嗎啡、人工合成大麻素HU210對(duì)NAC中谷氨酸能神經(jīng)元傳遞效率的影響
發(fā)布時(shí)間：2018-11-12 19:12
【摘要】：大腦的獎(jiǎng)賞效應(yīng)包括各種天然獎(jiǎng)賞及成癮藥物獎(jiǎng)賞,這兩種獎(jiǎng)賞方式都伴隨腦內(nèi)核團(tuán)伏隔核神經(jīng)遞質(zhì)多巴胺含量的升高。多巴胺含量的變化依賴于一些神經(jīng)通路,與成癮效應(yīng)有關(guān)的通路主要指中腦邊緣多巴胺系統(tǒng)(mesolimbic dopamine system, MLDS)。成癮藥物等獎(jiǎng)賞性刺激通過多條途徑激活中腦邊緣多巴胺系統(tǒng)(MLDS)后使得伏隔核內(nèi)多巴胺的含量升高,從而產(chǎn)生有關(guān)獎(jiǎng)賞的信號(hào)。腦內(nèi)的中腦邊緣多巴胺系統(tǒng)中最主要的結(jié)構(gòu)基礎(chǔ)是從腦區(qū)腹側(cè)被蓋區(qū)(ventral tegmental area, VTA)到腦區(qū)伏隔核(nucleus accumbens,NAc)之間的神經(jīng)投射。與獎(jiǎng)賞效應(yīng)的形成的相關(guān)腦區(qū)有很多,分布從前腦至外側(cè)部分等相關(guān)的腦區(qū),如包括前額葉(prelimbic prefrontal cortex,PFC)、海馬(hippocampus,Hip)。伏隔核也是參與神經(jīng)系統(tǒng)內(nèi)有關(guān)獎(jiǎng)賞作用的重要腦區(qū),它可能產(chǎn)生神經(jīng)元結(jié)構(gòu)、功能上的適應(yīng)性變化。前額葉皮質(zhì)具有極其廣泛的神經(jīng)聯(lián)系和復(fù)雜的結(jié)構(gòu)形式,以及與其它腦區(qū)之間有著豐富、復(fù)雜的雙向性聯(lián)系。大腦前額葉對(duì)全腦結(jié)構(gòu)起著調(diào)節(jié)性和指導(dǎo)性作用,表現(xiàn)在接受以及綜合由腦的各個(gè)部位傳入的來自機(jī)體內(nèi)外的各種信息,并能整合后及時(shí)傳出神經(jīng)沖動(dòng),從而保證了神經(jīng)系統(tǒng)整體的協(xié)同和達(dá)到整個(gè)高級(jí)心理過程的統(tǒng)一。谷氨酸能神經(jīng)元存在于腦區(qū)PFC與腦區(qū)NAc之間,谷氨酸在腦內(nèi)的獎(jiǎng)賞效應(yīng)的形成過程中起重要作用。 成癮藥物最早應(yīng)用于臨床醫(yī)藥,用于減輕手術(shù)及其它疾病帶來的痛苦,例如嗎啡,可卡因,大麻,尼古丁等,但隨著科技發(fā)展,藥物濫用現(xiàn)象越來越嚴(yán)重,藥物成癮成為嚴(yán)峻的社會(huì)問題,藥物成癮的治療也成為研究的熱點(diǎn)。目前有實(shí)驗(yàn)關(guān)注于兩種成癮藥物之間的相互作用及相互影響。每一種成癮藥物作用機(jī)理及作用腦區(qū)的不同可能會(huì)對(duì)不同的神經(jīng)元的產(chǎn)生不同影響。有些神經(jīng)元上會(huì)存在遞質(zhì)共存現(xiàn)象,那么這些共存的遞質(zhì)相互之間就可能造成功能上、結(jié)構(gòu)上的依賴及影響,因此兩種成癮藥物之間的相互作用成為研究的一個(gè)有價(jià)值的思路。有文章稱大麻素能改變VTA內(nèi)的多巴胺(doparnine,DA)神經(jīng)元的電流變化,從而誘導(dǎo)產(chǎn)生了長時(shí)程減弱現(xiàn)(longterm-depression, LTD)。但很多精神藥物的作用效果與大麻素的機(jī)制不同,如可卡因、尼古丁、嗎啡及酒精等卻使得腦區(qū)VTA內(nèi)的DA神經(jīng)元發(fā)生不同電流變化,從而誘導(dǎo)產(chǎn)生長時(shí)程增(longterm-potentiation,LTP)。因此,成癮藥物的不同作用于神經(jīng)元的機(jī)理可能不同,對(duì)突觸可塑性產(chǎn)生不同影響,甚至是相反的作用。這暗示如果成癮藥物對(duì)突觸的作用效應(yīng)和機(jī)理相反,那么將兩種成癮藥物一起同時(shí)先后使用,那么兩種成癮藥物可能會(huì)出現(xiàn)藥理抵消現(xiàn)象,在動(dòng)物的機(jī)體表現(xiàn)上體現(xiàn)出中和效應(yīng)。有研究人員為了證明這種假想和推理是否正確,在動(dòng)物身體上聯(lián)合注射成癮藥品尼古丁及人工合成大麻素HU210,發(fā)現(xiàn)尼古丁在機(jī)體內(nèi)產(chǎn)生的LTP現(xiàn)象和人工合成大麻素在機(jī)體內(nèi)產(chǎn)生的LTD現(xiàn)象確實(shí)能夠相互抵消,并且當(dāng)兩種藥物聯(lián)合使用后在行為上表現(xiàn)為以前各自能分別產(chǎn)生的位置偏愛效應(yīng)(conditionned place preference,CPP)消失。另有研究指出,在可卡因造成的成癮自給要模型中,注射大麻素能明顯抑制該行為。目前有實(shí)驗(yàn)稱,嗎啡的急性作用能使神經(jīng)元上谷氨酸的傳遞效率增高并且這種機(jī)制是通過增加突觸前遞質(zhì)釋放而引起的,而注射大麻素會(huì)引起膠質(zhì)細(xì)胞海馬區(qū)的谷氨酸釋放量降低。在腦區(qū)VTA中,DA能神經(jīng)元能產(chǎn)生LTP現(xiàn)象可通過注射嗎啡引起,而產(chǎn)生LTD現(xiàn)象可通過注射大麻素產(chǎn)生。而對(duì)于兩種成癮藥物之間的相互作用及影響,現(xiàn)在還不清楚。 為探討兩種成癮藥物的聯(lián)合使用而造成的對(duì)神經(jīng)系統(tǒng)內(nèi)谷氨酸傳遞效率的影響及機(jī)制,本研究選取在體記錄的方法,選取記錄的位置為腦區(qū)PFC至腦區(qū)NAC之間的谷氨酸能神經(jīng)元,記錄通過電刺激對(duì)腦區(qū)PFC刺激后傳導(dǎo)至NAc殼區(qū)的場興奮性突觸后電位(field excitatory postsynaptic potential,EPSP)。急性嗎啡處理后再急性注射人工合成大麻素的谷氨酸能突觸EPSP的變化以及人工合成大麻素急性處理后再急性注射嗎啡的谷氨酸EPSP的變化。結(jié)果顯示,與對(duì)照組相比,急性嗎啡注射后,再注射人工合成大麻素20-30min時(shí),EPSP有增大趨勢(shì)。但是急性注射大麻素后,再次注射嗎啡時(shí),嗎啡的效果不能持續(xù)保持,提示NAC中兩種受體可能發(fā)生相互影響�？偨Y(jié)上述實(shí)驗(yàn)結(jié)果可得知：急性嗎啡后,腦區(qū)PFC-NAc的谷氨酸能突觸前膜遞質(zhì)釋放量增加,表現(xiàn)為EPSP顯著增大；再1小時(shí)后注射人工合成大麻素處理后,NAc中神經(jīng)元的EPSP在短期內(nèi)發(fā)生了一些增大的變化趨勢(shì)。而將這兩種成癮藥物調(diào)換順序注射時(shí),會(huì)得到一些不同的結(jié)果,暗示這兩種成癮藥物之間有相互影響,可能具體機(jī)制為受體之間的相互作用。阿片受體和大麻素受體在神經(jīng)元內(nèi)廣泛表達(dá),在某些區(qū)域共存。這種受體的變化在藥物成癮形成及藥物戒斷過程中起著極其重要的作用,本實(shí)驗(yàn)的研究結(jié)果能夠?yàn)閮煞N成癮藥物的相互影響及藥物成癮提供一定的參考價(jià)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.
【學(xué)位授予單位】：陜西師范大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2013
【分類號(hào)】：R749.61
本文編號(hào)：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.
【學(xué)位授予單位】：陜西師范大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2013
【分類號(hào)】：R749.61
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