Effects of scopolamine on morphine-induced conditioned place preference in mice

It is well known that the cholinergic system plays a crucial role in learning and memory. Psychopharmacological studies in humans and animals have shown that a systemic cholinergic blockade may induce deficits in learning and memory. Accumulated studies h

Pentylenetetrazole-induced status epilepticus following training does not impair expression of morphine-induced conditioned place preference

Learning and memory play an important role in morphine addiction. Status epilepticus (SE) can impair the spatial and emotional learning and memory. However, little is known about the effects of SE on morphine-induced conditioned place preference (CPP). Th

Irregular morphine administration affects the retention but not acquisition of conditioned place preference in rats

Drug addiction is increasingly viewed as the expression of abnormal associative learning following repeated exposures to the drugs of abuse Previous I studies have demonstrated that the patterns of repetition such as frequency and spacing are important to many kinds of learning and memory retention We hypothesized that drug repetition pattern might affect the reward-related learning although the total doses of the drug were the same. In the present study, we tested morphine-induced place preference following either regular or irregular pattern of morphine pairing in rats Regular morphine group received morphine administration daily at a regular time with the same dose Irregular morphine groups received morphine administration either at the same time but irregular doses, irregular time but same dose, or irregular time and irregular doses. We found that rats, who received irregular morphine pairing, exhibited similar acquisition of peace preference but different preference retentions compared with regular morphine-treated rats after the same total dose of morphine Rats, who received morphine administration at the same time but irregular doses and at irregular time and irregular doses, showed rapid disruption of place preference than the regular morphine group. Rats, who received morphine at irregular time but the same dose, showed similar retention of place preference to regular morphine group Our results suggest that the pattern of drug pairing plays an important role in the retention of reward-related memory This study may provide new evidence to broaden our understanding of the development and maintenance of drug craving (C) 2009 Elsevier B V. All rights reserved

Morphine conditioned place preference depends on glucocorticoid receptors in both hippocampus and nucleus accumbens

Learned association between drugs of abuse and context is essential for the formation of drug conditioned place preference (CPP), which is believed to engage many brain regions including hippocampus, and nucleus accumbens (NAc). The underlying mechanisms

特异突触可塑性干扰肽在小鼠吗啡条件化位置偏爱表达过程中的作用

在作为成瘾检测手段的条件化位置偏爱模型中,环境背景和成瘾药物间的关联性学习起着关键的作用.突触可塑性作为学习记忆可能的物质基础,在药物成瘾方面的研究也越来越多,但其表现形式,长时程增强(LTP)或者长时程抑制(LTD)在成瘾过程中所发挥的具体作用尚不得而知.因此,本文利用生物信息学手段,设计并合成了旨在分别阻断LTP和LTD的干扰肽,研究其对小鼠吗啡条件化位置偏爱的影响.结果发现,干扰肽Pep-A2和Pep-A3能够分别特异地阻断海马CA1区的LTP和LTD,在测试前尾静脉注射具有穿膜特性的LTP/LTD特异性干扰肽(Tat-A2/Tat-A3),均能阻断或损伤吗啡诱导的条件化位置偏爱的表达.此发现提示我们,LTP和LTD在成瘾性异常记忆的过程中均发挥着重要的作用.

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.

特异性干扰肽对海马突触可塑性的影响及其功能研究

在哺乳动物复杂的神经网络中，突触是信息传递的枢纽，其突触传递效能的持续性变化被称为突触可塑性（synaptic plasticity）。长时程增强（long-term potentiation，LTP）和长时程抑制（long-term depression，LTD）现象是两种经典的突触可塑性形式，被视作学习和记忆可能的物质基础，得到了广泛地关注。其中，海马CA1区谷氨酸能突触处的LTP和LTD目前研究得最为广泛。 α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid（AMPA）受体作为介导兴奋性谷氨酸能突触基础传递的主要受体，是海马CA1区LTP和LTD正常表达的必要条件。近期的研究表明，AMPA受体通过胞吞、胞吐及侧向移动等方式在细胞膜和细胞内进行着持续地循环。因此，通过调节AMPA受体的上、下膜，进而影响突触后膜上AMPA受体的数量，便能对LTP和LTD产生影响。在本研究中，我们利用生物信息学的手段，以AMPA受体为靶点，设计出了旨在特异阻断LTP或LTD的多肽。运用离体脑片全细胞记录方式，在海马CA1区证明了干扰肽Pep-A2能够特异地阻断LTP而不影响LTD，Pep-A3能够特异地阻断LTD而不影响LTP。并初步探究了其关键的作用位点，为进一步理解LTP和LTD具体的分子机理打下了基础。成瘾作为异常的学习记忆过程，势必涉及到突触可塑性的变化。而特异性地阻断LTP和LTD，对药物成瘾效果的影响却鲜有报道（Wang YT，2007）。在另一部分工作中，我们采用穿膜肽Tat-A2和Tat-A3，在吗啡条件化位置偏爱（morphine conditioned place preference，morphine CPP）模型小鼠的测试前进行系统给药，结果发现两种干扰肽均能阻断或损伤其CPP的表达过程。这一现象，提示我们LTP和LTD在条件化位置偏爱的表达过程中都是不可或缺的，同时也为人们更好地理解成瘾过程的机理，及开发专一有效的治疗药物提供了新的思路。

吗啡成瘾相关学习记忆的脑机制

重复使用吗啡将导致吗啡成瘾，其主要表现如依赖、耐受、敏感化以及吗啡停用后的戒断反应。其核心特征是强迫性吗啡使用：即成瘾者失去了对药物寻觅和摄取的控制。药物成瘾是一个复杂的生物学过程，近年来的研究表明学习记忆参与药物成瘾过程。学习记忆和药物成瘾都受到相似的神经营养因子，递质释放与转运的调控，它们都受到cAMP，CREB等调控因子的调控。研究发现在与成瘾相关的线索，如用药有关的人物、地点或暗示等，都可能恢复觅药和用药行为。当把成瘾相关的线索呈现给戒断中的人时，可以发现这些人表现异常，如心率、呼吸加快，血压升高，并表现明显的渴求行为，前额叶在这种线索导致的渴求行为中起重要作用。以前的研究证实条件化位置偏好(conditioned place preference，CPP)是一个很好的模型来研究环境线索在成瘾中作用，可以用来分析检测成瘾行为。因此，在实验一、二中，采用CPP模型来研究吗啡相关的学习记忆与胆碱系统，以及蛋白质合成的关系；实验三研究了前额叶和海马在吗啡成瘾和戒断过程中谷氨酸(GLU)和γ-氨基丁酸(γ-GABA)含量的变化。 (1)：学习和记忆依赖于多种递质的共同作用，不同的递质在不同的学习记忆中的作用也不一样。大量的研究表明胆碱系统在学习记忆中起重要作用，胆碱系统抑制剂可以导致学习记忆障碍。在本实验中，我们研究东莨菪碱(经典的抗胆碱能药物，影响记忆的获取过程)对吗啡以及食物相关的线索的记忆的影响，研究抑制胆碱系统对这两种线索相关的奖赏性学习记忆的影响。采用腹腔注射东莨菪碱，三个不同的剂量(0.5、1、2mg/kg)，在给吗啡(40 mg/kg)或者食物之前30分钟给东莨菪碱，连续给药4天。结果显示，除了0.5 mg/kg的东莨菪碱不能抑制食物导致的CPP外，其他剂量的东莨菪碱都明显抑制食物导致CPP。但是东莨菪碱并不能抑制吗啡导致的CPP，而且，2.0 mg/kg东莨菪碱强化了吗啡线索相关的学习记忆。这种结果表明吗啡导致的奖赏性学习和普通的普通记忆存在不同的机制。 (2)：记忆的形成需要蛋白质的合成，特别是长时程记忆。在记忆形成的不同阶段，蛋白质的合成对记忆的影响不一样，在学习前后较短的时间内给蛋白质合成抑制剂可以有效的抑制长时程记忆的形成。学习记忆参与吗啡成瘾过程，那么抑制蛋白质的合成是否也能抑制吗啡成瘾相关的学习记忆呢？本实验中，采用环己酰亚胺(蛋白质合成抑制剂，抑制记忆的巩固)来研究抑制蛋白质合成对吗啡线索相关的学习记忆的影响。腹腔给环己酰亚胺，剂量30mg/kg，给药时间为给吗啡前30分钟，同时，后30分钟以及后2小时。实验发现在给吗啡前后30分钟内给环己酰亚胺可以削弱对吗啡相关的线索的记忆，但是不能完全抑制这种记忆的形成，而且在吗啡后两小时给环己酰亚胺基本上对这种记忆没有抑制作用。这种结果表明吗啡相关的联合型学习记忆的形成并不完全依赖于蛋白质的合成，脑内还存在其他的途径来参与这种记忆过程。 (3)：GLU和GABA参与许多学习记忆过程，同样它们在吗啡成瘾过程中也起重要的作用。前额叶和海马在记忆中都起到重要的作用，而且它们在成瘾记忆中也扮演重要角色。那么在成瘾及戒断过程中，前额叶和海马中GLU和GABA会有什么变化呢？本实验利用高效液相色谱－紫外分析法分析在吗啡成瘾及戒断过程中前额叶和海马中总GLU和GABA的动态变化。实验发现在吗啡成瘾及戒断过程中，GABA和GLU在前额叶和海马中的总含量都没有显著的变化，尽管在给药和戒断中，这两种递质都下调然后逐渐上升，但是跟对照组比较都不显著。但是比较吗啡组之间的变化，可以看出前额叶GLU在给药及戒断过程中有比较显著的变化。该结果提示在吗啡成瘾和戒断过程中，GLU和GABA的总量并没有发生显著的改变。结合前人的研究我们认为，这两种递质在成瘾和戒断过程中，它们的合成，释放以及在突触间的转运等各个环节都受到影响，从而参与吗啡成瘾。

鸡胚吗啡用药对学习记忆和成瘾易感性的影响及其受体机制

Prenatal morphine exposure affects neural development of fetus by impairing learning and memory, and increasing susceptibility to morphine abuse. Because nervous systems have different developmental characteristics during different developmental stages, administration of morphine at different stages also has different effects on learning, memory, and susceptibility to morphine. Due to the precise developmental processes of neurotransmitter systems in chick embryo’s brain, and unique superiority of chick embryo model, the purpose of the present studies was to explore critical periods correlated to the memory impairment and the increasing susceptibility to morphine, via one-trial passive avoidance and conditioned place preference as behavior models. Then the possible roles of mu and delta opioid receptors as the possible mechanism were analyzed. Experiment 1 showed that injecting low dose of morphine (1 mg/kg) during the period embryonic 5 to 8 significantly impaired the function of learning and memory, worse than any other periods of the same treatment. Experiment 2 showed that injecting low dose of morphine during the period embryonic 17 to 20 significantly increased the susceptibility to morphine in the new-born chicks. The affected chicks acquired the morphine conditioned place preference more quickly, and maintained it much longer. Experiment 3 showed that during E5-8, injecting delta receptor antagonist naltrindole reversed the learning and memory impairment caused by morphine while delta receptor agonist DPDPE impaired learning and partial memory function. On the other hand, mu opioid receptors had little effect. As for E17-20, given naloxonazine can reverse the increases of susceptibility to morphine, and the mu receptor agonist DAGO cause the increases of susceptibility to morphine. Delta receptors have no effect. The above results demonstrated that prenatal morphine expousure at different developmental periods of chick embryo caused different influences on memory and susceptibility to morphine. That is, E5-8 is the critical period correlate to memory impairment; and E17-20 is the critical period correlate to susceptibility to morphine. Delta receptors were critical in learning and memory impairment while mu receptors in susceptibility.

吗啡相关情境线索的形成及效应表达的神经基础——海马与基底外侧杏仁核在其中的作用

Drug-associated cue-induced relapse to drug seeking causes most difficulties of therapy for drug addiction. Addicts are exposed to two forms of environmental stimuli during drug-taking: contextual stimuli (e.g. a house in which the drug is consumed) and discrete stimuli (DS, e.g. a crack pipe or a syringe for drug). These stimuli become contextual cues and discrete cues, respectively. The incentive value of contextual cues plays a great role in opiates relapse. Compared with drug self-administration model, conditioned place preference (CPP) reflects the approach behavior for drug cues, not concerned with acquisition of operant behaviors. The present study aimed to investigate the role of basolateral amygdala (BLA) and hippocampus in the effect of opiates-related contextual cues using CPP model. Establishing DS-dependent or contextual cues-dependent CPP, the effect of BLA or hippocampus inactivation prior to training phase on acquisition of contextual cues-opiates association was evaluated. Inactivation prior to test phase was used to evaluate roles of BLA and hippocampus in expression of contextual cues-dependent morphine CPP. The main results were as follows: Inactivation of BLA or dorsal hippocampus selectively impaired acquisition of contextual cue-dependent CPP, but inactivation of ventral hippocampus had no impact on acquisition of either DS-dependent or contextual cue-dependent morphine CPP. Inactivation of BLA selectively inhibited expression of contextual cue-depended CPP. Inactivation of ventral hippocampus inhibited expression of both DS-dependent and contextual cue-dependent morphine CPP. These results suggest that BLA and dorsal hippocampus contribute to contextual cue association with opiates but not DS-opiates association. BLA and ventral hippocampus play important roles in incentive value of contextual cues. The present study provides more information for the neurological substrates underlying contextual cues associated with opiates.

影响吗啡动物行为效应的因素及其机制

Credible and stable animal behavioral models are necessary to research the mechanisms of addiction in vivo, especially to study the relationship between memory or stress and drug addiction, which has been one of the focuses in this field. So the object of this study was to observe the influences of several factors on the behavioral effects of morphine shown in the paradigms of conditioned place preference (CPP) and locomotor activity (LA), and to explore the effects of adrenalectomy on LA induced by morphine in rats. In addition, the cortexes of rats were examined, which were exposed to chronic administration of several doses of morphine with or without foot shock. Moreover, a new behavioral model was built to quantify the motivation of drug seeking. The results showed that CPP was more sensitive to low dose of morphine than to high dose. The period of experiment could be shortened by increasing the training times everyday, whereas in this way the dose of morphine should be low enough to avoid the impact between the near two exposures to morphine. Effects of chronic administration of morphine on LA in rats were dose- and time- dependent, which supplied evidence to choose parameters in other behavioral models. The results obtained by the simplified LA paradigm showed that hyperactivity of low dose of morphine following hypoactivity, and naloxone had no effects on LA but blocked the locomotion effects of morphine. Obvious effects of morphine on LA of rats might depend on a reasonable level of plasma corticosterone, which may determine individual vulnerability to drug addiction. Stress may also potentiate the vulnerability by aggravating damage to cortex of rats induced by drug dose-dependently, which is suggested by the results of histological examination. The result that frontal and temporal cortexes and hippocampus were injured suggests that there may be a close relationship between memory and drug addiction. It was showed that the new behavioral model on the basis of Morris water maze might be used to quantify the motivation of drug-craving.

Effects of extremely low-frequency electromagnetic fields on morphine-induced conditioned place preferences in rats

In the present study, we examined the effects of extremely low-frequency (ELF) electromagnetic fields on morphine-induced conditioned place preferences in rats. During the conditioning phase (12 days), three groups of rats were placed in a sensory cue-defined environment paired with morphine (10 mg/kg, i.p.) following exposure to either 20 Hz (1.80 mT) or 50 Hz (2.20 mT) or sham electromagnetic fields for 60 min/day, respectively, and were placed in another sensory cue-defined environment paired with physiological saline (1 ml/kg, i.p.) without exposure to electromagnetic fields. After finishing 12 days of conditioning, preference tests for the morphine-paired place were performed during a 10-day withdrawal period. The exposure to electromagnetic fields substantially potentiated morphine-induced place preferences in rodents, suggesting that ELF electromagnetic fields can increase the propensity for morphine-induced conditioned behaviors. (C) 2005 Elsevier Ireland Ltd. All rights reserved.

Orientation preference and fractal character of short fatigue cracks in a weld metal

Short fatigue crack behaviour in a weld metal has been further investigated. The Schmid factor and the fractal dimension of short cracks on iso-stress specimens subjected to reversed bending have been determined and then applied to account for the distribution and orientation characteristics of short fatigue cracks. The result indicates that the orientation preference of short cracks is attributed to the large values of Schmid factor at relevant grains. The Schmid factors of most slip systems, which produced short cracks, are less than or equal to 0.4. Crack length measurements reveal that short crack path, compared to that of long crack, possesses a more stable and relatively larger value of fractal dimension. This is regarded as one of the typical features of short cracks.

Effect of several feeding stimulants on diet preference by juvenile gibel carp (Carassius auratus gibelio), fed diets with or without partial replacement of fish meal by meat and bone meal

The objectives of this work were to study the effects of several feeding stimulants on gibel carp fed diets with or without replacement of fish meal by meat and bone meal (MBM). The feeding stimulants tested were betaine, glycine, L-lysine, L-methionine, L-phenylalanine, and a commercial squid extract. Three inclusion levels were tested for each stimulant (0.18, 0.5%, and 1% for betaine and 0.1, 0.25 and 0.5% for the other stimulants). Two basal diets (40% crude protein) were used. one with 26% fish meal (FM), and the other with 21% fish meal and 6% MBM, Betaine at 0.1% in the fish meal group and at 0.5% in the meat and bone meal group was used in all experiments for comparison among stimulants. In the experiment on each stimulant, six tanks of fish were equally divided into two groups, one fed the FM diet, and the other fed the MBM diet. After 7 days' adaptation to the basal diet, in which the fish were fed to satiation twice a day, the fish were fed for another 7 days an equal mixture of diets containing varying levels of stimulants. Each diet contained a unique rare earth oxide as inert marker (Y2O3, Yb2O3, La2O3, Sm2O3 or Nd2O3). During the last 3 days of the experiment, faeces from each tank were collected. Preference for each diet was estimated based on the relative concentration of each marker in the faeces. Gibel carp fed the FM diet had higher intake than those fed the MBM diet, but the difference was significant only in the experiments on betaine, glycine and L-methionine. None of the feeding stimulants tested showed feeding enhancing effects in FM diets. All feeding stimulants showed feeding enhancing effects in MBM diets. and the optimum inclusion level was 0.5% for betaine, 0.1% for glycine, 0.25% for L-lysine, 0.1% for L-methionine. 0.25% For L-phenylalanine. and 0.1% for squid extract. The squid extract had the strongest stimulating effect among all the stimulants tested. (C) 2001 Elsevier Science B.V. All rights reserved.

Theoretical investigation on the phase stability of Nd2Fe14B and site preference of V, Cr, Mn, Zr and Nb

The stability of the excellent permanent magnetic compound Nd2Fe14B and substitution of Fe in the compound by V, Cr, Mn, Zr and Nb are investigated by using interatomic pair potentials which are converted from lattice-inversion method. Calculation shows that the substitution always makes the cell volume larger, and the increase of the volume is almost linear with substituent concentration. The calculated cohesive energy shows that the preferential order of substitution of Fe is Nb, V, Cr, Mn, Zr. Nevertheless, all the five substituting elements should most preferentially replace Fe in the j(2)' site, which has the greatest space among all six Fe sites. (C) 2005 Elsevier B.V. All rights reserved.