气味线索对小鼠形成吗啡依赖及渴求的影响

利用条件化位置偏好模型研究气味线索对吗啡依赖及渴求的影响,其结果发现,单一嗅觉条件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后依然寻求与吗啡相关的气味线索,说明吗啡相关气味条件线索诱发了小鼠对吗啡的渴求。多巴胺D1或D2受体拮抗剂能阻断小鼠对气味线索的寻求。该结果表明嗅觉系统在药物成瘾过程中具有一定作用。     

乙醇和乙醛在采后园艺作物保鲜中的作用

概述了乙醇和乙醛对果蔬和切花采后生理,如乙烯合成、呼吸作用、果实后熟软化和风味的影响,并对乙醇和乙醛在防治果蔬采后病虫害和生理病害中的应用作了介绍。     

血浆脑源性神经营养因子水平与酒依赖患者认知功能的研究

目的:研究酒依赖患者与正常对照者之间血浆脑源性神经营养因子(BDNF)水平的差异;研究酒依赖患者认知功能与血浆BDNF水平的关系.方法:纳入符合美国精神障碍诊断与统计手册第四版(DSM-Ⅳ)酒依赖诊断标准的酒依赖患者38例和正常对照30例,应用威斯康星卡片分类测验(WCST)和理解记忆测验评定入组对象的认知功能,并应用酶联免疫吸附试验(ELISA法)检测血浆BDNF水平,统计方法采用t检验、秩和检验和直线相关分析.结果:酒依赖患者组血浆BDNF水平低于对照组[(3138.79± 1195.38)pg/ml与(3656.03± 899.56)pg/ml,P＜0.05].酒依赖患者组威斯康星卡片分类测验(WC ST)中的正确数和完成分类数的得分低于对照组,有统计学差异(P＜0.01);而错误数、持续性错误数、随机错误数均高于对照组,差异有统计学意义(P＜0.01).患者组理解记忆得分低于对照组(P＜0.01).患者组血浆BDNF水平与以下指标呈正相关:威斯康星卡片分类测验中的正确数(r=0.90755,P＜0.0001)、完成分类数(r=0.78427,P＜0.0001);理解记忆得分(r=0.48340,P=0.0021);患者组血浆BDNF水平与以下指标呈负相关:威斯康星卡片分类测验中的错误数(r=-0.90883,P＜0.0001)、持续性错误数(r=-0.82513,P＜0.0001)、随机错误数(r=-0.75373,P＜0.0001).结论:(1)本组酒依赖患者血浆BDNF水平低于正常;(2)本研究提示酒依赖患者认知功能损害程度越重其血浆BDNF水平就越低.     

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。     

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。     

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。     

多巴胺D2受体基因TaqIB多态性与酒依赖的关系

目的:探讨汉族人群中多巴胺D2受体(DRD2)基因TaqIB多态性与酒依赖的相关性.方法:采用聚合酶链式反应-限制性片断长度多态性(PCR-RFLP)技术,检测酒依赖组(80例)和对照组(95例)的DRD2基因TaqIB多态性的基因型和等位基因频率.结果:酒依赖组和时照组的DRD2基因TaqIB多态性的基因型和等位基因频率有显著性差异,等位基因B2的携带者显著降低其嗜酒的发生率(OR:1.636,P＜0.05).结论:本研究提示,在汉族人群中DRD2基因TaqIB多态性与酒依赖存在相关性,TaqIB2等位基因可能是降低酒依赖发病的影响因子.     

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。     

云南彝族人群CYP2E1基因多态性与酒依赖的关联性研究

目的：探讨云南彝族人群中的酒精依赖患者和云南彝族人群中健康人在CYP2E1基因的一个SNP（Rs3813867）的等位基因和基因型频率的不同,试图找出酒依赖的危险基因,比较它与其他人群之间在CYP2E1PstI位（rs3813867）基因多态性的不同。方法：对110个酒精依赖者和330名健康的志愿者不喝酒（对照组）的CYP2E1PstI位的多态性,等位基因频率和基因型频率进行测定。采用PCR—RFLP方法进行基因分型。结果：CYP2 E1 Psfl位的多态性,等位基因频率和基因型频率是相似的在酒精依赖者和对照组（72．7％vs72．1％,C1／C1）,（25．5％vs25．8％,C1／C2）,（1．8％vs2．1％为C1／C2）和（85．5％vs85％c1的）,（14．5％VSl5％为c2）。结论：CYP2E1的基因型和等位基因分布在酒精依赖组和对照组之间没有显着性差异（P〉0．05）,在这两个民族在AD组和对照组基因型分布有差异（P〈0．001）。     

乙醇与乙醛对心脏的影响及其可能机制的探讨

通过研究乙醇、乙醛对离体心脏和神经干的影响,探讨乙醇、乙醛对心脏作用的可能机制.用不同浓度的乙醇和乙醛处理牛蛙蛙心灌流标本和坐骨神经标本,用BL-420 系统对给药前后心脏的心率和振幅以及神经干最小刺激强度作记录.乙醇和乙醛可以引起神经兴奋性的改变从而影响神经冲动的传导,而且其影响具有明显的量效依赖关系,低浓度的乙醇和乙醛能使神经的兴奋性增加,高浓度则降低;乙醇对心脏的心率和振幅均有抑制作用,低浓度的乙醛对心脏心率和振幅有促进作用,高浓度的乙醛对心脏造成不可恢复的损伤.乙醇、乙醛对心脏的影响效果不同,但两者均可直接影响及通过神经而间接影响心脏的活动.     

Pleiotrophin differentially regulates the rewarding and sedative effects of ethanol

Pleiotrophin (PTN) is a cytokine with important roles in dopaminergic neurons. We found that an acute ethanol (2.0 g/kg, i.p.) administration causes a significant up‐regulation of PTN mRNA and protein levels in the mouse prefrontal cortex, suggesting that endogenous PTN could modulate behavioural responses to ethanol. To test this hypothesis, we studied the behavioural effects of ethanol in PTN knockout (PTN^?/?) mice and in mice with cortex‐ and hippocampus‐specific transgenic PTN over‐expression (PTN‐Tg). Ethanol (1.0 and 2.0 g/kg) induced an enhanced conditioned place preference in PTN^?/? compared to wild type mice, suggesting that PTN prevents ethanol rewarding effects. Accordingly, the conditioning effects of ethanol were completely abolished in PTN‐Tg mice. The ataxic effects induced by ethanol (2.0 g/kg) were not affected by the genotype. However, the sedative effects of ethanol (3.6 g/kg) tested in a loss of righting reflex paradigm were significantly reduced in PTN‐Tg mice, suggesting that up‐regulation of PTN levels prevents the sedative effects of ethanol. These results indicate that PTN may be a novel genetic factor of importance in alcohol use disorders, and that potentiation of the PTN signalling pathway may be a promising therapeutic strategy in the treatment of these disorders.

     

Involvement of Serotonin in the Pathogenesis of Alcohol Addiction

We studied the contents of serotonin (5-HT) in a few brain structures (hypothalamus, midbrain, and neocortex) and in blood of rats with genetically determined preference of either ethanol solution or water as a liquid for drinking (groups preferring ethanol, PE, or preferring water, PW, respectively). Rats of the PE group differed from PW animals by significantly higher levels of 5-HT in the hypothalamus and blood. Peroral introduction of 4 g/kg ethanol into PE rats resulted in rapid (in not more than 15 min) sharp increases in the 5-HT content in the hypothalamus, neocortex, and blood, but 45 min after ethanol introduction the 5-HT contents in the hypothalamus, midbrain, neocortex, and blood noticeably dropped. It is suggested that within this time interval condensation of 5-HT with acetaldehyde (AcAdh, the first metabolite of ethanol oxidation) is intensified. This results in the production of -carbolines, analogs of morphine-like alkaloids, which are ligands of the opioid receptors. Under conditions of the development of alcohol addiction (free access of PE animals to the ethanol solution and water for several months), the content of 5-HT in the brain structures and blood increased in a parallel manner with an increase in the daily consumption of alcohol. Our findings are proof of the significant involvement of the serotoninergic system in the development of the euphoria state after single alcohol consumption and motivation for its consumption in the course of formation of alcohol addiction.     

大鼠酒精躯体依赖及动机行为研究

目的：诱导大鼠产生酒精依赖,观察大鼠产生的躯体依赖及行为学改变。方法：20只雄性SD大鼠,其中饮酒组和对照组各10只。通过6％（v／v）酒精溶液作为饮酒组大鼠唯一饮水来源共28d,测量血酒精浓度。根据旷场行为、戒断症状和强迫游泳等方法来判断是否成功诱导大鼠产生酒精躯体依赖及动机行为改变。结果：整个实验过程饮酒组大鼠血酒精浓度没有发生明显变化。饮酒组大鼠旷场测试中水平活动量在饮酒第7d比对照组显著降低（P〈0．05）;垂直活动量在饮酒第7、14d比对照组显著降低（P〈0．05）;饮酒组大鼠戒断2-48h酒精戒断评分均显著高于对照组（P〈0．01）且评分在戒断第6h最高;戒断24、48h的大鼠在强迫游泳中绝对不动时间比对照组显著延长（P〈0．05）。结论：大鼠持续饮用6％（v／v）浓度酒精溶液可以诱导出大鼠对酒精的严重躯体依赖和抑郁状态,并抑制大鼠在新奇环境中的活动能力和动机行为。     

Genetically correlated effects of selective breeding for high and low methamphetamine consumption

Improved prevention and treatment of drug addiction will require deeper understanding of genetic factors contributing to susceptibility to excessive drug use. Intravenous operant self-administration methods have greatly advanced understanding of behavioral traits related to addiction. However, these methods are not suitable for large-scale genetic experiments in mice. Selective breeding of mice can aggregate 'addiction alleles' in a model that has the potential to identify coordinated effects of multiple genes. We produced mouse lines that orally self-administer high (MAHDR) or low (MALDR) amounts of methamphetamine, representing the first demonstration of selective breeding for self-administration of any psychostimulant drug. Conditioned place preference and taste aversion results indicate that MAHDR mice are relatively more sensitive to the rewarding effects and less sensitive to the aversive effects of methamphetamine, compared to MALDR mice. These results validate the oral route of self-administration for investigation of the motivational effects of methamphetamine and provide a viable alternative to intravenous self-administration procedures. Gene expression results for a subset of genes relevant to addiction-related processes suggest differential regulation by methamphetamine of apoptosis and immune pathways in the nucleus accumbens of MAHDR and MALDR mice. In each line, methamphetamine reduced an allostatic state by bringing gene expression back toward 'normal' levels. Genes differentially expressed in the drug-naï ve state, including Slc6a4 (serotonin transporter), Htr3a (serotonin receptor 3A), Rela [nuclear factor κB (NFκB)] and Fos (cFos), represent candidates whose expression levels may predict methamphetamine consumption and susceptibility to methamphetamine reward and aversion.     

Neurochemical Mechanisms Underlying Alcohol Addiction: Model Experiments on Rats

We measured the activities of the main alcohol-metabolizing enzymes (alcohol dehydrogenase, AlDH, and aldehyde dehydrogenase, AdhDH) in the blood serum, comparing these indices with the contents of ethanol and its main metabolite, acetaldehyde (AcAdh), in the blood, and also measured the contents of catecholamines (adrenaline, noradrenaline, and dopamine) in the blood and in different brain structures (hypothalamus, midbrain, and neocortex) of rats in the states of acute alcohol intoxication and chronic alcohol addiction. It was shown that, because of dissimilar changes in the activities of AlDH and AdhDH under conditions of alcohol intoxication, the dynamic balance between endogenous ethanol and AcAdh existing in the norm is disturbed, which results in an increase in the level of AcAdh. Such a phenomenon probably is one of the crucial factors underlying the development of alcohol addiction.     

Acetaldehyde addition and pre-adaptation to the stressor together virtually eliminate the ethanol-induced lag phase in Saccharomyces cerevisiae

AIMS: To show that the ethanol-induced lag phase in yeast can be almost eliminated by combining pre-adaptation with acetaldehyde supplementation. METHODS AND RESULTS: Pre-adaptation to noninhibitory concentrations of ethanol and supplementation of unadapted cultures with acetaldehyde each separately reduced the lag phase of ethanol-inhibited cultures by c. 70%. By combining the two methods the ethanol-induced lag phase was virtually eliminated (90% reduction in lag time). CONCLUSIONS: Pre-adaptation to ethanol and acetaldehyde supplementation appear to promote yeast growth through different mechanisms, which are additive when combined. SIGNIFICANCE AND IMPACT OF THE STUDY: The combination of the above procedures is a potentially powerful tool for reducing the lag of stressed cultures, which may have practical applications: e.g. in reducing the lag of yeasts inoculated into lignocellulosic hydrolysates employed in fuel ethanol production.     

大鼠基底外侧杏仁核组蛋白乙酰化对吗啡成瘾记忆的调控作用

为了探索组蛋白乙酰化对吗啡成瘾记忆相关分子表达调控机制,文章选取健康成年雄性SD大鼠34只,随机分为正常对照组(n = 6)及基底外侧杏仁核(Basolateral amygdala, BLA)颅内定位手术组(n =28)。在条件性位置偏爱(Conditioned place preference, CPP)训练阶段,大鼠BLA内给予组蛋白去乙酰化酶抑制剂曲古抑菌素A(Trichostafin A, TSA)并且腹腔注射吗啡溶液(10.0 mg/kg),对照组给予相同体积的10%二甲基亚砜(Dimethyl sulfoxide,DMSO)或盐水。应用蛋白质印记方法,检测吗啡诱导大鼠CPP建立后BLA内组蛋白H3K14乙酰化和脑源性神经营养因子(Brain-derived neurotrophic factor, BDNF)蛋白表达水平。结果显示,腹腔注射10 mg/kg吗啡能成功建立CPP。吗啡、TSA联合给药组大鼠比单纯吗啡给药组大鼠表现出更强烈的CPP(P<0.0001)。吗啡和TSA都能使BLA内的组蛋白H3乙酰化水平和BDNF的表达显著增高(P < 0.0001),同时二者之间具有协同作用。结果表明,大鼠BLA内组蛋白乙酰化水平与吗啡成瘾记忆形成有关,抑制BLA内组蛋白去乙酰化酶(Histone deacetylases, HDACs)的活性可强化吗啡诱导的线索记忆的形成;大鼠BLA内BDNF参与了吗啡诱导的线索记忆的形成并可能受到组蛋白乙酰化的调控。