酒精对大鼠背侧纹状体长时程突触抑制的影响

【作者】 夏建勋；

【导师】 袁孝如；

【作者基本信息】 南京医科大学 ， 生理学， 2004， 硕士

【摘要】 酒精滥用、酒精依赖已经成为世界各国较为普遍的社会问题。有研究提示，酒精滥用与高离婚率、高暴力犯罪、高交通事故有明显相关。据有关统计，世界上大约有10％的职业人口酗酒，对社会造成重大的经济损失；与此同时，也对家庭和社会造成严重危害。酒精与大脑和神经系统的亲和力最强，长期慢性酒精中毒，可致大脑、神经系统功能损害，严重时可出现幻觉、幻视、幻听等精神障碍。因此，研究能够防治酒精中毒和长期饮酒所造成的躯体依赖(Dependence)、耐受(Tolerance)以及由此导致的戒断综合症(Withdrawal Syndrome)的有效方法具有重要的医学和社会学意义。 酒精可通过作用于脑内奖赏系统(Rewarding System)引起伏核(Necleus Accumbens,NAcc)内多巴胺(DA)释放增多，从而产生欣快感即奖赏效应来促使机体主动摄入药物，长期大量饮酒会使中枢神经系统内发生一系列的适应性改变，造成躯体依赖和耐受以及戒断综合症的产生。酒精成瘾最关键的问题在于戒断后复吸(Relapse)率很高，这是目前成瘾研究中急需解决的问题。 许多证据表明，成瘾行为的产生和发展过程中有学习记忆机制参与，药物成瘾病人的复吸行为包含着联合型学习(Associative Learning)。服药行为的建立需要条件反射机制的参与，这种习得性反应(learned response)在戒断后仍然可以长期保留下来，可能是引起复吸的神经生物学基础。 纹状体(Striatum)是构成基底神经节的一个核团，由腹侧纹状体和背侧纹状体组成，接受来自大脑皮层的谷氨酸能纤维传入和来自中脑黑质的多巴胺能纤维传入。其中腹侧纹状体又称伏核，是引起奖赏效应的重要脑区；背侧纹状体也是成瘾物质作用的重要靶区域，基于背侧纹状体(dorsal Striatum)神经通路的联合型学习与运动执行(performance of actions)和习惯化行为(habitual behavior)的建立有密切关系，可能是涉及成瘾物质复吸行为的重要神经生物学机制。因此，南京医科j、学硕尸护位沦文本研究观察急慢性酒精作用对背侧纹状体突触可塑性的影响将有助于阐明酒精对运动认知功能的损害和复吸的机制。本项研究分两部分:第一部分:以SD大鼠背侧纹状体脑片作为研究材料，观察灌流20-80mM的酒精对纹状体突触可塑性的影响，并初步探讨其可能的作用机制。研究结果发现:对照组给予强直刺激后诱导出明显的LTD，20蒯酒精可以轻微增强LTD的诱导，4 OmM酒精可以轻微抑制LTD的诱导，6OmM和80mM酒精可明显抑制LTD的诱导，在一定酒精浓度范围内呈现量效关系，其中以60蒯酒精的作用最强。第二部分:以6%(v/v)酒精水溶液作为大鼠饮水的唯一来源，建立慢性酒精成瘾动物模型。分别在大鼠饮酒和戒断的不同时程(饮酒10天、20天、30天、戒断l天、3天、5天)取其脑片，观察纹状体长时程突触抑制的时相变化和发展过程，并探讨其可能的作用机制。研究结果发现:在饮酒的不同时程(10天，20天，30天)和戒断1天SD大鼠背侧纹状体LTD的诱导均发生了不同程度的抑制，其中以饮酒10天组的抑制作用最强，饮酒20天和30天组的抑制作用逐步减弱，而戒断1天组的抑制作用又较30天组有所增强，但仍较20天组弱。结论:酒精对背侧纹状体LTD诱导的影响及其发生发展的变化可能与酒精成瘾习惯的产生及酒精对运动和认知功能的损害有关。更多还原

【Abstract】 Alcohol abuse (Alcohol dependence) has become a popular social problem in almost all the nations of the world. Some of researches indicated that alcohol abuse was obviously related to high rate of divorce, high violence and high traffic accidents. It was estimated that about 10% of the professional abused alcohol which may lead to enormous economic loss, meanwhile the severe harm to family and society in the world. Ethanol, the main component of alcohol, has the highest affinity to Central Nerve System. Chronic alcoholism could contribute to impairment of nerve system and brain functions, even some psychiatric disorder such as hallucination, heteroptics, acousma and so on. For all these reasons, it is of great medical and sociological importance to find some effective methods to treat and prevent alcoholism and alcoholism-associated phenomena such as physical dependence, tolerance, and withdrawal syndrome.Alcohol could bring euphoria to people by increasing dopamine release in the Nucleus Accumbens through its activation on rewarding system in brain, and make people to take drugs. Adaptations happened in CNS after long term excessive alcohol consumption may lead to the development of physical dependence, tolerance and withdrawal syndrome. The focus of alcoholism research at present is that even after long time of abstinence the risk of relapse remains high.Many evidences demonstrated the establishment and development of addictive behavior involved learning and memory mechanism. It was suggested that associative learning was involved in relapse of drug addicts. Development of drug-taking needs the participation of conditioned reflex, this learned response could persist for a long time even after abstinence which may be the neurobiological basis underlyingthe relapse.Striatum is an important structure of basal ganglion, which is composed of ventral striatum and dorsal striatum receiving glutamatergic afferent from prefrontal cortex and dopaminergic afferent originating from ventral tegmental area of midbrain. Dorsal striatum, namely Nucleus Accumbens, is the key brain area mediating rewarding effect. Whereas dorsal striatum is a target on which drugs act as well, dorsal striatum-based associative learning plays an important role in the development of performance of actions and habitual behavior, and may be the crucial neurobiological mechanism underlying the relapse. So, investigating the effect of ethanol on synaptic plasticity of dorsal striatum will be helpful to identify the mechanism of not only impaired movement and cognitive functions by ethanol but also the relapse.This study was divided into two parts: the first part was to observe the effect of superfusion of different concentrations of ethanol (20 to 80mM) on induction of corticostriatal LTD in brain slice of dorsal striatum of SD rats and explored the possible mechanism primarily. The results indicated a typical LTD was induced after HFS in control group, superfusion of 20mM ethanol could facilitate the induction of corticostriatal LTD slightly, 40mM ethanol could inhibit the induction of corticostriatal LTD slightly, whereas 60mM and 80mM ethanol could significantly inhibit it in which 60mM ethanol had the strongest inhibitory effect. The second part of this research established an animal model of alcoholism using alcohol solution of concentration of 6% as only drinking water, then the time-dependent changes and developmental processes of LTD of corticostriatal brain slice at different periods of alcohol-drinking and withdrawal (alcohol-drinking 10 days, 20days, 30days, withdrawal Lday, 3days, 5days) were observed respectively, andthe possible mechanism was discussed. The results showed the induction of corticostriatal LTD was inhibited to different extent at different period of alcohol-drinking (10days, 20days, 30days) and withdraw Lday. The inhibitory effect on corticostriatal LTD of ethanol was strongest at alcohol-drinking 10 days while weakened gradually at the following 20 days. It was interesting that the inhibitory effect on corticost更多还原