吗啡成瘾的大鼠行为改变及其与脑内单胺类神经介质含量变化的关系

本文以64只大鼠为材料,采用饮服和腹腔注射吗啡的方法,建立大鼠对吗啡成瘾性的实验模型,观察它们的行为改变和脑内单胺类神经介质含量的变化,结果发现:两种方法都可使大鼠成瘾,成瘾时间在给药后的第四周左右形成;成瘾后的大鼠对药物产生明显的依赖性,每天对吗啡的摄取量大致稳定在35mg/kg左右;如突然停药大鼠表现出不安静状态,活动增加,体重下降;食物运动性条件反应的反应时与戒断前相比明显缩短,错误次数减少;成瘾后的大鼠脑内单胺类神经介质的含量也发生改变,NE和DA有所下降,而5-HT和5-HIAA则显著升高,对于这种变化是原发性的还是继发性的还需进一步研究。     

吗啡行为及条件性行为敏感化效应及其个体差异

目的：考察吗啡处理下,大鼠行为敏感化及条件性行为敏感化效应及其个体差异性表现。方法：根据大鼠在初次抵达的新颖环境中水平活动量的高低,将大鼠划分为高反应大鼠（High responder, HR）和低反应大鼠（Low responder, LR）,应用自动监测大鼠活动箱,分别考察HR和LR大鼠在行为及条件性行为敏感化效应表达上的差异。结果：（1）连续5天吗啡给药,LR大鼠活动量显著升高,HR大鼠无此效应;（2）条件测试日（第6天）,给药与环境匹配大鼠,活动量较给药与环境非匹配组动物和对照组动物显著为高;此效应在HR和LR大鼠同时存在;（3）从给予吗啡到给予盐水,发现LR大鼠活动量显著下降,而HR大鼠活动量无显著改变。结论：在连续给药下,LR大鼠较HR大鼠,在行为敏感化效应的形成中,具有更为显著的效应,此效应为LR动物对吗啡更高的药物效应,而非条件效应所致,同时HR和LR大鼠都可以对吗啡条件性线索产生应答,产生条件性行为敏感化效应。     

电击信号应激对大鼠体液免疫及内分泌功能的影响

研究了足电击及以电击装置为信号刺激所诱发的情绪应激对大鼠原发性体液免疫反应及内分泌的影响。 结果表明每天１０分钟,共６天的足电击对大鼠抗特异性抗原ＯＶＡ的原发性体液免疫反应无明显作用,而此电击作 用结合每天１０分钟,共８天的情绪应激则可显著降低大鼠体液免疫反应及脾脏指数。同时该应激可显著提高大鼠 血儿茶酚胶和皮质酮水平。该研究证明了情绪应激对大鼠体液免疫功能的调节作用,并对交感神经系统和下丘脑－ 垂体－肾上腺（ＨＰＡ）轴在其中所起的作用进行了初步探讨。     

应激对大鼠行为和部分脑区谷氨酸含量的影响

以旷场试验法测定动物在急、慢性躯体性和心理性应激时的行为变化,以快速断头冷冻匀浆法,用ＨＩＴＡＣＨＩ－８３５氨基酸分析仪测定应激各期视皮层、海马、下丘脑、小脑谷氨酸含量。并对正常动物经侧脑室微量注射Ｌ－ＡＰ４后观察行为变化。结果显示,急性应激期动物行为活动增加,慢性应激期减少：应激时,大鼠部分脑区的谷氨酸含量与对照组相比在不同时期呈显著性差异;侧脑室微量注射Ｌ－ＡＰ４提示行为活动减弱可能与脑内Ｇｌｕ系统的活动有关。     

胸腺肽对心理应激引起老年大鼠免疫功能降低的改善作用

研究胸腺肽作为一种免疫增强剂,是否参与调节应激对免疫系统的作用,心理应激采用可控／不可控电击的模型。结果表明,受到６天,每天半小时的可控或不可控的足底电击后,与不受电南的对照组相比,不可控组老年大鼠的免疫功能明显下降,而可控组没有明显变化．;肾上腺糖皮质激素的分泌量在受到电击后显著升高。     

不同刺激强度训练后一日龄小鸡的记忆形成

一日龄小鸡,分别接受不同浓度的回避性刺激物邻氨基苯甲酸甲酯（ＭｅＡ）训练,间隔一定时间后测试记忆保持。主要结果为：５％和２０％ＭｅＡ训练,分别使动物记忆保持１５分钟和５０分钟左右,相当于记忆形成多阶段模型中的ＳＴＭ和ＩＴＭ阶段。４０％ＭｅＡ训练,记忆保持到训练后８－１０小时,相当于不依赖新糖蛋白合成的ＬＴＭ形成的早期阶段。只有６０％以上浓度的ＭｅＡ训练才使记忆保持至少２４小时。上述结果提示,利用弱化训练的方法,不仅可以将ＳＴＭ,ＩＴＭ和ＬＴＭ分离开,而且可把ＬＴＭ形成的早期阶段分离出来独立研究,增加了对ＬＴＭ新的理解,为进一步探讨记忆形成机制提供了一条新的途径。     

肝脏缺血预处理研究中的哲学思考

1　预处理研究与原型启示1 1　预处理发展史1 986年 ,Ｍｕｒｒｙ等首次报道结扎犬冠状动脉 5ｍｉｎ,再灌注 1 0ｍｉｎ ,重复进行 4次 ,不仅未产生累加性缺血损伤 ,反而可以减轻随后 45ｍｉｎ缺血所致的心肌损伤 ,他们将心脏遭受短暂缺血后能耐受随后较长时间缺血损伤的现象称为缺血预处理 (ｉｓ ｃｈｅｍｉｃｐｒｅｃｏｎｄｉｔｉｏｎｉｎｇ ,ＩＰＣ) [1] 。该现象已在不同种属动物与临床病人以及不同的实验模型 (在体心脏、离体心脏、培养的心肌细胞)、心脏以外组织器官(如肝、小肠、大脑、视网膜 )得到证实[2 ] 。整体动物进行肝脏缺血预…     

药物成瘾行为的脑机制及其研究进展

药物成瘾是脑内相关核团和细胞在药物反复作用下发生适应性变化的时间依赖过程。成瘾的适应性学说从ｃＡＭＰ水平调节、阿片和多巴胺受体与Ｇ蛋白家族耦联等方面,为成瘾形成机制提供了最基本的生物学范畴的理论解释。实验证据在一定程度上揭示了从给药到耐受、敏感、依赖,再到撤药症状的生物变化过程。然而,阐明从急性给药到特殊脑区持续性的适应机制仍然是当前成瘾研究最具挑战性的目标之一。     

非失语脑中风患者的神经心理障碍与一年疗效和康复预测的关系

本文以７９例脑中风患者为对象,研究结果如下：１．自编ＡＤＬ,再测信度和结构效度合格。２．一年前后ＡＤＬ、ＤＮＦ及疗效与同期测定的插棍测验、瑞文测验、小棍测验、临摹图形、说同类词及抑郁（一年后）有显著相关。３．初发病时这些指标及图形拼凑测验与一年后ＡＤＬ、ＤＮＦ及疗效也有显著相关。４．ＤＮＦ１和ＡＤＬ１对疗效有明显预测作用,可解释变量的３５％（ＡＤＬ２）、３７％（疗效）和４１％（ＤＮＦ２）。单独心理变量可解释变量的２７％（ＡＤＬ２）、３３％（ＤＮＦ２）和２１％（疗效）。     

CNTF对应激大鼠行为障碍和海马CA1神经元损害的作用

实验采用 ｏｐｅｎ ｆｉｅｌｄ测定、 Ｎｉｓｓｌ染色、 Ｂｉｅｌｓｃｈｏｗｓｋｙ－Ｇｒｏｓ－Ｌａｗｒｅｎｔｊｅｗ染色和常规透射电镜技术,观察急性和慢性足底电击应激大鼠的ｏｐｅｎ ｆｉｅｌｄ行为和海马ＣＡ１神经元形态的变化,及双侧海马注射睫状神经营养因子（ＣＮＴＦ）对它的影响。结果表明,急性应激大鼠ｏｐｅｎ ｆｉｅｌｄ行为活动增加,海马ＣＡ１神经元形态无明显变化;慢性应激大鼠ｏｐｅｎ ｆｉｅｌｄ行为活动减少,海马ＣＡ１神经元出现明显的损伤性形态变化;睫状神经营养因子对对照组大鼠和急性应激大鼠的ｏｐｅｎ ｆｉｅｌｄ行为和海马ＣＡ１神经元形态均无明显作用,但可显著减轻慢性应激大鼠海马ＣＡ１神经元损伤程度,改善其行为障碍。实验结果提示睫状神经营养因子可能通过保护海马神经元从而改善慢性应激大鼠的行为障碍。     

Further evaluation of morphine aversion: maintenance of a taste aversion using a low, nonaversive morphine dose

Previously, in an investigation of morphine-conditioned taste aversion (CTA), we found that limited preexposure to a low, nonaversive (non-CTA-inducing) dose of morphine (2.5 mg/kg) was as effective as preexposure to a higher, CTA-inducing dose (15 mg/kg) in blocking the formation of a subsequent morphine CTA. In the present study, we examined the capacity of this low, 2.5-mg/kg morphine dose to maintain a CTA initially induced by the 15-mg/kg dose. A standard CTA procedure was used. Results indicated that rats given three initial taste-drug pairings with 15 mg/kg morphine followed on subsequent pairing days by treatment with the low, non-CTA-inducing, 2.5-mg/kg dose continued to exhibit a strong CTA over 8 pairing days. A similar pattern was observed for animals continuing to receive taste-drug pairings with the 15-mg/kg dose. Animals receiving only one taste-drug pairing with the 15-mg/kg dose, followed on subsequent pairing days by 2.5-mg/kg conditioning, failed to show such a pattern of CTA. An intermediate CTA pattern was seen with animals conditioned with 15, 10, 5, and repeated 2.5-mg/kg doses over consecutive pairing days. These data suggest that exposure to a low dose of morphine, with no apparent CTA-inducing properties, is sufficient to maintain a previously established morphine taste aversion. Potential implications for understanding the apparent discriminative complexity of morphine's motivational properties are discussed.     

Interoceptive conditioning through repeated suppression of morphine-abstinence

Experimental evaluation of Wikler’s interoceptive conditioning hypothesis of relapse to opioid use in ex-addicts requires a preliminary study of the degree of physical dependence produced by two methods of drug administration. Wistar rats were made physically dependent on morphine by single daily intravenous injections or by a continuous i.v. infusion. Rats received the same total daily dose regardless of administration schedule. The initial daily morphine dose was 20 mg/kg, and was increased every fourth day by 20 mg/kg, until a dose of 200 mg/kg per day was reached. The rats were maintained at the highest dose level for 18 days, at which time morphine was discontinued. Body weight and water intake were the primary variables measured during addiction, maintenance, and abstinence phases of the study. Equivalent and parallel changes in mean weight and water intake in injection and infusion rats indicate equivalent degrees of physical dependence were developed. This finding allows separation of the contribution of conditioning factors and of protracted abstinence in facilitating opioid self-administration in formerly-dependent organisms.     

The effects of adenosine receptor agonists and antagonists on morphine state-dependent memory of passive avoidance

Pretraining administration of morphine (5 mg/kg, intraperitonically) in a step-down passive avoidance task led to state-dependent learning with impaired retrieval on the test day that was dose-dependently restored by pretest administration of morphine (0.5, 1, 3, and 5 mg/kg). This restoration was reversible by pretest naloxone administration. Pretest administration of adenosine receptor antagonists theophylline or 8-phenyltheophylline (8-PT) did not alter morphine-induced amnesia. However, both the antagonists inhibited the restoration of memory by pretest morphine (5 mg/kg). Adenosine A(1) receptor agonists N(6)-cyclohexyladenosine (CHA) or N(6)-phenylisopropyladenosine (R-PIA) only at the higher doses used, and adenosine A(2) receptor agonist 5'-N-ethylcarboxaminoadenosine (NECA), at all doses used, decreased morphine-induced amnesia in a dose-dependent manner. Pretest administration of low doses of CHA, R-PIA, or NECA significantly showed additive effects with low dose pretest morphine (1 mg/kg) in restoring memory. The promnestic effects of high-dose CHA and R-PIA were inhibited by theophylline or 8-PT but not by naloxone. The additive effects of low-dose CHA or R-PIA and morphine were inhibited by theophylline, 8-PT, or a higher dose of naloxone. The promnestic effect of NECA and its additive effect with low-dose morphine were both inhibited by theophylline and naloxone but not by 8-PT. It is concluded that activation of the adenosinergic system, through both A(1) and A(2) receptors, can reverse morphine-induced amnesia and is involved in morphine state of memory.     

N-Methyl-D-aspartate receptors in the ventral tegmental area are involved in retrieval of inhibitory avoidance memory by nicotine

The interaction of opiate, cholinergic, glutamatergic and (possibly) dopaminergic inputs in the ventral tegmental area (VTA) influencing a learned behavior is certainly a topic of great interest. In the present study, the effect of intra-VTA administration of N-methyl-d-aspartate (NMDA) receptor agents on nicotine's effect in morphine state-dependent learning was investigated. An inhibitory avoidance (IA) task was used for memory assessment in male Wistar rats. Subcutaneous (s.c.) administration of morphine (5 and 7.5mg/kg) immediately after training decreased IA response on the test day, which was reinstated by pre-test administration of the same doses of the opioid; this is known as state-dependency. Moreover, pre-test administration of nicotine (0.2, 0.4 and 0.6 mg/kg, s.c.) also reversed the decrease in IA response because of post-training morphine (5mg/kg). Here, we also show that when infused into the VTA before testing, NMDA (0.01 and 0.1 microg/rat) reverse the post-training morphine effect on memory. In addition, the sub-effective doses of NMDA (0.0001 and 0.001 microg/rat) in combination with a low dose of nicotine (0.1mg/kg) which had no effects by themselves, synergistically improved retrieval of IA memory on the test day. In contrast, pre-test administration of a competitive NMDA receptor antagonist D-AP5 (0.5, 1 and 2 microg/rat) which had no effect alone prevented the nicotine reversal of morphine effect on memory. Our data indicate that NMDA receptors in the VTA are involved in the reversing effect of nicotine on morphine induced state-dependency.     

Tail-pinch hyperalgesia and analgesia: Test-specific opioid and nonopioid actions

Reactivity to noxious stimuli in rats is altered following acute exposure to tail-pinch. However, while our laboratory has reported that tail-pinch produces hyperalgesia as measured by the flinch-jump test and attenuates analgesic responses following morphine and cold-water swims, others have found that tail-pinch elicits an opioid-sensitive analgesia on the hot plate test and a nonopioid-sensitive analgesia on the writhing test. The first experiment of the present study examined whether tail-pinch altered responses on two somatic pain tests and showed that tail-pinch significantly decreased both jump thresholds and tail-flick latencies. In assessing whether tail-pinch hyperalgesia on the jump test was mediated by endogenous opioids, the second experiment indicated that low (0.1 and 0.5 mg/kg) doses of naloxone eliminated tail-pinch hyperalgesia by selectively lowering control thresholds and a high (10 mg/kg) dose of naloxone eliminated tail-pinch hyperalgesia by selectively increasing thresholds following tail-pinch. Further, the third experiment showed that morphine-tolerant rats (10 mg/kg morphine daily over 14 days) did not exhibit tail-pinch hyperalgesia on the 15th day, an effect attributable to a selective lowering of control thresholds. The fourth experiment was a direct replication of the observation that tail-pinch produces analgesia on the writhing test which is not antagonized by naloxone. These results demonstrate that the pain test employed and the amount of prior tail-pinch experience are critical variables in determining the direction of tail-pinch effects upon pain perception in rats.     

东莨菪碱对吗啡诱导的大鼠行为敏感化的影响

药物重复处理导致的行为敏感化与成瘾过程密切相关。本实验检验东莨菪碱对吗啡诱导的大鼠行为敏感化发展和转化的影响。实验一动物分为3组,分别进行生理盐水（对照组）、吗啡（10mg/kg,吗啡组）、吗啡（10mg/kg）＋东莨菪碱（3mg/kg,吗啡-东莨菪碱组）前处理,36小时腹腔注射4次（第1~2天）。自然戒断7天（第3~9天）。第10天,所有动物均使用吗啡（4mg/kg）激发,记录动物的自发活动量;第24天,吗啡组和吗啡-东莨菪碱组动物重复第10天的操作。实验二动物分为3组,分别接受生理盐水（对照组）、吗啡（10mg/kg,吗啡组）、吗啡（10mg/kg,吗啡-东莨菪碱组）处理,36小时腹腔注射4次（第1~3天）;间隔12小时后,3组动物分别接受生理盐水、生理盐水和东莨菪碱（3mg/kg）处理,仍为36小时腹腔注射4次（第3 ~5天）。第6~9天不进行药物处理。第10天和第17天,分别使用吗啡（4mg/kg）激发,记录动物的活动量。记录时间均为两小时(10分钟为一个记录单元)。结果表明,东莨菪碱能够抑制吗啡诱导的行为敏感化的发展,一定程度上也能够延缓行为敏感化的转化但没有阻断这种转化     

Amphetamine and morphine produce a conditioned taste and place preference in the house musk shrew (Suncus murinus)

Rats have been shown to avoid consuming a flavor, but prefer a location, previously paired with amphetamine or morphine. A series of 4 experiments evaluated the hedonic properties of amphetamine and morphine in the house musk shrew (Suncus murinus), an insectivore that (unlike rats) is capable of vomiting when exposed to toxins. Unlike rats, amphetamine (20 mg/kg) and morphine (20 mg/kg) produced both a conditioned sucrose (0.3 M) and saccharin (0.1%) preference in shrews (administered intraperitoneally), when measured by both a 1- and a 2-bottle test. At the same dose, both drugs also produced a place preference in shrews. These results suggest that the potential of rewarding drugs to produce taste avoidance may vary on the basis of the ability of the species to vomit.     

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

Evidence suggests that the nitric oxide (NO)/soluble guanylyl cyclase (sGC)/cGMP dependent protein kinase (PKG) signaling pathway plays a key role in memory processing, but the actual participation of this signaling cascade in the hippocampal CA1 during morphine-induced reward memory remains unknown. 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 (i.p.) injection of 4mg/kg morphine exhibited CPP, whereas rats treated with only 0.2mg/kg 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 4mg/kg morphine. Intra-CA1 injection of 7-NI blocked the consolidation of CPP induced by 4mg/kg 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 (0.2mg/kg, i.p.) 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 reward memory.     

Conditioned increases in locomotor activity produced with morphine as an unconditioned stimulus, and the relation of conditioning to acute morphine effect and tolerance

Rats administered 5 mg/kg morphine SO4, through subcutaneously implanted catheters, during each of several daily sessions in an open field showed a progressive increase in locomotor activity measured in the open field prior to each morphine administration. Since the increases in activity were not observed in rats given morphine in a different environment (home cage) and saline in the open field, it is concluded that the increases were due to conditioning. In addition, the increases in activity were retained over a 7-day rest period; they were also produced when a second opiate (5 microgram/kg etorphine HCl) was substituted for morphine, were not seen when 2 mg/kg naloxone HCl (ip) was administered during treatment, and were present in rats showing tolerance to opiate-produced hypoactivity. Morphine's direct effect on activity is believed to have a biphasic dose-response curve; therefore, the relation of dose to conditioning was also studied. Increases in activity were the only conditioned behaviors observed; they were present only at the higher doses (16, 4, and 1 vs. .25, .065, and 0 mg/kg), and they occurred whether or not the dose was associated with unconditioned hypoactivity. The discussion deals with the relation of conditioning and morphine tolerance, the question of whether the unconditioned stimulus of morphine conditioning is a compensatory or a direct effect of morphine, and the similarity of conditioned increases in activity produced by morphine and by other stimuli that are reinforcing.     

Tolerance to the antinociceptive effect of intrathecal morphine in intact and chronic spinal rats

The antinociceptive effect of daily acute intrathecal morphine injections on the tail-flick withdrawal response was compared in Intact rats and rats that were spinally transected 3 to 4 weeks prior to morphine administration (Spinal rats). Spinal rats became tolerant to repeated intrathecal injections of 5, 15, or 30 micrograms of morphine within 3 days. Intact rats were not tolerant to these doses after 4 daily injections. Spinal rats, made tolerant to repeated intrathecal morphine injections, were not tolerant to a subcutaneous injection of 6.0 mg/kg of morphine. These data suggest that, in intact animals, tolerance to the antinociceptive effect of spinal morphine is modulated by descending, supraspinal input.