吗啡、人工合成大麻素HU210对NAC中谷氨酸能神经元传递效率的影响
发布时间：2018-11-12 19:12
【摘要】：大脑的奖赏效应包括各种天然奖赏及成瘾药物奖赏,这两种奖赏方式都伴随脑内核团伏隔核神经递质多巴胺含量的升高。多巴胺含量的变化依赖于一些神经通路,与成瘾效应有关的通路主要指中脑边缘多巴胺系统(mesolimbic dopamine system, MLDS)。成瘾药物等奖赏性刺激通过多条途径激活中脑边缘多巴胺系统(MLDS)后使得伏隔核内多巴胺的含量升高,从而产生有关奖赏的信号。脑内的中脑边缘多巴胺系统中最主要的结构基础是从脑区腹侧被盖区(ventral tegmental area, VTA)到脑区伏隔核(nucleus accumbens,NAc)之间的神经投射。与奖赏效应的形成的相关脑区有很多,分布从前脑至外侧部分等相关的脑区,如包括前额叶(prelimbic prefrontal cortex,PFC)、海马(hippocampus,Hip)。伏隔核也是参与神经系统内有关奖赏作用的重要脑区,它可能产生神经元结构、功能上的适应性变化。前额叶皮质具有极其广泛的神经联系和复杂的结构形式,以及与其它脑区之间有着丰富、复杂的双向性联系。大脑前额叶对全脑结构起着调节性和指导性作用,表现在接受以及综合由脑的各个部位传入的来自机体内外的各种信息,并能整合后及时传出神经冲动,从而保证了神经系统整体的协同和达到整个高级心理过程的统一。谷氨酸能神经元存在于脑区PFC与脑区NAc之间,谷氨酸在脑内的奖赏效应的形成过程中起重要作用。 成瘾药物最早应用于临床医药,用于减轻手术及其它疾病带来的痛苦,例如吗啡,可卡因,大麻,尼古丁等,但随着科技发展,药物滥用现象越来越严重,药物成瘾成为严峻的社会问题,药物成瘾的治疗也成为研究的热点。目前有实验关注于两种成瘾药物之间的相互作用及相互影响。每一种成瘾药物作用机理及作用脑区的不同可能会对不同的神经元的产生不同影响。有些神经元上会存在递质共存现象,那么这些共存的递质相互之间就可能造成功能上、结构上的依赖及影响,因此两种成瘾药物之间的相互作用成为研究的一个有价值的思路。有文章称大麻素能改变VTA内的多巴胺(doparnine,DA)神经元的电流变化,从而诱导产生了长时程减弱现(longterm-depression, LTD)。但很多精神药物的作用效果与大麻素的机制不同,如可卡因、尼古丁、吗啡及酒精等却使得脑区VTA内的DA神经元发生不同电流变化,从而诱导产生长时程增(longterm-potentiation,LTP)。因此,成瘾药物的不同作用于神经元的机理可能不同,对突触可塑性产生不同影响,甚至是相反的作用。这暗示如果成瘾药物对突触的作用效应和机理相反,那么将两种成瘾药物一起同时先后使用,那么两种成瘾药物可能会出现药理抵消现象,在动物的机体表现上体现出中和效应。有研究人员为了证明这种假想和推理是否正确,在动物身体上联合注射成瘾药品尼古丁及人工合成大麻素HU210,发现尼古丁在机体内产生的LTP现象和人工合成大麻素在机体内产生的LTD现象确实能够相互抵消,并且当两种药物联合使用后在行为上表现为以前各自能分别产生的位置偏爱效应(conditionned place preference,CPP)消失。另有研究指出,在可卡因造成的成瘾自给要模型中,注射大麻素能明显抑制该行为。目前有实验称,吗啡的急性作用能使神经元上谷氨酸的传递效率增高并且这种机制是通过增加突触前递质释放而引起的,而注射大麻素会引起胶质细胞海马区的谷氨酸释放量降低。在脑区VTA中,DA能神经元能产生LTP现象可通过注射吗啡引起,而产生LTD现象可通过注射大麻素产生。而对于两种成瘾药物之间的相互作用及影响,现在还不清楚。 为探讨两种成瘾药物的联合使用而造成的对神经系统内谷氨酸传递效率的影响及机制,本研究选取在体记录的方法,选取记录的位置为脑区PFC至脑区NAC之间的谷氨酸能神经元,记录通过电刺激对脑区PFC刺激后传导至NAc壳区的场兴奋性突触后电位(field excitatory postsynaptic potential,EPSP)。急性吗啡处理后再急性注射人工合成大麻素的谷氨酸能突触EPSP的变化以及人工合成大麻素急性处理后再急性注射吗啡的谷氨酸EPSP的变化。结果显示,与对照组相比,急性吗啡注射后,再注射人工合成大麻素20-30min时,EPSP有增大趋势。但是急性注射大麻素后,再次注射吗啡时,吗啡的效果不能持续保持,提示NAC中两种受体可能发生相互影响。总结上述实验结果可得知：急性吗啡后,脑区PFC-NAc的谷氨酸能突触前膜递质释放量增加,表现为EPSP显著增大；再1小时后注射人工合成大麻素处理后,NAc中神经元的EPSP在短期内发生了一些增大的变化趋势。而将这两种成瘾药物调换顺序注射时,会得到一些不同的结果,暗示这两种成瘾药物之间有相互影响,可能具体机制为受体之间的相互作用。阿片受体和大麻素受体在神经元内广泛表达,在某些区域共存。这种受体的变化在药物成瘾形成及药物戒断过程中起着极其重要的作用,本实验的研究结果能够为两种成瘾药物的相互影响及药物成瘾提供一定的参考价值。
[Abstract]:The reward effect of the brain includes a variety of natural and addictive drug rewards, both of which are accompanied by an increase in the dopamine content of the nucleus of the nucleus of the brain. The change of the dopamine content depends on some of the neural pathways, and the pathway associated with the addiction effect mainly refers to the mesencephalic dopamine system (MLDS). A reward-like stimulus, such as an addictive drug, activates the midbrain-edge dopamine system (MLDS) by a plurality of pathways, causing the level of dopamine in the nucleus to rise, thereby producing a signal about the reward. The main structure of the dopamine system in the brain of the brain is the nerve projection from the ventral side of the brain region to the nucleus accumbens (NAc) of the brain region. The associated brain regions associated with the formation of the reward effect have a large number of associated brain regions, such as prefrontal cortex, PFC, and Hippocampus, Hip, and the like. The photovoltaic nucleus is also an important brain region involved in the reward function in the nervous system, which may produce neuronal structure and functional adaptability. The prefrontal cortex has a very wide range of neural connections and complex structural forms, as well as a rich, complex, bi-directional contact with other brain regions. the frontal lobe of the brain functions as a regulating and guiding function on the whole brain structure, so as to ensure the overall coordination of the nervous system and the unity of the whole high-level psychological process. Glutamate can play an important role in the formation of the reward effect of glutamate in the brain between the brain region PFC and the brain region NAc. Addiction drugs are first used in clinical medicine, and are used to relieve the pain caused by the operation and other diseases, such as morphine, cocaine, hemp, nicotine, etc., but with the development of science and technology, the phenomenon of drug abuse is becoming more and more serious, and the drug addiction becomes a serious society The treatment of drug addiction is also a problem. The study is focused on the interaction between two kinds of addictive drugs and their interaction with each other. The effect of each addictive drug on the mechanism of action and the effect of different brain regions may be different to the production of different neurons. The effects of these coexistent drugs on the function, structure, and influence on some neurons, so the interaction between the two addictions becomes a valuable part of the study. It is suggested that cannabinoids can change the current change of the dopamine (DA) neurons in VTA, thereby inducing a long-time attenuation (LT). D). But the effect of many psychotropic substances is different from that of cannabinoids, such as cocaine, nicotine, morphine and alcohol, so that DA neurons in the brain region VTA have different current changes, thereby inducing a long-time increase (longterm-level, LT, P). As a result, the different effects of the addictive drugs on the neurons may be different and have different effects on the synaptic plasticity, or even the opposite. This suggests that if the effect and mechanism of the addictive drug on the synapse are the opposite, then the two addictive drugs can be used together at the same time. The results show that the LTP and synthetic cannabinoids produced in the body of the body can indeed be linked to each other in order to prove the correctness of this hypothesis and the reasoning, and the combination of the nicotine and the synthetic cannabinoid HU210 on the body of the animal. Cancelled, and when the two drugs are used in combination, they behave in behavior as previously generated position preference (CPP), respectively. It's gone. It's another study that the injection of cannabinoids can be significantly inhibited in the model of addiction self-sufficiency caused by cocaine. It is now experimentally reported that the acute effect of morphine can increase the transmission efficiency of glutamate on the neurons and this mechanism is caused by increasing the release of the pre-synaptic release, and the injection of cannabinoids can cause glutamate release in the hippocampus of the glial cells. in that VTA of the brain, the occurrence of the LTP phenomenon in the DA-energy neuron can be caused by injection of morphine, and the occurrence of the LTD phenomenon can be caused by injection of the cannabinoid. It's produced. And for the interaction and influence of two kinds of addictions, it's not yet It is clear that in order to study the effect and mechanism of the combined use of two kinds of addictive drugs on the transmission efficiency of glutamate in the nervous system, the method of the body recording is selected, and the position of the record is selected as the valley ammonia between the brain area PFC and the NAC of the brain area. The acid-energy neurons, recording the field excitability postsynaptic potential transmitted to the NAc shell region after stimulation of the PFC in the brain region by electrical stimulation, EPSP, the changes of the glutamate-capable synapse EPSP after acute morphine treatment and the changes of the synaptic EPSP of the synthetic cannabinoid and the glutamate EP of the acute injection of morphine after the acute treatment of the cannabinoid The results showed that, compared with the control group, after acute morphine injection, after injection of synthetic cannabinoid for 20-30min, EPSP There is a tendency to increase. However, after acute injection of the cannabinoid, the effect of morphine is not sustained until morphine is injected again, suggesting that both receptors in NAC may The results of these experiments showed that the release of glutamate in the pre-synaptic membrane of the PFC-NAc in the brain region increased with the increase of the EPSP, and the EPSP of the neurons in the NAc was increased in the short term after the injection of the synthetic cannabinoid after 1 hour. The changing trend of the two types of addictive drugs will result in some different results, suggesting that there is a mutual influence between these two kinds of addictive drugs, which may be specific to the receptor. The interaction between the opioid receptor and the cannabinoid receptor is widely expressed in the neurons, at some point, The change of this receptor plays a very important role in the formation of drug addiction and drug withdrawal.
【学位授予单位】：陕西师范大学
【学位级别】：硕士
【学位授予年份】：2013
【分类号】：R749.61
本文编号：2327967
[Abstract]:The reward effect of the brain includes a variety of natural and addictive drug rewards, both of which are accompanied by an increase in the dopamine content of the nucleus of the nucleus of the brain. The change of the dopamine content depends on some of the neural pathways, and the pathway associated with the addiction effect mainly refers to the mesencephalic dopamine system (MLDS). A reward-like stimulus, such as an addictive drug, activates the midbrain-edge dopamine system (MLDS) by a plurality of pathways, causing the level of dopamine in the nucleus to rise, thereby producing a signal about the reward. The main structure of the dopamine system in the brain of the brain is the nerve projection from the ventral side of the brain region to the nucleus accumbens (NAc) of the brain region. The associated brain regions associated with the formation of the reward effect have a large number of associated brain regions, such as prefrontal cortex, PFC, and Hippocampus, Hip, and the like. The photovoltaic nucleus is also an important brain region involved in the reward function in the nervous system, which may produce neuronal structure and functional adaptability. The prefrontal cortex has a very wide range of neural connections and complex structural forms, as well as a rich, complex, bi-directional contact with other brain regions. the frontal lobe of the brain functions as a regulating and guiding function on the whole brain structure, so as to ensure the overall coordination of the nervous system and the unity of the whole high-level psychological process. Glutamate can play an important role in the formation of the reward effect of glutamate in the brain between the brain region PFC and the brain region NAc. Addiction drugs are first used in clinical medicine, and are used to relieve the pain caused by the operation and other diseases, such as morphine, cocaine, hemp, nicotine, etc., but with the development of science and technology, the phenomenon of drug abuse is becoming more and more serious, and the drug addiction becomes a serious society The treatment of drug addiction is also a problem. The study is focused on the interaction between two kinds of addictive drugs and their interaction with each other. The effect of each addictive drug on the mechanism of action and the effect of different brain regions may be different to the production of different neurons. The effects of these coexistent drugs on the function, structure, and influence on some neurons, so the interaction between the two addictions becomes a valuable part of the study. It is suggested that cannabinoids can change the current change of the dopamine (DA) neurons in VTA, thereby inducing a long-time attenuation (LT). D). But the effect of many psychotropic substances is different from that of cannabinoids, such as cocaine, nicotine, morphine and alcohol, so that DA neurons in the brain region VTA have different current changes, thereby inducing a long-time increase (longterm-level, LT, P). As a result, the different effects of the addictive drugs on the neurons may be different and have different effects on the synaptic plasticity, or even the opposite. This suggests that if the effect and mechanism of the addictive drug on the synapse are the opposite, then the two addictive drugs can be used together at the same time. The results show that the LTP and synthetic cannabinoids produced in the body of the body can indeed be linked to each other in order to prove the correctness of this hypothesis and the reasoning, and the combination of the nicotine and the synthetic cannabinoid HU210 on the body of the animal. Cancelled, and when the two drugs are used in combination, they behave in behavior as previously generated position preference (CPP), respectively. It's gone. It's another study that the injection of cannabinoids can be significantly inhibited in the model of addiction self-sufficiency caused by cocaine. It is now experimentally reported that the acute effect of morphine can increase the transmission efficiency of glutamate on the neurons and this mechanism is caused by increasing the release of the pre-synaptic release, and the injection of cannabinoids can cause glutamate release in the hippocampus of the glial cells. in that VTA of the brain, the occurrence of the LTP phenomenon in the DA-energy neuron can be caused by injection of morphine, and the occurrence of the LTD phenomenon can be caused by injection of the cannabinoid. It's produced. And for the interaction and influence of two kinds of addictions, it's not yet It is clear that in order to study the effect and mechanism of the combined use of two kinds of addictive drugs on the transmission efficiency of glutamate in the nervous system, the method of the body recording is selected, and the position of the record is selected as the valley ammonia between the brain area PFC and the NAC of the brain area. The acid-energy neurons, recording the field excitability postsynaptic potential transmitted to the NAc shell region after stimulation of the PFC in the brain region by electrical stimulation, EPSP, the changes of the glutamate-capable synapse EPSP after acute morphine treatment and the changes of the synaptic EPSP of the synthetic cannabinoid and the glutamate EP of the acute injection of morphine after the acute treatment of the cannabinoid The results showed that, compared with the control group, after acute morphine injection, after injection of synthetic cannabinoid for 20-30min, EPSP There is a tendency to increase. However, after acute injection of the cannabinoid, the effect of morphine is not sustained until morphine is injected again, suggesting that both receptors in NAC may The results of these experiments showed that the release of glutamate in the pre-synaptic membrane of the PFC-NAc in the brain region increased with the increase of the EPSP, and the EPSP of the neurons in the NAc was increased in the short term after the injection of the synthetic cannabinoid after 1 hour. The changing trend of the two types of addictive drugs will result in some different results, suggesting that there is a mutual influence between these two kinds of addictive drugs, which may be specific to the receptor. The interaction between the opioid receptor and the cannabinoid receptor is widely expressed in the neurons, at some point, The change of this receptor plays a very important role in the formation of drug addiction and drug withdrawal.
【学位授予单位】：陕西师范大学
【学位级别】：硕士
【学位授予年份】：2013
【分类号】：R749.61
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