几种药物对吗啡相关的条件位置偏好影响的研究进展

条件化位置偏好（conditionedplacepreference,CPP）,常用于研究药物成瘾的相关记忆。这里主要综述了一些药物对CPP的影响。神经肽S,神经肽FF,肌肽,孤啡肽,α-2受体激动剂,L-左旋千金藤啶碱,东莨菪碱,丙戊酸钠,巴氯芬对吗啡CPP有抑制效应;聚肌胞苷酸,氟伏沙明和金刚烷胺能增强吗啡CPP;阿坎酸能抑制乙醇和某些类别的滥用药物的条件化奖赏效应,但不影响吗啡引起的条件化奖赏效应;褪黑激素逆转吗啡诱导的奖赏效应;人重组干扰素-α导致吗啡CPP的恢复。     

多巴胺D2受体拮抗剂、激动剂对SD大鼠条件化位置偏好的影响

通过慢性吗啡处理方式建立起SD大鼠吗啡依赖的条件化位置偏好(CPP)模型,用行为学手段研究多巴胺(DA)D2受体拮抗剂及激动剂对SD大鼠CPP的影响,探讨眶额叶DAD2受体在阿片精神依赖中的作用。通过腹腔注射吗啡同环境因素相结合,建立大鼠吗啡依赖的CPP模型;采用局部脑内微量注射法向额叶注射DAD2受体拮抗剂或激动剂或盐水(对照组),以得到SD大鼠在戒断期间的CPP的时间数据。CPP显示DAD2受体拮抗剂组与对照组相比,从戒断第2天起,前者表现出更明显的CPP增加现象,差异显著(P<0·05)。而DAD2受体激动剂组与对照组相比无显著差异(P>0·05)。采用腹腔小剂量注射吗啡,成功地建立了吗啡依赖SD大鼠的CPP模型;眶额叶微量注射DAD2受体拮抗剂增加了CPP时间,提示眶额叶多巴胺系统在吗啡依赖的过程中有着较为重要的作用;也提示了对于已经成瘾的动物,损伤其眶额叶,会使药物渴求增强。因而提示对于药物依赖患者进行手术干预治疗要极其慎重。     

巴氯芬对慢性吗啡依赖后条件化位置偏好和戒断症状的抑制

小鼠连续7天腹腔注射吗啡(40mg/kg)建立条件化位置偏好模型,连续皮下递增注射吗啡(25、50、75、100、125、150mg/kg),成瘾后腹腔注射纳络酮(6mg/kg)诱导戒断症状(跳跃行为)建立戒断模型。腹腔注射GABAB受体激动剂巴氯芬(2mg/kg)可以有效地抑制吗啡诱导的条件化位置偏好和减轻纳络酮诱导的戒断症状,结果表明GABA系统参与动物成瘾后渴求和戒断过程,激动GABAB受体可以在一定程度上抑制成瘾的心理和生理戒断症状。     

乙醛在小鼠酒依赖性行为中的作用研究

乙醛为酒精代谢的中间产物,但其在酒依赖中的作用不清楚.通过条件化位置偏好(CPP)和条件化味觉偏好(CTP)试验,分析乙醛对小鼠乙醇依赖性行为的影响,研究乙醛在酒依赖中的作用.研究发现,经0.8%乙醇预处理7d后,小鼠训练8次则表现出对乙醇的条件化位置偏好(n=6,P<0.01),而经乙醛训练的小鼠则对乙醛无明显条件化偏好行为(n=6,P>0.05).当用0.8%乙醇、0.4%乙醛混合训练乙醇依赖性小鼠时,其位置偏好行为减弱(n=6,P<0.01).10%乙醇预处理的小鼠味觉偏好乙醇(n=6,P<0.01),而当乙醇中加入1%乙醛时,其味觉偏好现象减弱(n=6,P<0.01).1%乙醛训练7d后的小鼠不表现对乙醇的味觉偏好,但选择摄入乙醛及乙醇、乙醛混合溶液的量有所增加.结果表明乙醛在小鼠酒依赖行为中可能存在一定促进作用.     

恒河猕猴吗啡成瘾模型的初步建立

吗啡成瘾的非人灵长类动物恒河猕猴(Macaca mulatta)模型的实验结果表明,猕猴可建立吗啡条件化位置偏好(conditioned place preference,CPP),且其与吗啡线索相关的记忆可持续(36.3±1.3)月。该研究可以为药物成瘾研究提供有效的非人灵长类动物行为模型。     

小鼠脑内NO/NOS-cGMP信号系统与吗啡依赖形成的机制

本文观察了吗啡依赖小鼠脑组织ｃＧＭＰ含量,钙依赖性及非钙依赖性ＮＯＳ活性的变化,蛋白激酶Ａ对ＮＯＳ活性的磷酸化调节以及一氧化氮合酶（ＮＯＳ）抑制剂对吗啡依赖形成的影响。结果发现：（１）小脑,纹状体,海马及大脑皮质ｃＧＭＰ含量明显下降;（２）纹状体及大脑皮质钙依赖性ＮＯＳ活性明显升高,而ＩＰ２０（ＰＫＡ抑制剂）可抑制比变化,小脑及海马依赖性ＮＯＳ活性及以上各脑区非钙依赖性ＮＯＳ活性无明显变化;（３）     

慢性吗啡依赖树鼩模型的建立

吗啡是一种有效的镇痛药,但易使动物产生耐受性和成瘾性。在该实验中,中缅树鼩(Tupai a belangeri chinensis)连续7d,每天接受三次肌肉注射递增剂量(5、10、15、20mg/kg体重)吗啡后对吗啡产生耐受和依赖;吗啡注射完成后,腹腔注射纳洛酮(1.25mg/kg体重)催瘾,可诱导其条件性位置厌恶(conditioned place aversion,CPA)及相应吗啡戒断症状的出现。该结果提示树鼩慢性吗啡依赖模型的建立可用于研究吗啡依赖和耐受的生物学机制,以及减轻戒断症状药物的筛选。     

青春期小鼠与成年小鼠在吗啡和食物诱导条件化位置偏爱建立上的异同

该实验通过采用吗啡诱导的条件位置偏爱(conditioned place preference,CPP)与食物诱导CPP相结合的方法来研究青春期小鼠和成年小鼠的普通学习记忆和成瘾学习记忆之间是否存在差异。结果发现:1)成年小鼠能够建立吗啡诱导CPP,而青春期小鼠不能建立;2)青春期小鼠和成年小鼠都能够建立食物诱导CPP。吗啡诱导CPP的结果提示,青春期小鼠和成年小鼠在成瘾学习记忆上有差异,青春期小鼠的成瘾记忆能力较弱。食物诱导CPP的结果提示,青春期小鼠和成年小鼠在普通学习记忆上没有差异。吗啡诱导CPP和食物诱导CPP的结果比较提示,小鼠的普通学习记忆系统和成瘾学习记忆系统发育进程是不平行的。     

人参皂甙Rg1可改善吗啡依赖大鼠空间学习障碍

长时间应用阿片类制剂如吗啡、海洛因等会诱发脑的适应性改变,从而出现药物成瘾或依赖。以往研究显示,阿片成瘾在许多方面与学习记忆过程类似,相关学者认为是学习的一种异化形式,而这一异化行为的形成是脑内某一记忆系统非适应性回归介导的。另一方面,长时间应用阿片本身也会导致学习记忆能力受损。     

慢性吗啡给予、戒断及再给药过程中大鼠海马感觉门控的动态变化

药物成瘾被认为是药物长期作用于脑而产生的一种慢性复吸性脑疾病,长期反复的药物（如吗啡）滥用会导致一系列严重后果,如药物依赖、药物耐受、强迫性药物寻求等。本实验利用条件化位置偏好（conditioned place preference,CPP）模型来检测大鼠对吗啡依赖和心理渴求等过程;采用双声刺激听觉诱发电位来研究大鼠在慢性吗啡给予、戒断以及再给药过程中海马感觉门控（N40）的动态变化。吗啡组大鼠注射吗啡（10mg／kg,i．p．）12d,经历第一次戒断12d,再次注射吗啡（2．5mg／kg,i．P．）1d,之后经历第二次戒断2d;对照组大鼠注射同体积生理盐水,其余实验条件与吗啡组相同。CPP实验表明,这种药物给予方法促使大鼠对吗啡产生药物依赖和心理渴求。双声刺激诱发电位实验表明,吗啡组大鼠在吗啡给予期间海马感觉门控受到损伤;第一次戒断期的第1～2天海马感觉门控能力减弱,第3天增强,第4～12天逐渐恢复到正常水平;再次给予吗啡后海马感觉门控能力与对照组相比显著降低,并且随后2d的戒断期内海马感觉门控能力也一直保持较低水平,表明再次给药使大鼠海马感觉门控对吗啡更加敏感化。结果提示,长期反复的吗啡给予及再给药干扰了海马的感觉门控能力,吗啡成瘾对大脑可能产生长期影响。     

Effects of the non-competitive NMDA receptor antagonist ketamine on morphine-induced place preference in mice

The effects of ketamine, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, on morphine-induced place preference were examined in mice. Morphine (1-5 mg/kg, s.c.) produced a dose-related place preference in mice. Ketamine alone (3, 10 mg/kg, i.p.), like dizocilpine alone (0.2 mg/ kg, i.p.), also produced a preference for the drug-associated place. Pretreatment with ketamine (10 mg/ kg, i.p.) or dizocilpine (0.1 and 0.2 mg/kg, i.p) suppressed the place preference produced by morphine in a dose-dependent manner. These findings provide the first demonstration that ketamine alone produces a place preference using the conditioned place preference (CPP) paradigm, but that mice treated with ketamine combined with morphine show neither a morphine- nor a ketamine-induced place preference.     

Effects of the non-competitive NMDA receptor antagonist ifenprodil on the morphine-induced place preference in mice

The effects of ifenprodil, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, on the morphine-induced place preference were examined in mice. Morphine (1-5 mg/kg, s.c.) produced a dose-related place preference in mice. In contrast, ifenprodil alone (5-20 mg/kg, i.p.) did not produce either preference or aversion for the drug-associated place. Pretreatment with ifenprodil (5-20 mg/kg, i.p.) suppressed the place preference produced by morphine in a dose-dependent manner. These results indicate that ifenprodil suppresses the rewarding effect produced by morphine.     

Computerized odor psychophysical testing in mice

An automated odor psychophysical procedure was developed andused to determine absolute sensitivity to n–amyl acetate.Mice were trained to initiate a trial by interrupting a photobeamat the rear of the test chamber, then sample an odor port andindicate the presence or absence of odorant by either quicklywithdrawing from the port or by continuing to sample the port.Once the air dilution olfactometer had been adjusted prior toa training or testing session, a microcomputer was used to recordall responses by the animal, to control the delivery of stimulito the odor port and to control all events in the test chamber.Correct reponses on both odor and control trials were reinforcedand incorrect responses on both types of trials were punishedwith a forced ‘time-out’ period. The odor sensitivityof all mice was estimated, using a tracking procedure, and wasthen studied in detail using schedules in which odor concentrationswere presented in ascending, descending and random order. Withall three schedules, thresholds to n-amyl acetate were between1x10^-12 and 1 x10^-13 M. Threshold estimates obtained from twoof these same animals more than 1 year later were within 0.25log units of the original values. This method should prove valuablein future studies of nasal chemoreception in mice.     

A preputial odor imprinted on female mice

Female mice (Mus musculus) which were reared by a preputialectomized female and exposed to an intact male from 14 to 18 days of age preferred the odor of an intact male over that of a preputialectomized male when tested at 15 weeks of age. However, those females which were exposed to an intact male from 28 to 32 days of age preferred the odor of a preputialectomized male over that of an intact male, and those females which were exposed to an intact male from 0 to 4 days of age showed no reliable preferences. Females which were reared by an intact female and exposed a preputialectomized male for 4 days tended to reverse preferences. Females which were exposed to a preputialectomized male from 14 to 18 days of age preferred the odor of a preputialectomized male. However, females which were exposed to a preputialectomized male from 28 to 32 days of age preferred the odor of an intact male, as did females which were exposed to a preputialectomized male from 0 to 4 days.     

Performance of mice in an automated olfactometer: odor detection, discrimination and odor memory

Mice were trained on a variety of odor detection and discrimination tasks in 100- or 200-trial sessions using a go, no-go discrete trials operant conditioning procedure. Odors, presented for 1 s on each trial, were generated by an air dilution olfactometer (for threshold tests) and an easily constructed eight-channel liquid dilution unit (for two- and multiple-odor discrimination tasks). Mice rapidly acquired the operant task and demonstrated excellent stimulus control by odor vapors. Their absolute detection threshold for ethyl acetate was similar to that obtained with rats using similar methods. They readily acquired four separate two-odor discrimination tasks and continued to perform well when all eight odors were presented in random order in the same session and when reinforcement probability for correct responding was decreased from 1 to 0.5. Memory for these eight odors, assessed under extinction after a 32 day rest period, was essentially perfect. Time spent sampling the odor on S+ and S- trials was highly correlated with response accuracy. When accuracy was at chance levels (e.g. initial trials on a novel task), stimulus sampling time on both S+ and S- trials was approximately 0.5-0.7 s. As response accuracy increased, sampling time on S+ trials tended to increase and remain higher than sampling time on S- trials.     

Avian dependence on sound pressure level as an auditory distance cue

Sound pressure level (SPL) has received little attention as a distance cue or signal for communication because of the methodological difficulty of determining source SPL from free-ranging signallers and because SPL is presumed to be unreliable as a distance cue. Eastern towhees, Pipilo erythrophthalmus (Emberizidae, Passeriformes), in south-central Florida give a simple call during territorial interactions. I obtained measurements of call-source SPL with a calibrated microphone positioned 100+/-10 cm from caged male eastern towhees. Measurements of source SPL were highly variable, but much of this variation can be predicted from measurements of call duration or call frequency variables (spectrotemporal variables). Male towhees accurately perceived the distance of a speaker after it played synthetic calls that matched the amplitude and structure of natural 84-dB and 78-dB call types. Subjects flew further in response to an attenuated (-6 or -12 dB) version of an otherwise identical 84-dB call and flew shorter in response to an amplified (+6 dB) version of this same call. Towhees misjudged speaker distance in approximately half of the trials that included a discrepancy (-6, -12 or +6 dB SPL) between playback source SPL and predicted spectrotemporal variables. These distance errors suggest that towhees assess auditory distance partly from the difference between perceived SPL and source SPL, determined from spectrotemporal variables. Copyright 2000 The Association for the Study of Animal Behaviour.     

One-trial associative odor learning in neonatal mice

Behavior genetics studies in mice demand efficient training protocols for rapid phenotypic screening. However, the capacity of neonatal mice to form and retain associative memories has been difficult to study due to their limited sensorimotor capacities. The present study describes a method for robust, naturalistic associative learning in neonatal mice as young as 3 days old. After removal of the dam from the home cage for 2 h, preweanling CD-1 mice of ages 3, 5, and 10 days postnatal were conditioned to associate an arbitrary odorant with the suckling and milk delivery that ensued upon her return to the home cage. After a second maternal deprivation, neonates were tested on their acquired preference for that odorant. Neonates exhibited a learned preference for the conditioned odorant over a novel control odorant. No learning was observed without deprivation, that is, when the dam was removed only briefly for scenting. One-trial learning sufficed to show clear preferences for the conditioned odorant, although repeated training (three sessions over 8 days) significantly increased the expression of preference. The development of neonatal associative learning protocols requiring minimal human intervention is important for the behavioral phenotyping of mutant and transgenic strains, particularly those modeling developmental disorders.     

Antagonism by nalmefene of systemic and intrathecal morphine-induced analgesia in mice

Nalmefene is an orally active opiate antagonist structurally related to naloxone and naltrexone. In this study using two different strains of mice (Swiss Cox and ICR), the antagonist activity of nalmefene given subcutaneously (sc) was quantified by determination of the apparent pA2 values against the antinociceptive activity (tail flick and hot plate tests) of morphine given sc or intrathecally (lumbar spinal cord). The apparent pA2 values (constrained to a slope of -1) were 8.06 (7.79-8.33) in Swiss Cox mice and 7.81 (7.62-8.00) in ICR mice in the tail flick test with sc morphine. These values were larger than the corresponding value for naloxone in ICR mice, 7.35 (7.10-7.60). The hot plate test provided similar results: the apparent pA2 values for nalmefene with sc morphine were 8.14 (7.89-8.39) in Swiss Cox mice and 7.81 (7.65-7.97) in ICR mice, values which were different from naloxone 7.33 (7.23-7.42) in ICR mice. Apparent pA2 values for nalmefene with intrathecal morphine were not different from those for naloxone in the tail flick test. Thus, these sets of results suggest that it may be worthwhile to further determine whether systemic nalmefene might possibly possess an advantage over naloxone in antagonizing systemic side effects of morphine arising from local spinal morphine administration.