Bibliometric analysis of nicotine research in China during the period of 1991 to 2007

With the widespread exposure of people to nicotine through recreational use of tobacco products, research into nicotine has attracted increasing attention. Tobacco smoking is by far the most important cause of lung cancer. As the world's largest producer and consumer of tobacco products, China bears a large proportion of the global burden of smoking-related disease; therefore, information on nicotine publications should be collected to formulate future research policy. In the present study, we investigated nicotine-related research articles published by Chinese authors that were indexed in the Science Citation Index (SCI) from 1991 to 2007. An indicator "citations per publication" (CPP) was used in the study to evaluate the impact of journals, articles, and institutes. The quantity of publications has increased at a quicker pace than the worldwide trend. Article visibility, measured as the frequency of being cited, also increased during the period. However, the overall quality of articles, based on the impact factor of journals publishing those articles, dropped behind the worldwide average level. There has been an increase in international collaboration, mainly with researchers in the USA. The average CPP of international co-authorship articles was higher than that of single country publications. Besides the USA, nicotine research in China will benefit from more collaboration with Taiwan, England, and Germany. Some 110 of 264 articles were published by a single institute, and the top six institutes were compared from various angles. Seventy-two subject categories were covered, and trends (in terms of both quantity and quality) of nicotine research in China were compared with worldwide trends. In addition, analysis of keywords in both nicotine and lung cancer research fields was applied to indicate research interests. Mutual cooperation among multiple disciplines needs further strengthening.

Effects of addiction-associated and affective stimuli on the attentional blink in a sample of abstinent opiate dependent patients

The attentional blink reveals the limits of the brain's ability in information processing. It has been extensively studied in people with neurological and psychiatric disturbances to explore the temporal characteristics of information processing and exami

Interaction of corticosterone and nicotine in regulation of prepulse inhibition in mice

The aim of the present Study was to investigate if different levels of circulating corticosterone (CORT) modulate the effect of nicotine on prepulse inhibition (PPI), a measure of sensorimotor gating that is disrupted in schizophrenia and other mental illnesses. Four groups of mice were investigated: sham-operated, adrenalectomized (ADX) and implanted with a cholesterol pellet, ADX and implanted with a 10 mg CORT pellet, or ADX and 50 mg, of CORT. Different CORT levels or doses of nicotine did not significantly affect startle responses. Baseline PPI was significantly reduced in mice implanted with the highest dose of CORT. In ADX mice implanted with cholesterol, nicotine treatment influenced PPI depending on the prepulse intensity. In ADX mice implanted with 50 mg of CORT, treatment with 10 mg/kg of nicotine caused a significant increase in PPI at all prepulse intensities. Binding studies showed that corticosterone treatment had significantly affected nicotinic acetylcholine receptor (nAChR) density in the mouse brain. Treatment with 50 mg CORT decreased I-125-epibatidine binding in the globus pallidus and I-125-alpha-bungarotoxin binding in the claustrum. These results suggest a possible interaction of corticosterone and nicotine at the level of the alpha4- and alpha7-type nAChR in the regulation of PPI. In situations of high circulating levels of corticosterone, nicotine may be beneficial to restore disruption of PPI. (C) 2004 Elsevier Ltd. All rights reserved.

Stress enables synaptic depression in CA1 synapses by acute and chronic morphine: Possible mechanisms for corticosterone on opiate addiction

The hippocampus, being sensitive to stress and glucocorticoids, plays significant roles in certain types of learning and memory. Therefore, the hippocampus is probably involved in the increasing drug use, drug seeking, and relapse caused by stress. We have studied the effect of stress with morphine on synaptic plasticity in the CA1 region of the hippocampus in vivo and on a delayed-escape paradigm of the Morris water maze. Our results reveal that acute stress enables long-term depression (LTD) induction by low-frequency stimulation (LFS) but acute morphine causes synaptic potentiation. Remarkably, exposure to an acute stressor reverses the effect of morphine from synaptic potentiation ( similar to 20%) to synaptic depression ( similar to 40%), precluding further LTD induction by LFS. The synaptic depression caused by stress with morphine is blocked either by the glucocorticoid receptor antagonist RU38486 or by the NMDA-receptor antagonist D-APV. Chronic morphine attenuates the ability of acute morphine to cause synaptic potentiation, and stress to enable LTD induction, but not the ability of stress in tandem with morphine to cause synaptic depression. Furthermore, corticosterone with morphine during the initial phase of drug use promotes later delayed-escape behavior, as indicated by the morphine-reinforced longer latencies to escape, leading to persistent morphine-seeking after withdrawal. These results suggest that hippocampal synaptic plasticity may play a significant role in the effects of stress or glucocorticoids on opiate addiction.

Molecularly imprinted solid-phase extraction sorbent for removal of nicotine from tobacco smoke

A sorbent showing specific affinity for nicotine was prepared by molecular imprinting technique, using nicotine as the template, methacrylic acid (MAA) as the functional monomer, ethyleneglycol dimethacrylate (EDMA) as the crosslinker and chloroform as the porogen. UV spectroscopic analysis in the molecular imprinting prepolymerization stage confirmed that nicotine could complex with the functional monomer by electrostatic interaction (ionic interaction and hydrogen bonding). The affinity and the binding properties of the imprinted polymer towards nicotine were investigated by equilibrium rebinding experiments. The results indicated the presence of nicotine-specific binding sites in the imprinted polymer, and that the imprinted polymer had a good capacity (90 mumol/g polymer) for nicotine. The elution conditions were optimized on the column packed with the imprinted polymer to elute nicotine quantitatively. The imprinted polymer was used as a solid-phase extraction (SPE) material for the removal of nicotine from tobacco smoke. The results obtained showed that the imprinted polymer was superior in terms of removing nicotine in tobacco smoke, compared with the commercial filter tip.

EEG activities in the orbitofrontal cortex and dorsolateral prefrontal cortex during the development of morphine dependence, tolerance and withdrawal in rhesus monkeys

Investigating the activities of the prefrontal cortex (PFC) in the process of addiction is valuable for understanding the neural mechanism underlying the impairments of the PFC after drug abuse. However, limited data are obtained from primate animals and few studies analyze Electroencephalogram (EEG) in the gamma band, which plays an important role in cognitive functions. In addition, it is yet unclear whether drug abuse affects the orbitofrontal cortex (OFC) and dorsolateral PFC (DLPFC) - the two most important subregions of the PFC - in similar ways or not. The aim of this study is to address these issues. We recorded EEG in the OFC and DLPFC in three rhesus monkeys. All animals received a course of saline (NaCl 0.9%, 2 ml) injection (5 days) followed by 10 days of morphine injection (every 12 h), and then a further series of saline injection (7 days). A main finding in the present study was that morphine decreased EEG power in all frequency bands in a short period after injection in both the OFC and DLPFC in monkeys. And gamma power decreased not just in short period after morphine injection but lasted to 12 h after injection. Moreover, we found that although the changes in EEG activities in the OFC and DLPFC at 30-35 min after injection were similar, the DLPFC was more sensitive to the effect of morphine than the OFC. (c) 2005 Elsevier B.V. All rights reserved.

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 induces Beclin 1-and ATG5-dependent autophagy in human neuroblastoma SH-SY5Y cells and in the rat hippocampus

Chronic exposure to morphine can induce drug addiction and neural injury, but the exact mechanism is not fully understood. Here we show that morphine induces autophagy in neuroblastoma SH-SY5Y cells and in the rat hippocampus. Pharmacological approach shows that this effect appears to be mediated by PTX-sensitive G protein-coupled receptors signaling cascade. Morphine increases Beclin 1 expression and reduces the interaction between Beclin 1 and Bcl-2, thus releasing Beclin 1 for its pro-autophagic activity. Bcl-2 overexpression inhibits morphine-induced autophagy, whereas knockdown of Beclin 1 or knockout of ATG5 prevents morphine-induced autophagy. In addition, chronic treatment with morphine induces cell death, which is increased by autophagy inhibition through Beclin 1 RNAi. Our data are the first to reveal that Beclin 1 and ATG5 play key roles in morphine-induced autophagy, which may contribute to morphine-induced neuronal injury.

应激和成瘾对海马突触可塑性及学习记忆的影响

海马突触可塑性是从细胞和分子水平上来阐述学习记忆机制，是学习记忆比 较直观的物质基础的一个体现。成瘾，是一种病态的、不可控制的吸食成瘾性药 物的行为，从某种角度来看，它也是一种记忆，通过篡夺正常生理神经通路产生 比正常生理反应强烈的可塑性，进而形成更有害的记忆。成瘾和学习记忆有很多 通路上甚至机制上的交叉，所以一部分研究学习记忆的方法可以用来研究成瘾。 应激，会影响正常的生理状态，并引发进一步的生化反应，进而影响到海马突触 可塑性和学习记忆。应激既然可以影响到学习记忆，而且成瘾的部分特征和学习 记忆又很相似，同时成瘾过程中基本上也伴随着应激，那么，应激在成瘾过程中 到底起着什么样的作用呢?它又是如何起作用的呢？ 本文的实验致力于回答其中的部分问题，我们通过对吗啡成瘾过程中海马的 突触可塑性和学习记忆的研究发现：单次急性吗啡处理会在非应激动物上诱导出 突触增强，但是应激可以逆转吗啡引起的突触增强，诱导出长时程的突触抑制， 但是皮质酮的拮抗剂RU38486 可以阻断这种效果。皮质酮和吗啡可以产生动物 延迟逃避的现象，说明应激在成瘾过程中的重要影响。本实验对于应激在成瘾方 面的影响进行了研究，进一步的揭开了应激在其中的部分作用机制，这对于以后 的成瘾的形成及复吸的治疗都有一定的贡献。

海马突触可塑性与异常记忆

5-羟色胺(5-HT)是中枢神经系统内非常重要的神经递质，广泛参与各种行为和生理过程。5-羟色胺功能低下可导致多种精神类疾病尤其是焦虑、抑郁和创伤后应激障碍等，而这些疾病都伴有学习和记忆的障碍；海马是参与学习记忆的重要脑区。海马接受5-HT神经元的直接投射且富含5-HT受体，因而海马也可以通过5-HT系统调控焦虑、抑郁及学习记忆。海马突触可塑性是学习记忆的细胞分子机制，是学习记忆的基础。我们条件性敲除转录因子Lmx1b得到中枢5-HT缺失小鼠，利用该小鼠进行中枢神经系统5-HT功能的研究。我们发现该小鼠的脑结构和运动能力正常；水迷宫空间学习能力正常，但空间记忆受损；焦虑水平降低，但是环境恐惧学习和记忆能力增强，增强的恐惧记忆能被外源给予的5-HT逆转；在中枢5-HT缺失小鼠中，应激对海马可塑性的作用即损伤LTP易化LTD消失，外源给予5-HT可以恢复应激的效果。这些结果提示应激导致海马LTP损伤可能是保护机制，缺乏这种保护机制可能导致恐惧记忆相关的创伤后应激障碍(PTSD)的易感。成瘾的核心特征是对药物的强迫性渴求和复吸。成瘾与学习记忆有很多共同的脑区和分子通路，它可能通过篡夺正常生理神经通路而产生比正常生理反应更强烈的可塑性，形成有害的异常记忆。以前的报道证实海马的兴奋性突触可塑性在成瘾过程中的适应性改变可能是成瘾的机制；但是成瘾涉及复杂的生物机制，因而不可能仅是兴奋性突触可塑性的贡献。我们研究了5-HT系统和抑制性系统（主要是GABA能系统）在成瘾中的贡献。利用中枢5-HT缺失小鼠，我们发现5-HT缺失小鼠的吗啡显著地易化了5-HT CKO的海马LTP，同时也导致成瘾行为持续不消退；5-HT和5-HT1a受体激动剂能逆转此现象。这提示毒品成瘾可能导致中枢5-HT缺失，进而增强海马LTP，使毒品相关记忆牢固不消退。GABA能系统是中枢神经系统最重要的抑制性系统，我们研究发现一次吗啡对内源性大麻受体（CB1R）依赖的抑制性突触的长时程抑制（Inhibitory long-term depression，I-LTD）没有影响，成瘾后I-LTD抑制，而吗啡成瘾后戒断导致了内源性大麻受体(CB1R)和L-型钙通道(LTCC)依赖的GABA能LTD (I-LTD)，使I-LTD增大了一倍，提示在吗啡成瘾阶段过程中，有组合突触可塑性发生，进而增强了突触可塑性的调控范围。 本论文是对中枢5-HT系统对海马兴奋性突触可塑性在焦虑、应激、成瘾等异常记忆中的调节作用以及海马抑制性系统在成瘾和戒断中的贡献进行研究，表明恐惧记忆和毒品成瘾记忆存在许多共同的细胞分子机理，对今后治疗焦虑、创伤后应激障碍和成瘾提供了新的思路。

吗啡戒断的应激和突触可塑性机理

突触可塑性（syanptic plasticity）是指在某种条件下突触传递效能的持 续性变化，是从细胞和分子水平上来阐述学习记忆的机制，是学习记忆的基础， 存在多种形式，主要包括长时程增强（LTP）和长时程抑制（LTD）等。应激（stress） 就是指机体对各种内、外界刺激因素所作出的适应性反应的过程。应激会影响正 常的生理状态，并引发进一步的生化反应，进而影响到海马突触可塑性和学习记 忆。成瘾（addiction）是指对药物的使用失去控制，或者强迫性的寻求和使用 药物，而不顾由此带来的恶性后果，从某种角度来看，它也是一种记忆，通过篡 夺正常生理神经通路而产生比正常生理反应更强烈的可塑性，进而形成有害的异 常记忆，其最核心的特征就是对药物的强迫性渴求和复吸。成瘾一旦形成，可能 成为伴随一生的状态，即使经过长期的戒断，也会表现出强烈的渴求以及有复吸 的高度危险性。成瘾和学习记忆有很多神经通路甚至分子机制上的交叉，所以一 部分研究学习记忆的方法可以用来研究成瘾，反之，成瘾也是一种很好的研究学 习记忆的模型。 既然应激可以影响突触可塑性和学习记忆，而对于吸毒者来说，戒断本身就 是一种应激，那么探讨应激和戒断对突触可塑性和学习记忆的影响，对临床上的 戒毒工作将有着重要意义。基于此，本文将围绕这个问题而开展实验工作。 我们采用电生理、行为学及生化等研究方法对吗啡戒断过程中突触可塑性和 学习记忆,以及应激在其中的作用进行了一些研究。电生理的结果表明：在吗啡 戒断过程中,海马LTP 的大小呈现出倒－U 型曲线，其中戒断4 天时LTP 最大。 应激可以将最大的LTP 提前在戒断18 小时出现，而糖皮质激素受体拮抗剂米非司酮或者熄灭剂量的吗啡能够阻断最大的LTP 出现。同时，海马下托－伏隔核通 路的突触可塑性也出现类似的戒断时间依赖性的改变。行为学研究发现：戒断过 程中，大鼠的疼痛阈值降低，同时降低急性吗啡的镇痛效应，而这种变化能够被 应激或米非司酮所改变。另外，条件位置偏爱实验结果显示吗啡条件位置偏爱的 形成依赖于海马和伏隔核糖皮质激素受体。生化实验结果显示：戒断过程中，AMPA 受体亚型GluR1 和GluR2/3 及其调节分子CaMKⅡ会出现表达动态改变。 本实验对于应激和戒断对突触可塑性和学习记忆的影响进行了研究，进一步 揭开了应激在戒断中的部分作用机制，这将对于以后研究治疗毒品渴求和复吸有 一定的贡献

吗啡成瘾与学习记忆的关系及其相关脑机制的研究

药物成瘾是一种慢性、易复发的脑疾病，以强迫性的药物寻求行为和药物使用行为为特征。尽管人们关注成瘾已一个世纪有余，对其脑机制也有一定的了解，但至今为止，我们仍然不能彻底治愈这种危害人类健康的疾病。本论文的研究目的在于从学习记忆的角度去研究药物成瘾的脑机制，为我们进一步理解药物成瘾相关记忆的特点、寻找可能的治疗方法提供一定的实验依据。在本论文中，第一部分，我们对药物成瘾相关脑机制的研究情况进以综述。通过分别介绍有关药物成瘾的一些理论模型，进而从不同的角度解释有关成瘾的一些现象。但是，这些模型各有利弊，我们很难用一种模型去解释其所有的方面，这也充分说明成瘾是一种极其复杂的脑疾病。针对目前大家比较公认的学习记忆模型，我们进行了进一步的详细介绍，分别从参与药物成瘾的脑区和核团、神经环路、神经递质系统以及分子和细胞机制的角度对药物成瘾和学习记忆的相关性进行了总结。第二部分，我们介绍了我博士期间的一些研究工作，围绕药物成瘾的脑机制以及如何利用这些知识来设计方案去治疗成瘾。我们分别研究了药物相关记忆的形成，记忆的保持以及记忆的再巩固过程的特征，并利用这些特征来探讨治疗成瘾的可行性。在研究方法方面，我们利用药物相关记忆研究的行为学范式——条件化位置偏好模型，并结合药理学、脑区局部损伤等方法研究了药物相关记忆的特征；此外，我们用药理学、经颅直流电刺激的手段初步探讨治疗成瘾的方法可行性。通过以上研究，我们发现：吗啡相关记忆的产生过程需要体感皮层的参与，而记忆提取导致渴求的过程需要内感觉皮层的参与；吗啡使用的剂量和用药时间的规律性在吗啡相关记忆的保持强度和抗消退方面发挥着重要作用；吗啡相关记忆与其他的记忆，如空间记忆等不同，在提取之后用β肾上腺素受体的拮抗剂不能阻断其再巩固过程；用经颅电刺激的方法去失活药物成瘾相关的脑区，可以显著的降低吸烟被试的抽烟量。虽然我们的研究结果揭示了药物相关学习记忆的一些重要特征，并初步探讨了一些治疗成瘾的方法的可行性，但是，由于药物成瘾的复杂性，我们完全研究清楚其脑机制，并彻底治疗成瘾仍需大量的后续研究。

1、吗啡成瘾及吗啡对其他学习记忆的影响 2、老年猕猴初级视觉皮层细胞时间及空间特性的改变

一、 药物滥用是一种慢性、复发性脑疾病。药物滥用将导致药物成瘾（addiction），其主要表现有药物依赖、药物耐受、药物敏感化以及药物停用后的戒断症状（withdraw symptom）。药物成瘾的核心特征是强迫性觅药和用药行为。药物成瘾会导致药物滥用者认知功能的损伤和认知偏差，并会造成滥用者情绪异常。药物成瘾是一个复杂的生物学过程，有着及其复杂的机理。对药物成瘾机制的解释有很多种，主要认为成瘾过程是一种学习记忆过程，学习记忆的机制在药物成瘾过程中起到了非常重要的作用。首先，学习记忆和药物成瘾过程都受到了相似的神经营养因子以及神经递质系统的调控，例如：它们都受cAMP，CREB等调控因子的调控。其次，研究发现与成瘾相关的线索，如用药有关的人物、地点或暗示等，在药物戒断很长时间后都会恢复吸毒者的用药行为。并且，当把与成瘾相关的线索呈现给毒品戒断中的人时，这些人会出现心率、呼吸加快，血压升高等现象，甚至表现出明显的渴求行为。药物对学习记忆的影响是复杂的，虽然重复使用药物会导致药物成瘾，并且这个过程需要学习记忆机制的参与，但同时使用吗啡却会对其他类型的学习记忆（如：恐惧性学习记忆、一次性被动回避学习记忆和水迷宫空间学习记忆）造成破坏。学习前给予吗啡可以剂量及状态依赖地破坏被动回避试验以及空间辨别试验的记忆获取过程。学习过程结束后立即给予吗啡可以破坏一次性被动回避试验、主动回避试验和恐惧条件化试验的记忆巩固过程。测试前给予吗啡可以破坏空间辨别试验的记忆提取过程。本研究的目的在于更进一步地了解使用吗啡导致吗啡成瘾以及使用吗啡导致学习记忆的各个阶段受损的机制。为此我们采用了药理学以及多种行为学的方法，1、用PTZ诱发的癫痫持续状态干扰吗啡成瘾的学习记忆过程，进一步比较了吗啡成瘾的学习记忆与其他学习记忆，例如：空间学习记忆以及食物奖赏学习记忆的机制有何异同；2、研究了β-肾上腺素系统与阿片系统在空间记忆巩固过程中的相互作用；3、我们还研究了NMDA受体的激动剂和拮抗剂在吗啡破坏空间记忆提取过程中的作用。研究结果发现： 1．戊四唑诱发的癫痫持续状态，对吗啡建立的条件化位置偏好没有任何影响，动物仍然对阳性箱（吗啡匹配箱）表现出明显的偏好。但是癫痫持续状态破坏了食物建立的条件化位置偏好，并且还破坏了水迷宫和Y迷宫检测的空间记忆。癫痫持续状态破坏了食物建立的条件化位置偏好，原因不是由于其影响了动物的食欲。此外，癫痫持续状态也没有持续地破坏动物的活动能力，因此，对动物活动量的影响也不是造成其他学习记忆破坏的原因。这些结果说明，吗啡成瘾的学习记忆和普通的学习记忆在机制上可能存在不同之处。为了说明这个问题，我们还需要进行其他更深入的研究。 2、训练后立即单独注射吗啡（0.25和2.5 mg/kg）或心得安（2，10和20 mg/kg）都不会破坏动物Y-迷宫空间记忆的巩固过程，动物仍然能识别新异环境，并在里面停留较长时间。但是，训练后同时注射吗啡和心得安却可以破坏动物空间记忆的巩固过程。并且，较高剂量的吗啡（2.5 mg/kg）加上较高剂量的心得安（10和20 mg/kg）对记忆的破坏更严重，实验组动物在新异环境停留的时间显著低于对照组。这说明阿片系统和去甲肾上腺素系统在破坏记忆巩固的过程中可能有协同作用。 3、记忆提取前30分钟注射吗啡（1和10 mg/kg）可以剂量依赖地破坏Y-迷宫空间记忆的提取。单独注射NMDA受体的激动剂NMDA（1，2和4 mg/kg）对动物的空间记忆提取没有影响，但是，单独注射NMDA受体拮抗剂MK-801（0.05，0.1和0.2 mg/kg）剂量依赖地破坏了空间记忆的提取。同时注射吗啡（10 mg/kg）和NMDA（2 mg/kg）可以阻断吗啡对空间记忆造成的破坏作用。相反，共同注射吗啡（1 mg/kg）和MK-801（0.05 mg/kg）可以加重吗啡对空间记忆造成的破坏作用。这说明谷氨酸系统可以干扰吗啡对记忆提取过程的影响。 二、衰老严重地影响了人们的视觉功能，然而眼睛光学系统的老年性改变并不能完全解释清楚这种视觉功能衰退。一般认为是神经系统的退化导致了这种老年性功能降低。但是，研究显示视网膜（retina）和外膝体（dorsal lateral geniculate nucleus, dLGN）在衰老的过程中神经元的数量和体积以及神经元的功能特性，如对比度敏感性、空间分辨率等，都没有明显的变化，因此，人们推测老化导致的神经系统的变化发生在更高级的视觉皮层。过去几年的研究发现老年动物视觉皮层细胞发生了一系列反应特性的改变，如：老年动物皮层细胞的方向选择性和方位选择性降低以及细胞反应的潜伏期延长。这些细胞水平的变化被认为是老年性视觉功能衰退的神经机制。为了更全面地了解衰老过程对视觉皮层的影响以及细胞反应改变与整体功能降低之间的关系，本研究采用活体动物细胞外单位记录的方法，比较了青年和老年猕猴初级视觉皮层细胞时间反应特性和空间反应特性的差异。研究结果发现：老年动物初级视觉皮层细胞的时间频率和空间频率敏感性明显比年轻动物降低。表现为老年动物初级视觉皮层细胞的最优时间和空间频率、空间分辨率（spatial resolution, SR）和较高时间截至频率（high temporal frequency cut-off, TF50）都显著低于年轻动物初级视觉皮层细胞，同时伴随着这些功能的降低，老年动物初级视觉皮层细胞的自发放增加，对视觉刺激的反应增加，但是信噪比却显著降低。这些结果表明，老年动物初级视觉皮层细胞的功能在老化过程中都普遍降低。这可能是导致老年人视觉功能降低的原因。

慢性阿片类物质滥用对空间认知功能的影响及嗅觉系统与吗啡成瘾的相互作用

中文摘要 　 Ⅰ　慢性阿片类物质滥用对空间认知功能的影响本章首先对成瘾的神经生物学机制进行综述，然后介绍我的实验研究内容，实验目的是探讨海马在阿片类成瘾中的作用，及阿片类物质滥用对空间认知功能的影响。实验1采用单细胞记录技术，记录自由活动大鼠在慢性吗啡给予后戒断期间海马CA1区神经元发放频率，比较其在吗啡相关环境（阳性环境）及无关环境（阴性环境）中神经元发放频率的变化，且比较神经元发放变化率在各组间的差异。实验2检测了在海洛因戒断初期海洛因依赖者的地图/图标跟随及地图/图标工作记忆的能力。实验3采用Y迷宫行为范式检测在戒断不同时期，慢性吗啡给予对小鼠Y迷宫空间识别能力的影响。实验结果如下：实验1：吗啡戒断后，大鼠海马CA1区部分神经元在阳性环境及阴性环境中的发放率有显著性差异，这些神经元分为两类：Ⅰ类神经元在阳性环境中发放频率高于在阴性环境，Ⅱ类神经元在阳性环境中发放频率低于在阴性环境，其中吗啡组的Ⅱ类神经元发放变化率与盐水组相比存在显著性差异。实验2：海洛因依赖者，尤其女性海洛因依赖者，在地图跟随及地图/图标工作记忆中的成绩明显低于正常被试。实验3：在吗啡戒断第2天、第9天、第19天，小鼠Y迷宫空间识别记忆能力均受到损伤。以上实验结果表明，海马神经元在吗啡相关环境与无关环境中发放频率不同，从而编码了环境刺激与药物经历相关的记忆，在阿片类药物成瘾中起到一定作用；以及阿片类物质滥用损伤了大脑空间认知功能。 Ⅱ　嗅觉系统与吗啡成瘾的相互作用本章首先对嗅觉系统的功能及脑疾病引起嗅觉功能异常进行了综述，然后介绍我的实验研究内容，实验目的是探讨嗅觉系统在吗啡成瘾过程中的作用，及慢性吗啡给予对嗅觉功能的影响。实验1：利用条件化位置偏好模型（CPP），研究气味线索对吗啡依赖及渴求的影响。结果发现，单一嗅觉刺激使小鼠建立条件化位置偏好，形成吗啡依赖。当改变外界环境，动物进入完全新异的环境，依然寻求与吗啡相关的气味线索，说明吗啡相关气味线索能有效诱发小鼠对吗啡的渴求。实验2：研究短期及长期吗啡给予后小鼠嗅觉功能的变化。结果发现， 4天或21天的吗啡给予导致小鼠嗅觉敏感度降低（嗅觉阈值升高），而嗅觉辨别能力没有显著影响。小鼠嗅觉记忆能力受到损伤，随着吗啡给予时间的延长，这种记忆损伤更加明显。我们的实验表明嗅觉系统在吗啡依赖及渴求过程起到非常重要的作用，吗啡成瘾导致部分嗅觉功能的损伤。与药物相关的环境线索是诱发渴求及复吸的原因之一，因此，至少在啮齿类动物模型上，用嗅觉刺激作为药物相关的环境线索来研究渴求及复吸的机制，可能是较好的研究方法。