MK-801与环境线索交互作用对吗啡行为敏感化的影响

为探讨MK-801与环境线索交互作用对吗啡诱导行为敏感化的影响,将42只大鼠随机分为对照组,MK-801组,吗啡组（匹配和非匹配）和MK-801+吗啡组（匹配和非匹配）。行为敏感化模型建立分为发展期,戒断期和表达期三个阶段。实验结果发现：同时给予MK-801（0.1mg·kg-1）会促进吗啡（5mg·kg-1）诱导大鼠行为敏感化的发展,而且会使MK-801成为大鼠行为敏感化表达所必需的条件性刺激。MK-801的内部线索作用过强,从而削弱了环境的外部线索作用。研究结果表明：MK-801对吗啡诱导行为敏感化的影响存在状态依赖（state-dependency）现象,提示在NMDA受体与行为敏感化关系的研究中应考虑选择刺激特性更小的药物     

毒扁豆碱对吗啡导致的大鼠行为敏感化的抑制作用

药物滥用导致的行为敏感化被认为与成瘾过程密切相关。本实验探讨吗啡导致的大鼠行为敏感化与神经递质乙酰胆碱的关系。实验动物分为3组,分别进行生理盐水、吗啡（10.0mg/kg）、吗啡（10.0mg/kg）＋胆碱酯酶抑制剂毒扁豆碱（0.2mg/kg）前处理,36小时腹腔注射4次。前处理结束1周所有动物注射小剂量吗啡（4.0mg/kg）;使用生理盐水前处理的动物,第2周注射毒扁豆碱（0.2mg/kg）;使用吗啡前处理的动物,第2周注射小剂量吗啡＋毒扁豆碱（0.2mg/kg）,第3周再次注射小剂量吗啡。动物每次接受注射后立即记录其在两小时内的活动量(10分钟为一个记录单元)。结果表明,毒扁豆碱既能够抑制吗啡诱导的行为敏感化,也能够阻断小剂量吗啡对行为敏感化的“点燃”作用。由此推论,吗啡导致的行为敏感化与其抑制乙酰胆碱分泌有关。     

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     

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。     

纳络酮、地卓西平(MK-801)对大鼠食物渴求的影响

实验以条件性位置偏爱（CPP）的表达为渴求模型观察纳络酮及MK-801对大鼠食物CPP表达,探讨摄食行为调控的心理机制。48只SD大鼠分成食物组（24）与对照组（24）,3轮食物匹配训练后,在CPP表达前分别注射生理盐水、纳络酮（1.0 mg˙kg -1）及MK-801(0.1 mg˙kg -1),观察各组动物在食物匹配训练侧停留时间的变化。结果发现,MK-801促进食物CPP的表达,但纳络酮对食物CPP的表达没有显著影响。以上结果表明MK-801（0.1mg˙kg -1）增强动物的食物渴求至少是其增加摄食量的原因之一,而1.0 mg˙kg -1的纳络酮降低动物的摄食量并不是由于食物渴求的下降导致的。MK-801与纳络酮调节动物摄食行为的心理机制可能不一致。     

内隐联想测验中他人重要性对自我心理表征的影响

联合采用联想匹配任务和内隐联想测验（IAT）任务,考察了自我—他人分类中的他人重要性对自我—高奖赏相似性的影响。研究将中性的几何图形与自我、不同重要性的他人（实验一为陌生人,实验二为朋友）建立联结,并将自我（暂时建立联结的图形）高奖赏联合任务与自我低奖赏联合任务下的反应差异（即IAT值）作为自我—高奖赏相似性的指标,结果表明：（1）联想匹配任务中自我和朋友以及自我和陌生人之间都存在显著的自我优势效应;（2）IAT任务中,自我和高奖赏只在他人为朋友的自我—他人分类判断时才具有相似性,而他人为陌生人时二者不具有相似性。这说明他人重要性改变了自我的心理表征。     

内隐联想测验中他人重要性对自我心理表征的影响

联合采用联想匹配任务和内隐联想测验（IAT）任务，考察了自我—他人分类中的他人重要性对自我—高奖赏相似性的影响。研究将中性的几何图形与自我、不同重要性的他人（实验一为陌生人，实验二为朋友）建立联结，并将自我（暂时建立联结的图形）高奖赏联合任务与自我低奖赏联合任务下的反应差异（即IAT值）作为自我—高奖赏相似性的指标，结果表明：（1）联想匹配任务中自我和朋友以及自我和陌生人之间都存在显著的自我优势效应；（2）IAT任务中，自我和高奖赏只在他人为朋友的自我—他人分类判断时才具有相似性，而他人为陌生人时二者不具有相似性。这说明他人重要性改变了自我的心理表征。     

吗啡对不同距离条件下大鼠信号追踪和目标追踪的影响

条件刺激短暂呈现并消失后, 奖赏立即呈现, 多次匹配后诱导出动物对条件刺激(信号追踪)或奖赏呈现装置如食盒(目标追踪)的接近。条件刺激与食盒间的距离是影响信号/目标追踪反应和损害联结学习的重要变量, 成瘾药物能够增加奖赏的诱因动机, 进而增加个体的奖赏寻求行为。距离能否通过损害联结学习而减弱成瘾药物的动机放大作用尚未见到报道。本实验采用autoshaping模型, 考察8、30和60 cm距离条件下吗啡处理对大鼠信号追踪和目标追踪的影响。结果发现：(1)信号追踪随距离增加而减少, 目标追踪对距离不敏感。(2)急性吗啡处理减少8、30和60 cm条件下信号追踪而增加8和60 cm条件下目标追踪, 慢性吗啡处理在8和30 cm条件下减少信号追踪增加目标追踪; 消退检测中, 吗啡前暴露减少8和60 cm条件下信号追踪而增加60 cm条件下目标追踪。(3)辨别反转学习中, 吗啡前暴露使30和60 cm条件下的大鼠偏爱旧信号、辨别力受损, 减少8、30和60 cm条件下大鼠对新信号的接触。这些结果提示, 距离较少影响吗啡的信号追踪抑制作用和目标追踪增强效应, 而易化吗啡前暴露对反转学习的损害。说明距离是易化成瘾药物对联结学习不利影响而非反转其动机放大作用的重要因素。     

啮齿动物主动母性行为动态改变的神经机制

主动母性行为是雌性哺乳动物在哺乳期内有效照料幼崽的一种动机行为, 对幼崽的生存和行为发展有重要影响。证据显示, 啮齿动物的主动母性行为会经历从产后早期的发动和维持到晚期衰退的动态改变, 反映了雌鼠对幼崽奖赏价值阶段性变化的适应; 这一过程不仅涉及分娩激素事件开启下丘脑内侧视前区(MPOA)-中脑腹侧被盖(VTA)-伏隔核(NA)-腹侧苍白球(VP)通路, 还需要杏仁核基底外侧核(BLA)和内侧前额皮层(MPFC)等脑区对上述通路进行实时调节。哺乳期主动母性行为动态改变及其神经机制的研究, 可以加深对行为进化和早期发展的认识, 也对人类母亲产后抑郁等临床问题的干预有借鉴意义。本文首先利用条件化位置偏好(CPP)任务的行为学证据分析幼崽奖赏价值与主动母性行为动态改变的关系; 然后系统阐述调控这一动态改变的神经机制; 最后对未来需要研究的一些重要问题或方向进行探讨。     

不同剂量舒芬太尼对Disposcope内窥镜气管插管血流动力学的影响

为评价不同剂量舒芬太尼复合靶控输注丙泊酚对Disposcope内窥镜气管插管血流动力学的影响,选择60例择期行气管插管全身麻醉患者,依据不同剂量舒芬太尼,分为三组（n=20）：A组0.2μg/kg,B组0.3μg/kg与C组0.4μg/kg.结果显示插管后1min,A组呼吸频率（HR）、收缩压（SBP）明显高于B组与C组（P＜0.05）;插管时,C组SBP＜90mmHg的例数明显多于A组与B组（P＜0.05）;插管后1min～5min期间,A组SBP＞140mmHg、HR＞90次/分的例数明显多于B组与C组（P＜0.05）,而C组HR＜60次/分的例数明显多于A组与B组（P＜0.05）.因此,0.3μg/kg舒芬太尼复合靶控输注丙泊酚诱导Disposcope内窥镜气管插管血流动力学稳定.     

冲动性对吗啡诱导的条件性位置偏爱及行为敏感化的影响

许多研究显示, 冲动性与尼古丁、可卡因、海洛因等药物成瘾显著相关, 但它对吗啡成瘾的影响尚未见到报道。本实验考察冲动性对吗啡诱导的条件性位置偏爱及行为敏感化的影响。实验采用延迟奖赏模型将大鼠的冲动性区分为高、中、低三个水平, 每个水平设置吗啡处理组和盐水处理组。结果发现：动物对吗啡诱导的条件性位置偏爱的程度表现为低冲动组>中冲动组>高冲动组, 并且中、低冲动组动物形成了条件性位置偏爱而高冲动组没有形成这种偏爱; 在行为敏感化表达期, 与相应的盐水组比较, 高、中冲动组动物的吗啡运动激活效应显著, 而低冲动组没有达到显著水平。这些结果提示, 条件性位置偏爱任务中, 动物的冲动性越高, 吗啡的强化效应越低; 行为敏感化任务中, 动物的冲动性越高, 吗啡的运动激活效应越高。由此可见, 动物的冲动性对吗啡诱导的条件性位置偏爱及行为敏感化的影响存在差异。     

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.     

Ventral tegmental area and substantia nigra neural correlates of spatial learning

The ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) may provide modulatory signals that, respectively, influence hippocampal (HPC)- and striatal-dependent memory. Electrophysiological studies investigating neural correlates of learning and memory of dopamine (DA) neurons during classical conditioning tasks have found DA neural activity in VTA and SNc to be tightly coupled with reinforcement expectations. Also, VTA integrity and DA in HPC have been found to regulate the encoding of HPC-dependent memories. Therefore, to determine the nature of the neural code HPC may receive from midbrain DA regions, the present study investigated VTA and SNc neural activity as navigating rats engaged in new spatial learning and experienced changes in expected goal locations. VTA and SNc cells were differentially engaged during training to a series of three novel goal locations. During task acquisition, the peak firing rates of VTA neurons decreased at the time of reward and shifted to time points before reward retrieval, whereas the peak firing rates of SNc neurons remained elevated at the time of reward during training to all three goal locations. Both VTA and SNc egocentric coding was strongest during training to the first goal location, which coincided with the time subjects learned the behavioral rules specific to the task. These data imply that VTA and SNc play complementary yet distinct roles in spatial learning to optimize adaptive behavior.     

Conditioned fear is modulated by D2 receptor pathway connecting the ventral tegmental area and basolateral amygdala

Excitation of the mesocorticolimbic pathway, originating from dopaminergic neurons in the ventral tegmental area (VTA), may be important for the development of exaggerated fear responding. Among the forebrain regions innervated by this pathway, the amygdala is an essential component of the neural circuitry of conditioned fear. The functional role of the dopaminergic pathway connecting the VTA to the basolateral amygdala (BLA) in fear and anxiety has received little attention. In vivo microdialysis was performed to measure dopamine levels in the BLA of Wistar rats that received the dopamine D(2) agonist quinpirole (1 μg/0.2 μl) into the VTA and were subjected to a fear conditioning test using a light as the conditioned stimulus (CS). The effects of intra-BLA injections of the D(1) antagonist SCH 23390 (1 and 2 μg/0.2 μl) and D(2) antagonist sulpiride (1 and 2 μg/0.2 μl) on fear-potentiated startle (FPS) to a light-CS were also assessed. Locomotor performance was evaluated by use of open-field and rotarod tests. Freezing and increased dopamine levels in the BLA in response to the CS were both inhibited by intra-VTA quinpirole. Whereas intra-BLA SCH 23390 did not affect FPS, intra-BLA sulpiride (2 μg) inhibited FPS. Sulpiride's ability to decrease FPS cannot be attributed to nonspecific effects because this drug did not affect motor performance. These findings indicate that the dopamine D(2) receptor pathway connecting the ventral tegmental area and the basolateral amygdala modulates fear and anxiety and may be a novel pharmacological target for the treatment of anxiety.     

成瘾药物心理依赖及复发的脑机制研究

围绕学习、记忆、情绪及应激等心理因素与复发的关系,应用阿片类物质心理依赖研究条件性位置偏爱,条件性位置厌恶,Morris水迷宫量化觅药动机模型,行为及条件性行为敏感化等多种动物行为模型,从情绪相关学习、记忆在成瘾行为中的作用,不同神经核团与神经递质系统活动性的改变,应激相关因素易化的成瘾易感性,自然奖赏与成瘾药物奖赏相关记忆的比较研究等方面,对应激与记忆相关的吗啡心理依赖及复发的脑机制进行了系列研究     

The central amygdala projection to the substantia nigra reflects prediction error information in appetitive conditioning

The central amygdala nucleus (CeA) plays a critical role in cognitive processes beyond fear conditioning. For example, intact CeA function is essential for enhancing attention to conditioned stimuli (CSs). Furthermore, this enhanced attention depends on the CeA's connections to the nigrostriatal system. In the current study, we examined the role of the CeA's connections to two midbrain dopamine regions, the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA), in processing CS information when predictions of reward or nonreward were confirmed or disconfirmed. Initially, two different retrograde tracers were injected into the SNc and the VTA of rats, to label CeA cells. Different groups of rats then received a visual CS either paired or unpaired with food. Finally, Fos induction was assessed after a test session in which rats were exposed to the visual CS alone or paired with food. Colabeling of Fos and the retrograde tracer(s) showed that CeA neurons projecting to the SNc, but not to the VTA, were engaged in processing CS information when the training and testing conditions differed. These results suggest that the CeA-nigral pathway represents prediction error information during appetitive conditioning.     

Observational learning in mice can be prevented by medial prefrontal cortex stimulation and enhanced by nucleus accumbens stimulation

The neural structures involved in ongoing appetitive and/or observational learning behaviors remain largely unknown. Operant conditioning and observational learning were evoked and recorded in a modified Skinner box provided with an on-line video recording system. Mice improved their acquisition of a simple operant conditioning task by observational learning. Electrical stimulation of the observer's medial prefrontal cortex (mPFC) at a key moment of the demonstration (when the demonstrator presses a lever in order to obtain a reward) cancels out the benefits of observation. In contrast, electrical stimulation of the observer's nucleus accumbens (NAc) enhances observational learning. Ongoing cognitive processes in the demonstrator could also be driven by electrical stimulation of these two structures, preventing the proper execution of the ongoing instrumental task (mPFC) or stopping pellet intake (NAc). Long-term potentiation (LTP) evoked in these two cortical structures did not prevent the acquisition or retrieval process--namely, mPFC and/or NAc stimulation only prevented, or modified, the ongoing behavioral process. The dorsal hippocampus was not involved in either of these two behavioral processes. Thus, both ongoing observational learning and performance of an instrumental task require the active contribution of the mPFC and/or the NAc.     

奖赏环路与阿片成瘾:喙内侧被盖核的调节作用

喙内侧被盖核(RMTg)位于腹侧被盖区(VTA)的尾部, 富含抑制性的γ-氨基丁酸(GABA)能神经元.RMTg是中脑边缘多巴胺系统的一个综合调节器.它的GABA能神经元接受外侧缰核(LHb)的输入, 然后投射到VTA多巴胺能神经元, 进而抑制多巴胺的释放.这三个脑区是奖赏环路的重要组成部分, 其中RMTg在阿片类物质激活的奖赏环路中尤为重要.阿片类物质主要通过抑制RMTg GABA能神经元使VTA多巴胺能神经元去抑制, 进而激活奖赏系统.因此, RMTg有望成为治疗药物成瘾(尤其是阿片成瘾)的一个重要靶点.此外, 胆碱类物质作用于RMTg的毒蕈碱受体能够抑制阿片类物质诱导的奖赏效应.未来研究应深入探讨RMTg调控的负性奖赏环路, 这对弱化觅药动机,促进消退和戒断具有重要意义.     

Extinction-induced neuroplasticity attenuates stress-induced cocaine seeking: a state-dependent learning hypothesis

Chronic drug use weakens excitatory neocortical input to the nucleus accumbens (NAc). We previously reported that extinction training, a form of inhibitory learning that progressively reduces cocaine-seeking behaviour when reward is withheld, reverses this deficit by up-regulating GluR1 and GluR2/3 subunits of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) glutamate receptors in the NAc. The level of GluR1 up-regulation is positively associated with a reduction in cocaine seeking, suggesting that extinction-induced up-regulation in AMPA receptors in the NAc opposes motivational influences that maintain cocaine seeking. This hypothesis is supported by the finding that over-expression of GluR1 and GluR2 in the NAc facilitates extinction of cocaine self-administration. Furthermore, a single extinction training session conducted during GluR1 and GluR2 over-expression strongly and selectively attenuates the ability of an environmental stressor to trigger relapse to cocaine seeking long after GluR1 and GluR2 over-expression declines. These results could suggest that excitatory input to the NAc promotes extinction learning, but only when memory is recalled under stressful situations. Recent studies indicate that both environmental stress and the frustrative stress of withholding reward during extinction of drug self-administration induce similar neurochemical events in the NAc. These neurochemical events could impose a "state-dependency" on extinction learning such that subsequent exposure to stress acts as a cue to enhance retrieval of extinction memory. Our results suggest that extinction-induced up-regulation in NAc AMPA receptors acts reciprocally to facilitate state-dependent extinction learning, as stressful situations evoke extinction memories that exert powerful inhibitory control over drug-seeking behaviour. These results may have important therapeutic implications for behaviour-based approaches aimed at treating drug addiction.     

Delayed backward conditioning of place preference induced by wheel running in rats

Backward conditioning of place preference has been obtained in hungry rats when wheel running (the rewarding US) is followed immediately by exposure to a distinctive chamber (the CS). We tested whether such backward conditioning would occur with a 10-min delay. In each of four paired exposures, a period of wheel running (2 or 22 h, in separate experiments) was followed by 10 min in the home cage and then 30 min in the CS chamber. Control rats were put in the CS chamber without wheel running. In other similar experiments, a 0-, 10-, or 30-min delay separated wheel running from exposure to the CS chamber. Reliable conditioned place preference (CPP) occurred when the delay was 0 or 10 but not 30 min. The strength of CPP decreased as the delay increased. These findings imply that the reward process initiated by wheel running remains active for some time after running stops. They support the view that the suppression of feeding produced by wheel running in hungry rats (activity anorexia) is mediated by this reward process.