗啡、苯丙胺、可卡因、尼古丁、酒精等)后,能增强实验动物的自发性活动反应(locomotor response),这种伴随着反复给药而出现的行为反应增强被称为行为敏化(behavioral sensitization).行为敏化的形成和表达与药物成瘾有着重要的关系,目前已经证明成瘾药物诱导的行为敏化对觅药行为和复吸的发生和维持有着重要的影响[1].敏化动物模型已经为研究药物成瘾的神经生物学机制提供了重要的实验手段[2].那么行为敏化是怎样形成的?它在药物成瘾中扮演的是个什么角色?环境因素在行为敏化中的作用又如何?这些问题的回答将有助于我们更好的理解敏化行为在药物成瘾中的作用.     

丰富环境对小鼠吗啡成瘾性的影响

目的:研究丰富环境对小鼠吗啡成瘾性的影响。方法:40只♂小鼠随机分为丰富环境组(n=20)和普通环境组(n=20),利用行为敏化和条件性位置偏爱实验评价动物的精神依赖性。结果:丰富环境降低小鼠吗啡(10mg·kg-1)行为敏化的形成,阻断吗啡(5mg·kg-1)诱导的条件性位置偏爱的建立。结论:丰富环境可能对吗啡的精神依赖性具有干预作用。     

甲基苯丙胺诱导小鼠行为敏化模型的构建与评估

目的:探讨不同剂量水平甲基苯丙胺(MA)所诱导的小鼠行为敏化模型的构建与评估方法。方法:40只C57BL/6J小鼠,随机分为5组:生理盐水对照组(NS)和0.5、2、5、10mg·kg-1MA剂量组,各组在形成期连续5d每天腹腔注射(ip)不同剂量药物并记录自主活动情况,转化期停药观察2d后,在d8表达期给予最后一次等量剂量MA,并记录自主活动情况。结果:(1)不同剂量MA作用于实验小鼠,在小剂量水平即能够诱导出明显的行为敏化现象,且随着药物浓度增大,呈现剂量依赖性变化;(2)在10mg·kg-1大剂量水平,小鼠表现为明显的刻板行为,在表达期同样出现了刻板行为的增强现象。结论:本实验为不同剂量的小鼠MA敏化模型提供了比较标准的构建和评估方法;2mg·kg-1MA作用于实验小鼠,诱导出了明显的行为敏化现象,同时其他精神运动改变如刻板行为出现较少,是构建药物依赖行为敏化模型较理想的剂量;利用该行为敏化模型可进一步分析和评估药物依赖治疗性药物的疗效。     

Y-IP5对小鼠吗啡行为敏化和条件性位置偏爱的影响

目的探讨新型化合物Y-IP5对吗啡诱导小鼠行为敏化和条件性位置偏爱(conditioned place preference,CPP)的影响。方法测定小鼠的自发活动,观察Y-IP5对小鼠自发活动及急性给予吗啡所诱导小鼠高活动性的影响;慢性吗啡处理小鼠,建立小鼠吗啡行为敏化和CPP模型,观察Y-IP5对行为敏化形成、转化、表达及CPP形成的影响。结果单次或多次给予Y-IP5都不影响小鼠的自发活动,但能抑制急性给予吗啡所致的小鼠高活动性(P<0.05);Y-IP5本身不诱导小鼠形成行为敏化和CPP,但能抑制吗啡诱导小鼠形成行为敏化和CPP(P<0.05),但Y-IP5对吗啡诱导小鼠行为敏化的转化和表达无抑制作用。结论Y-IP5对阿片类药物的精神依赖可能具有干预作用。     

眼镜蛇毒粗毒毒素Ⅳ对小鼠吗啡行为敏化的影响

目的 探讨眼镜蛇毒毒素Ⅳ对吗啡行为敏化的影响.方法 测定小鼠自主活动,观察毒素Ⅳ对小鼠自主活动影响.昆明种小鼠慢性吗啡处理,建立吗啡诱导行为敏化模型,观察毒素Ⅳ对吗啡行为敏化影响.结果 毒素Ⅳ(0.027、0.04、0.08 mg/kg)腹腔注射后,均能减少小鼠自主活动,降低吗啡诱导的高活动性,抑制小鼠吗啡行为敏化的获得,阻断小鼠吗啡行为敏化表达,其中中、高剂量毒素Ⅳ作用较显著.结论 毒素Ⅳ对中枢神经系统具有抑制作用,可以阻止吗啡成瘾行为形成,对吗啡诱导的敏化行为具有抑制作用,提示毒素Ⅳ对吗啡精神依赖性可能具有干预作用.     

行为敏化动物模型在药物依赖性评价中的应用

药物滥用和成瘾呈上升趋势。它既是一个严重的社会问题 ,又是一个非常重要的医学问题。因此 ,对作用于中枢神经系统的药物进行依赖性评价具有十分重要的意义。研究资料表明药物敏化与药物滥用和成瘾具有密切的关系 ,依赖性药物致敏化的药理学特性越来越受到重视。本文介绍了行为敏化动物模型建立的方法 ,阐述了行为敏化形成和表达的神经生物学机制 ,着重探讨了行为敏化动物模型在药物依赖性评价中的作用。     

噻诺啡灌胃给药对小鼠甲基苯丙胺行为敏化的影响

目的:探讨新型丁丙诺啡同系物-噻诺啡,灌胃(ig)给药对小鼠甲基苯丙胺行为敏化过程的影响。方法:测定小鼠的自主活动,观察ig噻诺啡对小鼠的自主活动及单次给予甲基苯丙胺所诱导的小鼠高活动性的影响。建立甲基苯丙胺诱导的小鼠行为敏化模型,观察噻诺啡对行为敏化形成、转化及表达的影响。结果:(1)单次ig噻诺啡(1 2 5 - 5 0mg·kg-1)可剂量依赖性地抑制小鼠的自主活动(P <0 . 0 1) ,其作用多次给药后产生耐受;(2 )噻诺啡对单次给予甲基苯丙胺所诱导的小鼠的高活动性无明显影响;(3)噻诺啡对甲基苯丙胺诱导小鼠行为敏化的形成和表达无明显作用,却可显著抑制敏化的转化过程(P <0 . 0 5 )。结论:ig噻诺啡可抑制小鼠中枢神经系统,阻断甲基苯丙胺诱导小鼠产生行为敏化的转化过程,提示噻诺啡对甲基苯丙胺的成瘾行为具有一定的干预作用。     

归元片对小鼠吗啡行为敏化的影响

目的 :探讨中药复方制剂归元片对吗啡行为敏化的影响。方法 :测定小鼠的自主活动 ,观察归元片对小鼠自主活动的影响。给小鼠慢性吗啡处理 ,建立吗啡诱导的行为敏化小鼠模型 ,观察归元片对吗啡行为敏化的影响。结果 :(1)归元片 (2 5 - 10g·kg- 1 )明显抑制小鼠的自主活动 ,并呈剂量依赖性 ;(2 )归元片剂量依赖性地阻断小鼠吗啡行为敏化的获得和表达 ,但对行为敏化的转换无影响。结论 :归元片对中枢神经系统具有抑制作用 ,可以阻止吗啡成瘾行为的形成 ,对吗啡诱导的敏化行为具有抑制作用。提示归元片对吗啡的精神依赖性可能具有干预作用     

噻诺啡对小鼠甲基苯丙胺行为敏化的影响

目的:探讨新型阿片受体部分激动剂-噻诺啡对小鼠甲基苯丙胺行为敏化过程的影响。方法:测定小鼠的自主活动,观察噻诺啡对小鼠的自主活动及急性甲基苯丙胺处理所致小鼠活动增强效应的影响。小鼠腹泻注射甲基苯丙胺2mg·kg~(-1)·d~(-1),连续7d,建立甲基苯丙胺诱导的小鼠行为敏化模型,观察噻诺啡对小鼠行为敏化的影响。结果:单次皮下注射噻诺啡(0.0625～1.0mg·kg~(-1))可剂量依赖性地抑制小鼠的自主活动(P<0.05),连续给药7d,噻诺啡对小鼠自主活动的抑制作用不产生敏化,而耐受。噻诺啡对急性甲基苯丙胺处理所致小鼠的高活动性无明显影响。噻诺啡对甲基苯丙胺诱导的小鼠行为敏化的形成和表达无显著作用,但可剂量依赖性地抑制敏化的转化(P<0.05或P<0.01)。结论:噻诺啡对中枢神经系统具有抑制作用,并且可以阻止甲基苯丙胺诱导小鼠产生行为敏化的转化过程,提示噻诺啡可能对甲基苯丙胺的成瘾行为具有一定的干预作用。     

地高辛对小鼠吗啡行为敏化的影响

目的:探讨地高辛对小鼠吗啡行为敏化的影响.方法:测定小鼠的自主活动,观察地高辛对小鼠自主活动的影响.急性吗啡(10 mg·kg-1,ip)处理小鼠前给予地高辛,观察地高辛对急性吗啡引起小鼠高活动性的影响.慢性吗啡处理小鼠,建立吗啡行为敏化模型,观察地高辛对吗啡行为敏化的影响.结果:(1)地高辛(0.5 mg·kg-1-...     

Environmental novelty and illumination modify ethanol-induced open-field behavioral effects in mice

Both spontaneous and drug-induced animal behaviors can be modified by exposure to novel stimuli or different levels of environmental illumination. However, research into how these factors specifically impact ethanol (ETH)-induced behavioral effects is currently lacking. We aimed to investigate the effects of these two factors, considered separately or in conjunction, on ETH-induced acute hyperlocomotor effect and its sensitization in adult male Swiss mice. Mice were placed in a novel or familiar open-field under normal light (200 lx) or low light (9 lx) immediately after receiving an ip injection of either 1.8 g/kg ETH or saline (SAL). After 7 days, all animals received an ip challenge injection of 1.8 g/kg ETH, and were placed in the open-field under the same light conditions described above. Novelty increased central locomotion and decreased grooming, while low light increased grooming. Acute ETH administration increased both total and peripheral locomotion and these effects were potentiated by low light. Both low light and novelty were able to facilitate ETH-induced locomotor sensitization, which was detected by the central locomotion parameter. However, there was no synergism between the effects of these two modulating factors on ETH-induced behavioral sensitization. We conclude that both the acute behavioral effects of ETH and behavioral sensitization induced by previous administration of this drug can be critically modified by environmental factors. In addition, our study stresses the importance of using different behavioral parameters to evaluate the interaction between environmental factors and ETH effects.     

Reactivation of morphine conditioned place preference by drug priming: role of environmental cues and sensitization

RATIONALE: Relapse is a major characteristic of drug addiction and remains the primary problem in treating drug abuse. Despite a great deal of research, the exact factors that determine renewed drug-seeking and persistent craving for them remain unclear. OBJECTIVE: The present study was designed to evaluate the role of environmental cues and behavioral sensitization in reactivation of place preference following long-term extinction of morphine conditioned place preference (CPP) in rats. METHODS: After being injected with morphine and saline alternately for 6 days to induce morphine CPP, the rats were subjected to extinction of conditioning for 21 days. The rats were then administered various doses of morphine, heroin, or cocaine and confined in the previous drug- or saline-paired compartment. CPP was determined. Some rats were treated with scopolamine or naloxone prior to administration of these three drugs. RESULTS: Morphine CPP disappeared following a 21-day extinction. A single injection of morphine, heroin, or cocaine evoked place preference for the previous drug-paired side. However, place preference for the previous vehicle-paired side was induced after the animals received a single injection of morphine, heroin or cocaine and confined to the previous vehicle-paired compartment. Administration of naloxone prior to drug treatment significantly attenuated the place preference induced by morphine or heroin, but had no significant effect on the place preference elicited by cocaine. Administration of the cholinergic antagonist scopolamine before morphine, heroin and cocaine inhibited the expression of place preference. CONCLUSIONS: Environment-related cues and behavioral sensitization play critical roles in the incentive motivation underlying drug-seeking behaviors.     

Stimulus and response factors affecting the development of behavioral sensitization to apomorphine

The present study was designed to assess the role of stimulus and response factors in the context-dependency of behavioral sensitization to the direct dopamine agonist apomorphine. In two experiments, male Wistar rats were given repeated injections of the direct dopamine agonist, apomorphine (5 mg/kg, SC), or vehicle at 24- to 72-h intervals and tested for locomotor activity for 30 min in either an openfield activity drum or a running wheel. In experiment 1, after eight activity sessions in either the activity drum or running wheel, one-half of the rats in each drug condition (apomorphine or vehicle) were tested in the alternate activity test environment. In both activity test environments, apomorphine produced progressively greater levels of locomotor activity with repeated treatment (i.e., sensitization). Moreover, sensitization to apomorphine transferred completely across test environments. That is, rats given apomorphine associated with one test environment (e.g., wheel) displayed equivalent sensitization when tested in the alternate environment (e.g., drum). Thus, changing external stimulus cues associated with repeated drug exposure did not affect the expression of sensitization. In experiment 2, rats were given either apomorphine or vehicle daily and tested for activity in a running wheel. For one-half the rats in each drug condition, the running wheel was free to move, but for the remainder the wheel was immobilized. After nine training sessions, all rats were given an apomorphine challenge injection and tested in a mobile wheel. After the challenge injection of apomorphine, rats previously treated with apomorphine and trained in the mobile wheel were significantly more active than rats previously treated with vehicle. In contrast, rats given equivalent apomorphine treatments and trained in the immobile wheel did not differ in activity from rats previously given only vehicle. Since the external stimulus cues associated with drug exposure for the mobile and immobile wheel groups were the same, this finding suggests that environmental factors affecting response expression are critical to the development of behavioral sensitization to apomorphine. Received: 20 March 1996/Final version: 4 October 1996     

5-羟色胺酸对吗啡诱导小鼠行为敏化的影响

研究中枢5-羟色胺能系统对吗啡诱导小鼠行为敏化的介导作用。选用雄性昆明小鼠，每天2次注射生理盐水或吗啡10mg／kg，连续3天。停药5天后，于第9天，进行吗啡激发试验，测定小鼠的自主活动60min，观察行为敏化效应。此外，选用5-羟色胺前体物质5-羟色氨酸作为工具药，分别在吗啡处理阶段（形成期），吗啡停药阶段（转换期）以及吗啡激发试验前腹腔注射20-80mg／kg5-羟色氨酸。激发试验给予吗啡后，立即测定小鼠的自主活动。实验第9天激发试验数据表明，每天2次反复给予吗啡的小鼠，其自主活动明显高于生理盐水对照组，说明小鼠对吗啡产生了行为敏化效应。5-羟色氨酸可以选择性抑制吗啡对小鼠行为敏化的诱导作用，其抑制作用呈剂量依赖性。然而，5-羟色氨酸对小鼠吗啡行为敏化的转换和表达无明显药理作用。因此，中枢5-羟色胺能系统的功能水平上调可能对吗啡诱导小鼠行为敏化效应具有一定的抑制作用。     

Low dose apomorphine induces context-specific sensitization of hypolocomotion without conditioning: Support for a new state dependent retrieval hypothesis of drug conditioning and sensitization

High doses of apomorphine induce sensitization to locomotor stimulant effects whereas low doses induce locomotor inhibition. We examined whether repeated low dose apomorphine induced sensitization and conditioning to the locomotor inhibitory effect. Three doses of the D1/D2 agonist, apomorphine, were used in a Pavlovian conditioning protocol: 0.05 mg/kg (autoreceptor level), 0.5 and 2.0 mg/kg (post-synaptic level). Rats received 5 daily apomorphine treatments paired or unpaired to an open-field environment (conditioning phase) followed by a saline test (conditioning test) and an apomorphine challenge test (sensitization test). Locomotion was measured for 30 min. During the acquisition phase, the 0.05 mg/kg paired treatment decreased locomotion while the high dose paired treatments increased locomotion. The 0.05 mg/kg paired treatment did not induce conditioning but induced inhibitory locomotor sensitization. The post-synaptic paired treatments produced conditioned and sensitized locomotor stimulation. For the low dose results, we propose an expanded contextual stimulus, which includes interoceptive drug cues. In the sensitization test, the same interoceptive drug cues and test environment cues are present as those during acquisition. In the conditioning test, normative dopaminergic activity is present which generates internal cues that may or may not generalize to the drug-induced cues and, permit or prevent retrieval of conditioning.     

The expression of locomotor sensitization to apomorphine is dependent on time interval between injection and testing

This study examined the onset of locomotor sensitization induced by apomorphine as a function of the temporal delay between drug injection and testing. In experiment 1, rats received three daily administrations of 2.0 mg/kg apomorphine or vehicle either immediately (0 min) or 20 min before being placed into the test environment for 20 min test sessions. Apomorphine given immediately before testing induced a stimulant effect during the first session and sensitization by the second session. However, when testing was delayed 20 min, apomorphine induced stimulant effects only after the third injection. In experiment 2, separate groups received a single 2.0 (mg/kg) apomorphine/vehicle injection immediately before being placed into the test environment for 60 min. In this experiment, apomorphine induced a stimulant effect at 0-20 and 20-40 min. However, the 20-40 interval increase in locomotion was relative to the low level of activity in the vehicle group and was not greater than the 0-20 min locomotion of the vehicle group. Thus, sensitization depends both on peak drug concentration and habituation state of the control group. The variable post-injection delays could be a useful method to study sensitization because it can avoid ceiling effects and changing baselines in the control groups.