免疫学和酶学途径治疗可卡因成瘾的可能性

可卡因滥用问题以美洲最为严重 ,美国约有 2 1 0万人可卡因成瘾 ,因此成为国际上关注的研究热点。然而迄今为止药物治疗的效果令人失望 ,迫切需要寻找新的途径。目前各国学者围绕化学、免疫学和酶学进行细胞、分子、基因等多层次的研究 ,已经在实验动物模型方面取得突破性进展。尤其是免疫药物疗法的效果非常显著 ,例如可卡因疫苗促使产生可卡因特异性抗体 ,可在一定程度上阻断可卡因进入脑内出现的强化作用。一系列研究显示 ,可卡因免疫疗法在阻断可卡因动物模型的强化效果方面 ,令人惊奇 〔1〕。但不能否认 ,免疫学或酶学方法研究药物滥用…     

催化性抗体

用多种策略可制备新类型的生物活性分子：催化性抗体（抗体酶）。抗体酶高专一地催化多种化学反应，可望用于性物学，化学和医药学领域。抗体酶的研究提供了生物催化的基本认识，如过渡态稳定，接近效应，一般酸碱催化，亲电和亲核反应等。     

甲基苯丙胺、可卡因和吗啡成瘾对糖代谢的影响及分子机制研究进展

药物成瘾是指滥用者对成瘾药物的强烈渴求,以至于强制性地慢性或周期性地服用成瘾药物.成瘾药物包括管制类药品及毒品,如甲基苯丙胺(METH)、可卡因和吗啡等.药物成瘾机制复杂,可导致机体糖代谢紊乱.METH、可卡因和吗啡通过胰岛素信号通路、磷脂酰肌醇3激酶/蛋白激酶B和AMP活化蛋白激酶信号通路可导致多巴胺、谷氨酸和γ-氨...     

催化抗体的研究进展

催化抗体的研究进展杨日芳，恽榴红，丁振闿（军事医学科学院毒物药物研究所，北京１００８５０）免疫化学历来是集中于抗原性和抗体。抗原之间相互作用的研究。但近年来，借助于机理化学与合成化学的工作，免疫体系细胞能够产生具有新功能的抗体──催化抗体或称抗体酶（...     

植物抗体用于人类免疫治疗

植物生物技术的巨大进展使人们能够更加有效地利用植物生产异源蛋白。其中，植物产生的单克隆抗体引起人们的极大关注。近年来，人们开展了一系列植物抗体的应用研究。本文就转基因植物产生的抗体及植物抗体在人类免疫治疗中的应用进行了综述。     

AGS3蛋白--可卡因成瘾的新靶点

美国南卡来罗那州医科大学生理和神经科学系Peter W. Kalivas教授的实验室研究发现,慢性给予可卡因的大鼠长期戒断后,前额皮质内G蛋白信号传导的一个激活子AGS3(activator of G protein signaling 3) 持续表达增加。研究还发现AGS3蛋白的上调与大鼠的觅药行为和运动敏感行为均相关,伏隔核中谷氨酸的信号传递功能也同时增强。该研究发表在最新一期的《神经元》杂志[Neuron, Vol 42(2), 181-183, 22 April 2004],这为药物成瘾治疗的研究提供了一个新的潜在靶点。前额皮质是与药物成瘾具有密切关系的部位。长期接触可卡因可以引起G蛋白信…     

物质成瘾与昼夜节律相互关系的研究进展

药物成瘾是一个突出的社会问题,给家庭和社会带来了巨大损失。然而其发生机制尚不完全清楚,近年来,在众多机制假说中生物节律机制的研究越来越受到关注。本文将以可卡因为例,从其体内代谢过程、对人体危害、作用机制,到昼夜节律系统、以及物质成瘾和昼夜节律两者相互关系的研究进展,做一详细综述。     

气体信号分子NO对可卡因戒断所致的大鼠成瘾记忆的影响

目的一氧化氮(NO)作为一种内源性气体信号分子,在中枢神经系统发挥广泛的生物学效应。有研究报道NO参与可卡因等药物成瘾的形成过程。近年来的研究发现,可卡因成瘾戒断会导致伏隔核(NAc)区突触表面的AM-PA受体表达上调,而这种上调被认为与可卡因的行为敏化的维持有关。然而,NO是否也在可卡因成瘾的戒断行为中发挥重要作用则尚未见报道。方法采用Western blotting技术结合脑片膜片钳和场电位记录方法,研究NO在可卡因成瘾戒断所致大鼠成瘾记忆中的作用及其机制。结果可卡因戒断导致大鼠NAc区突触部位GluR1和GluR2亚基的蛋白表达出现不成比例的上调,nNOS的表达、NO的含量,以及NSF的亚硝基化水平均有所增加。外源性使用NO供体可增加戒断大鼠NAc区的NSF亚硝基化水平并选择性上调突触部位GluR2的含量,逆转戒断后NAc区的突触可塑性变化。另外,外源性给予NO供体和亚硝酸钠均可通过增加NAc区NSF与GluR2的结合能力来阻断戒断后大鼠的行为敏化。结论可卡因戒断引起的NAc区NSF亚硝基化水平和突触部位GluR2亚基表达增加是大脑出现的一种内源性代偿机制,从而限制机体对可卡因的长时程异常行为反应。     

可卡因与阿片类药物成瘾中microRNA作用机制的研究进展

<正>1 micro RNA是一类具有广泛生物学作用的调控分子所谓非编码RNA(non-coding RNA,nc RNA),是指具有生物学功能但不能编码蛋白质生成的RNA,这类RNA的主要特征是含有大量的终止密码子而缺乏编码蛋白生成的开放阅读框(open reading frames,ORFs),是调控细胞生理的关键因子。mi RNA是一类进化上高度保守的nc RNA,于1993年在线虫体内发     

Pharmacological treatments for heroin and cocaine addiction

AIMS: To provide an overview of the pharmacological options for the treatment of heroin- and cocaine-dependent patients based on known biochemical pathways to addiction and the chronic disease model as a starting point for treatment planning. RESULTS: Recent pre-clinical and clinical studies indicate that different brain structures and different neurotransmitters are involved in different stages of the addiction process. In addition, clinical experience shows that heroin and cocaine addiction can best be conceptualised and treated as a chronic, relapsing disorder with the following treatment goals: crisis intervention, cure or recovery (detoxification, relapse prevention) and care or partial remission (stabilization and harm reduction). The various high-quality studies, systematic literature reviews and formal meta-analyses clearly demonstrate that today many proven effective interventions are available for crisis intervention, detoxification, stabilization and harm reduction for heroin-dependent patients. Interventions directed at relapse prevention are still problematic and only effective in a minority of motivated patients in stable living conditions and adequate social support. In contrast, no proven effective pharmacological interventions are available for the treatment of cocaine-dependent patients, maybe with the exception of some patient groups that seem to benefit from treatment with disulfiram or amantadine. Treatment innovations are primarily based on experimental animal studies. Newly developed cannabinoid receptor antagonists and cortisol synthesis inhibitors show great promise. CONCLUSION: Heroin addiction is a chronic relapsing disease that is difficult to cure, but stabilization and harm reduction can greatly increase the life time expectancy and the quality of life of the patient, his direct environment and society as a whole. Currently, no proven effective pharmacological interventions are available for cocaine addiction, and treatment has to rely on existing cognitive behaviour therapies combined with contingency management strategies.     

Pharmacological approaches to cocaine addiction

The involvement of central dopamine (DA) neurons in the rewarding action of cocaine is well established. Cocaine euphoria depends on DA activation, and cocaine increases DA neurotransmission by blocking synaptic reuptake. Chronic cocaine use, however, appears to deplete brain DA, and perhaps leads to cocaine craving and withdrawal states. Bromocriptine, a specific DA receptor agonist, appears to ameliorate cocaine craving. Possible clinical roles for bromocriptine, and for DA receptor antagonists, are outlined.     

Glutamate systems in cocaine addiction

All addictive drugs facilitate dopamine transmission, and determining the role of dopamine has been the predominant focus of biomedical research in addiction for 20 years. Newer data and hypotheses have begun to shift our focus to involvement of cortex and corticofugal glutamate projections. The rationale for shifting focus to glutamate ranges from evidence showing that cortical activity is altered in addicts to data from animal models demonstrating drug-induced changes in the function of proteins that regulate pre- and postsynaptic glutamate neurotransmission. Recent studies have particularly focused on involvement of a circuit that includes glutamate projections from the prefrontal cortex to the nucleus accumbens.     

Evaluation of the anticocaine monoclonal antibody GNC92H2 as an immunotherapy for cocaine overdose

The illicit use of cocaine continues in epidemic proportions and treatment for cocaine overdose remains elusive. Current protein-based technology offers a new therapeutic venue by which antibodies bind the drug in the blood stream, inactivating its toxic effects. The therapeutic potential of the anticocaine antibody GNC92H2 was examined using a model of cocaine overdose. Swiss albino mice prepared with intrajugular catheters were tested in photocell cages after administration of 93 mg/kg (LD50) of cocaine and GNC92H2 infusions ranging from 30 to 190 mg/kg. GNC92H2 was delivered 30 min before, concomitantly or 3 min after cocaine treatment. Significant blockade of cocaine toxicity was observed with the higher dose of GNC92H2 (190 mg/kg), where premorbid behaviors were reduced up to 40%, seizures up to 77% and death by 72%. Importantly, GNC92H2 prevented death even post-cocaine injection. The results support the important potential of GNC92H2 as a therapeutic tool against cocaine overdose.     

Costs and benefits of treatment for cocaine addiction in DATOS

Our objective was to examine the cost of long-term residential (LTR) and outpatient drug-free (ODF) treatments for cocaine-dependent patients participating in the Drug Abuse Treatment Outcome Studies (DATOS), calculate the tangible cost of crime to society, and determine treatment benefits. Subjects were 502 cocaine-dependent patients selected from a national and naturalistic nonexperimental evaluation of community-based treatment. Financial data were available for programs from 10 US cities where the subjects received treatment between 1991 and 1993. Treatment costs were estimated from the 1992 National Drug Abuse Treatment Unit Survey (NDATUS), and tangible costs of crime were estimated from reports of illegal acts committed before, during, and after treatment. Sensitivity analyses examined results for three methods of estimating the costs of crime and cost-benefit ratios. Results showed that cocaine-dependent patients treated in both LTR and ODF programs had reductions in costs of crime from before to after treatment. LTR patients had the highest levels and costs of crime before treatment, had the greatest amount of crime cost reductions in the year after treatment, and yielded the greatest net benefits. Cost-benefit ratios for both treatment modalities provided evidence of significant returns on treatment investments for cocaine addiction.     

Bromocriptine-desipramine protocol in treatment of cocaine addiction

Thirty-six male cocaine abusers, in withdrawal, were studied for 99 days in a double-blind design. Treatment with bromocriptine was significantly more effective than placebo in alleviating withdrawal symptoms. Adding desipramine to the bromocriptine regimen was significantly more effective than either placebo or bromocriptine alone. The authors hypothesize that these results support a model of dopamine depletion and receptor supersensitivity in cocaine withdrawal.