Ⅰ：BK_(Ca)通道参与尼古丁成瘾的实验研究;Ⅱ：龙胆苦苷下调伏隔核GluN2B受体抑制吗啡成瘾的实验研究
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摘要
第一部分
吸烟是引起致命心血管系统、中枢神经系统（CNS）疾病的重要危险因素，每年死于与吸烟有关疾病的人数日益攀升，如何使吸烟者摆脱烟草的困扰即探讨其成瘾机制是当前该领域关注的焦点。
烟草中的尼古丁，是产生烟草成瘾性或依赖性的主要成分，而引发成瘾的确切机制目前尚不清楚。成瘾和学习记忆过程有很多相同的神经生物学改变,与学习记忆有关的重要脑区、功能分子和离子通道参与了药物依赖的形成过程。大电导钙激活钾通道（BK_(Ca)）在CNS中分布广泛，参与多种神经活动。激活该通道可产生后超极化电位（AHP），降低细胞膜的兴奋性，减少神经元电活动。BK_(Ca)亦可通过影响神经元的兴奋性及神经递质的释放，参与调节神经网络的活动。我们前期的研究结果显示，BK_(Ca)通过影响杏仁核神经电活动而参与焦虑的发病过程，提示BK_(Ca)参与脑的高级神经活动。然而，BK_(Ca)通道是否参与尼古丁成瘾及机制如何尚未见报道。本课题采用分子生物学、行为学及电生理等实验方法，观察BK_(Ca)通道在小鼠尼古丁成瘾中的作用及作用机制，并探讨其潜在的药理学治疗的可能性。
目的
BK_(Ca)广泛分布于CNS中，通过影响神经元的兴奋性及神经递质的释放参与多种神经活动。我们前期的研究结果显示，BK_(Ca)通过影响杏仁核神经电活动而参与焦虑的发病过程，提示BK_(Ca)参与脑的高级神经活动。本课题将以伏隔核BK_(Ca)通道为研究对象，阐明BK_(Ca)通道参与尼古丁成瘾的作用及作用机制，并探讨其潜在的药理学治疗可能性。
方法
1.体外原代培养神经元，免疫荧光双标技术观察BK_(Ca)通道在兴奋性和抑制性神经元的表达，Western Blot方法分析尼古丁刺激下神经元BK_(Ca)通道表达的变化。
2.制备尼古丁成瘾小鼠模型，免疫荧光双标技术与Western Blot观察BK_(Ca)通道在尼古丁成瘾模型小鼠及正常对照小鼠伏隔核（NAc）中的表达变化。
3.颈部皮下注射BK_(Ca)通道特异性激动剂NS1619、拮抗剂Paxilline，观察对尼古丁成瘾小鼠行为学的影响。
4.脑立体定向注射BK_(Ca)通道shRNA慢病毒，RNA干扰（RNAinterference,RNAi）局部下调成瘾小鼠伏隔核BK_(Ca)的表达，24h后观察对尼古丁成瘾小鼠的行为改变。
5.采用脑薄片全细胞膜片钳技术，研究伏隔核BK_(Ca)通道对神经元兴奋性，以及介导后超极化（AHP）功能中的作用；行为学观察调节BK_(Ca)通道功能对小鼠尼古丁成瘾的影响。
结果
1.采用IHC方法以VGLUT2标记兴奋性神经元，GAD67标记抑制性神经元，BK_(Ca)通道与VGLUT2、GAD67阳性的神经元共存，提示BK_(Ca)通道在两种神经元均有表达。
2.体外原代神经元培养7d至成熟，给予50μM尼古丁刺激，于不同时间点收集并制备蛋白样品，WB方法观察尼古丁处理神经元24h起，BK_(Ca)蛋白表达降低。
3.采用颈部皮下注射尼古丁，连续5d，CPP实验检测小鼠对白箱的偏爱确定成瘾模型制备成功，WB方法发现小鼠伏隔核中BK_(Ca)的表达降低。
4.成瘾小鼠分别颈部皮下注射BK_(Ca)通道特异性激动剂NS1619、拮抗剂Paxilline，CPP发现NS1619可减少小鼠在白箱中的停留时间，即减弱了小鼠对尼古丁的觅药行为。
5.成瘾小鼠NAc脑立体定向注射慢病毒包装的BK_(Ca)shRNA，RNAi下调其在NAc局部的表达，同时可增强小鼠在白箱中的停留时间，即增加对尼古丁的觅药行为。
6.脑薄片全细胞膜片钳发现，尼古丁成瘾小鼠伏隔核神经元后超极化（AHP）幅度明显降低，其兴奋性明显增加，而BK_(Ca)通道被其特异性激动剂NS1619激活后使AHP幅度升高，显著降低成瘾小鼠伏隔核神经元兴奋性；尼古丁成瘾小鼠BK_(Ca)通道功能显著降低。
结论
1.我们采用体外原代神经元培养体系，证实BK_(Ca)表达于兴奋性和抑制性神经元，给予尼古丁刺激，BK_(Ca)的表达降低。
2.证实尼古丁成瘾小鼠NAc的BK_(Ca)表达降低；升高BK_(Ca)功能（激动剂NS1619）可减弱小鼠的觅药行为；相反，抑制BK_(Ca)蛋白表达可增加小鼠的成瘾性。
3.电生理结果进一步证实，BK_(Ca)通道通过调节神经元的兴奋性、调节神经网络的功能参与尼古丁成瘾，可作为潜在的治疗靶点。
第二部分
目的
龙胆苦苷是从龙胆科植物条叶龙胆干燥根茎中分离出的一种裂环烯醚萜类化合物。该化合物具有镇痛作用，并能抑制NMDA受体的GluN2B亚基在小鼠前扣带皮层的表达。NAc是药物成瘾作用的重要前脑结构。然而，龙胆苦苷对吗啡成瘾和NAc突触传递的作用，尚不清楚。
方法
采用条件性位置偏爱（Conditioned place preference, CPP）和自发活动（locomotor activity）行为敏化观察成瘾小鼠的觅药行为；全细胞膜片钳记录NAc中神经元兴奋性突触后电流（EPSCs）；Western blot检测相关蛋白的表达。
结果
小鼠给予龙胆苦苷可降低吗啡所致CPP效应，但对吗啡诱导的行为敏化没有影响。龙胆苦苷在吗啡戒断后一周内降低NMDA受体GluN2B亚基和多巴胺D2受体的过表达增强，但不影响NMDA受体GluN2A亚基和多巴胺D1受体。电生理结果表明龙胆苦苷亦可显著降低NAc中NMDA受体介导的EPSCs。
结论
研究证明，龙胆苦苷通过下调NAc中NMDA受体GluN2B亚基抑制吗啡的成瘾作用。
PartⅠ
Smoking is the important risk factor leading to severe cardiovascular andcentral nervous system (CNS) diseases, and the death rate of diseases related tosmoking increased dramatically. Therefore, how to get rid of smoking and clarifythe mechanisms involved in smoking addiction are the focuses in this field.
Nicotine, the main component of tobacco, is the major substance fornicotine addiction or dependence, while the mechanisms involved remainunclear. There are lots of similarities in neurobiological changes betweenaddiction and learning memory, including similar critical brain regions,functional molecules and ion channels. Among them, large conductanceCa~(2+)-activated K+-channel (BK_(Ca)) is widely expressed in the CNS and playsimportant roles in lots of neural activities. Activation of BK_(Ca)channel producesafter hyperpolarization (AHP), subsequently decreases excitability of the neurons. At the same time, BK_(Ca)takes part in neural networks throughmodulation of neuron excitability and neurotransmitter release. Our previousdata show that BK_(Ca)are involved in anxiety development by affecting neuronselectricphysiological activities in amygdala, suggesting BK_(Ca)may play a criticalrole in higher nervous activities including learning and memory. However,whether BK_(Ca)plays roles in nicotine addiction and the underlying mechanismsare still unclear. In this study, multiple methods including molecular biology,behavior test, and electrophysiology were used to investigate the roles andmechanisms of BK_(Ca)involved in nicotine addiction. It is hopeful that this studymay shed light on the possibility of potential target for nicotine addictiontreatment.
Objective
BK_(Ca)is widely expressed in the CNS and takes part in lots of neuralfunctions through modulation of neuron excitability and neurotransmitter release.Our previous data show that BK_(Ca)is involved in anxiety development byaffecting neurons electricphysiological activities in amygdala, implicating BK_(Ca)may play a critical role in higher nervous functions. In this study, we willexplore the roles of BK_(Ca)of nucleus accumbens septum (NAc) in thedevelopment of nicotine-addiction and the mechanisms involved in the process.It may shed light on the potential target for the therapy of nicotine addiction.
Methods
1. Immunofluorescence double-staining were used to check the expression ofBK_(Ca)in the excitatory and inhibitory neurons. The change of BK_(Ca)expression under nicotine stimulation was tested in the primary cultureneurons.
2. Nicotine-addiction mouse model was establish to investigate the alteration ofBK_(Ca)expression in mice NAc.
3. Roles of BK_(Ca)in nicotine-addiction were determined by subcutaneousinjection of NS1619(BK_(Ca)agonist) and Paxilline (BK_(Ca)antigonist) inaddicted mice and the behavioral changes accordingly.
4. Lentiviurs shRNA for BK_(Ca)was performed to further explore the roles ofBK_(Ca)nicotine-addiction.
5. Whole-cell patch clamp technique was used to investigate the effects ofBK_(Ca)channels on the excitability of neurons in NAc and the alteration ofBK_(Ca)channels in nicotine-addiciton.
Results
1. BK_(Ca)channels were observed coexsited in both VGLUT2positive andGAD67positive cells, implicating BK_(Ca)channels are expressed inexcitatory and inhibitory neurons.
2. Expression of BK_(Ca)in cultured neurons was found decreased after treatmentwith nicotine (50μM) for24hours.
3. Conditioned place preference (CPP) test was used to test nicotine-addiction,which was induced by subcutaneous injeciton of nicotine (0.5mg/kg) forsuccessive5days. Expression of BK_(Ca)in NAc was decreased significantlyin the addition mice.
4. Subcutaneous injection of NS1619, the agonist of BK_(Ca), decreaseddrug-seeking behavior in addiction mice.
5. Knocked down BK_(Ca)expression in NAc by shRNA promoted drug-seekingbehaviors.
6. Using the whole-cell patch clamp technique we found that NS1619, theBK_(Ca)agonist, increasd the peak of the fAHP in the NAc neurons of addiction mice. The function of BK_(Ca)channels was decreased in thenicotine-addiction mice.
Conclusions
1. BK_(Ca)channels were expressed in both excitatory and inhibitory neurons andthe expression of BK_(Ca)was decreased after nicotine treatment.
2. Expression of BK_(Ca)channels was decreased in NAc of nicotine-addictionmice. Increase of BK_(Ca)channel function (using agonist NS1619) coulddecrease drug-seeking behavior, however, inhibition of BK_(Ca)expressionby shRNA caused enhancement of drug-seeking behavior.
3. Whole-cell patch-clamp recordings reveal that BK_(Ca)channels involve in thedevelopment of nicotine-addiction by regulating the excitability of thenetwork. Modulation of the BK_(Ca)channels may be the potential target forthe treatnment of drug addition.
PartⅡ
Objective: Gentiopicroside (Gent) is one of the secoiridoid compoundisolated from Gentiana lutea. This compound exhibits analgesic activities andinhibits the expression of GluN2B-containing N-methyl-D-aspartate (NMDA)receptors in the anterior cingulate cortex in mice. Nucleus accumbens (NAc) is aforebrain structure known for its role in drug addiction. However, little is knownabout the role of Gent on morphine dependence and synaptic transmissionchanges in the NAc.
Methods: Conditioned place preference (CPP) test and behavioralsensitization of locomotor activity were used to investigate drug-seeking relatedbehaviors. Brain slices containing NAc were prepared, and whole-cell patch-clamp recordings were performed to record the excitatory postsynapticcurrents (EPSCs). Expression of proteins was detected by Western blot analysis.
Results: Systemic administration of Gent attenuated the CPP effect inducedby morphine, but had no effect on morphine-induced behavioral sensitization.Gent significantly reversed overexpression of GluN2B-containing NMDAreceptors and dopamine D2receptors in NAc during the first week of morphinewithdrawal. However, the compound did not affect the overexpression ofGluN2A-containing NMDA receptors, GluA1, and dopamine D1receptors.Lastly, Gent significantly reduced NMDA receptors-mediated EPSCs in theNAc.
Conclusions: Our study provides strong evidence that Gent inhibitsmorphine dependence through downregulation of GluN2B-containing NMDAreceptors in the NAc.
吸烟是引起致命心血管系统、中枢神经系统（CNS）疾病的重要危险因素，每年死于与吸烟有关疾病的人数日益攀升，如何使吸烟者摆脱烟草的困扰即探讨其成瘾机制是当前该领域关注的焦点。
烟草中的尼古丁，是产生烟草成瘾性或依赖性的主要成分，而引发成瘾的确切机制目前尚不清楚。成瘾和学习记忆过程有很多相同的神经生物学改变,与学习记忆有关的重要脑区、功能分子和离子通道参与了药物依赖的形成过程。大电导钙激活钾通道（BK_(Ca)）在CNS中分布广泛，参与多种神经活动。激活该通道可产生后超极化电位（AHP），降低细胞膜的兴奋性，减少神经元电活动。BK_(Ca)亦可通过影响神经元的兴奋性及神经递质的释放，参与调节神经网络的活动。我们前期的研究结果显示，BK_(Ca)通过影响杏仁核神经电活动而参与焦虑的发病过程，提示BK_(Ca)参与脑的高级神经活动。然而，BK_(Ca)通道是否参与尼古丁成瘾及机制如何尚未见报道。本课题采用分子生物学、行为学及电生理等实验方法，观察BK_(Ca)通道在小鼠尼古丁成瘾中的作用及作用机制，并探讨其潜在的药理学治疗的可能性。
目的
BK_(Ca)广泛分布于CNS中，通过影响神经元的兴奋性及神经递质的释放参与多种神经活动。我们前期的研究结果显示，BK_(Ca)通过影响杏仁核神经电活动而参与焦虑的发病过程，提示BK_(Ca)参与脑的高级神经活动。本课题将以伏隔核BK_(Ca)通道为研究对象，阐明BK_(Ca)通道参与尼古丁成瘾的作用及作用机制，并探讨其潜在的药理学治疗可能性。
方法
1.体外原代培养神经元，免疫荧光双标技术观察BK_(Ca)通道在兴奋性和抑制性神经元的表达，Western Blot方法分析尼古丁刺激下神经元BK_(Ca)通道表达的变化。
2.制备尼古丁成瘾小鼠模型，免疫荧光双标技术与Western Blot观察BK_(Ca)通道在尼古丁成瘾模型小鼠及正常对照小鼠伏隔核（NAc）中的表达变化。
3.颈部皮下注射BK_(Ca)通道特异性激动剂NS1619、拮抗剂Paxilline，观察对尼古丁成瘾小鼠行为学的影响。
4.脑立体定向注射BK_(Ca)通道shRNA慢病毒，RNA干扰（RNAinterference,RNAi）局部下调成瘾小鼠伏隔核BK_(Ca)的表达，24h后观察对尼古丁成瘾小鼠的行为改变。
5.采用脑薄片全细胞膜片钳技术，研究伏隔核BK_(Ca)通道对神经元兴奋性，以及介导后超极化（AHP）功能中的作用；行为学观察调节BK_(Ca)通道功能对小鼠尼古丁成瘾的影响。
结果
1.采用IHC方法以VGLUT2标记兴奋性神经元，GAD67标记抑制性神经元，BK_(Ca)通道与VGLUT2、GAD67阳性的神经元共存，提示BK_(Ca)通道在两种神经元均有表达。
2.体外原代神经元培养7d至成熟，给予50μM尼古丁刺激，于不同时间点收集并制备蛋白样品，WB方法观察尼古丁处理神经元24h起，BK_(Ca)蛋白表达降低。
3.采用颈部皮下注射尼古丁，连续5d，CPP实验检测小鼠对白箱的偏爱确定成瘾模型制备成功，WB方法发现小鼠伏隔核中BK_(Ca)的表达降低。
4.成瘾小鼠分别颈部皮下注射BK_(Ca)通道特异性激动剂NS1619、拮抗剂Paxilline，CPP发现NS1619可减少小鼠在白箱中的停留时间，即减弱了小鼠对尼古丁的觅药行为。
5.成瘾小鼠NAc脑立体定向注射慢病毒包装的BK_(Ca)shRNA，RNAi下调其在NAc局部的表达，同时可增强小鼠在白箱中的停留时间，即增加对尼古丁的觅药行为。
6.脑薄片全细胞膜片钳发现，尼古丁成瘾小鼠伏隔核神经元后超极化（AHP）幅度明显降低，其兴奋性明显增加，而BK_(Ca)通道被其特异性激动剂NS1619激活后使AHP幅度升高，显著降低成瘾小鼠伏隔核神经元兴奋性；尼古丁成瘾小鼠BK_(Ca)通道功能显著降低。
结论
1.我们采用体外原代神经元培养体系，证实BK_(Ca)表达于兴奋性和抑制性神经元，给予尼古丁刺激，BK_(Ca)的表达降低。
2.证实尼古丁成瘾小鼠NAc的BK_(Ca)表达降低；升高BK_(Ca)功能（激动剂NS1619）可减弱小鼠的觅药行为；相反，抑制BK_(Ca)蛋白表达可增加小鼠的成瘾性。
3.电生理结果进一步证实，BK_(Ca)通道通过调节神经元的兴奋性、调节神经网络的功能参与尼古丁成瘾，可作为潜在的治疗靶点。
第二部分
目的
龙胆苦苷是从龙胆科植物条叶龙胆干燥根茎中分离出的一种裂环烯醚萜类化合物。该化合物具有镇痛作用，并能抑制NMDA受体的GluN2B亚基在小鼠前扣带皮层的表达。NAc是药物成瘾作用的重要前脑结构。然而，龙胆苦苷对吗啡成瘾和NAc突触传递的作用，尚不清楚。
方法
采用条件性位置偏爱（Conditioned place preference, CPP）和自发活动（locomotor activity）行为敏化观察成瘾小鼠的觅药行为；全细胞膜片钳记录NAc中神经元兴奋性突触后电流（EPSCs）；Western blot检测相关蛋白的表达。
结果
小鼠给予龙胆苦苷可降低吗啡所致CPP效应，但对吗啡诱导的行为敏化没有影响。龙胆苦苷在吗啡戒断后一周内降低NMDA受体GluN2B亚基和多巴胺D2受体的过表达增强，但不影响NMDA受体GluN2A亚基和多巴胺D1受体。电生理结果表明龙胆苦苷亦可显著降低NAc中NMDA受体介导的EPSCs。
结论
研究证明，龙胆苦苷通过下调NAc中NMDA受体GluN2B亚基抑制吗啡的成瘾作用。
PartⅠ
Smoking is the important risk factor leading to severe cardiovascular andcentral nervous system (CNS) diseases, and the death rate of diseases related tosmoking increased dramatically. Therefore, how to get rid of smoking and clarifythe mechanisms involved in smoking addiction are the focuses in this field.
Nicotine, the main component of tobacco, is the major substance fornicotine addiction or dependence, while the mechanisms involved remainunclear. There are lots of similarities in neurobiological changes betweenaddiction and learning memory, including similar critical brain regions,functional molecules and ion channels. Among them, large conductanceCa~(2+)-activated K+-channel (BK_(Ca)) is widely expressed in the CNS and playsimportant roles in lots of neural activities. Activation of BK_(Ca)channel producesafter hyperpolarization (AHP), subsequently decreases excitability of the neurons. At the same time, BK_(Ca)takes part in neural networks throughmodulation of neuron excitability and neurotransmitter release. Our previousdata show that BK_(Ca)are involved in anxiety development by affecting neuronselectricphysiological activities in amygdala, suggesting BK_(Ca)may play a criticalrole in higher nervous activities including learning and memory. However,whether BK_(Ca)plays roles in nicotine addiction and the underlying mechanismsare still unclear. In this study, multiple methods including molecular biology,behavior test, and electrophysiology were used to investigate the roles andmechanisms of BK_(Ca)involved in nicotine addiction. It is hopeful that this studymay shed light on the possibility of potential target for nicotine addictiontreatment.
Objective
BK_(Ca)is widely expressed in the CNS and takes part in lots of neuralfunctions through modulation of neuron excitability and neurotransmitter release.Our previous data show that BK_(Ca)is involved in anxiety development byaffecting neurons electricphysiological activities in amygdala, implicating BK_(Ca)may play a critical role in higher nervous functions. In this study, we willexplore the roles of BK_(Ca)of nucleus accumbens septum (NAc) in thedevelopment of nicotine-addiction and the mechanisms involved in the process.It may shed light on the potential target for the therapy of nicotine addiction.
Methods
1. Immunofluorescence double-staining were used to check the expression ofBK_(Ca)in the excitatory and inhibitory neurons. The change of BK_(Ca)expression under nicotine stimulation was tested in the primary cultureneurons.
2. Nicotine-addiction mouse model was establish to investigate the alteration ofBK_(Ca)expression in mice NAc.
3. Roles of BK_(Ca)in nicotine-addiction were determined by subcutaneousinjection of NS1619(BK_(Ca)agonist) and Paxilline (BK_(Ca)antigonist) inaddicted mice and the behavioral changes accordingly.
4. Lentiviurs shRNA for BK_(Ca)was performed to further explore the roles ofBK_(Ca)nicotine-addiction.
5. Whole-cell patch clamp technique was used to investigate the effects ofBK_(Ca)channels on the excitability of neurons in NAc and the alteration ofBK_(Ca)channels in nicotine-addiciton.
Results
1. BK_(Ca)channels were observed coexsited in both VGLUT2positive andGAD67positive cells, implicating BK_(Ca)channels are expressed inexcitatory and inhibitory neurons.
2. Expression of BK_(Ca)in cultured neurons was found decreased after treatmentwith nicotine (50μM) for24hours.
3. Conditioned place preference (CPP) test was used to test nicotine-addiction,which was induced by subcutaneous injeciton of nicotine (0.5mg/kg) forsuccessive5days. Expression of BK_(Ca)in NAc was decreased significantlyin the addition mice.
4. Subcutaneous injection of NS1619, the agonist of BK_(Ca), decreaseddrug-seeking behavior in addiction mice.
5. Knocked down BK_(Ca)expression in NAc by shRNA promoted drug-seekingbehaviors.
6. Using the whole-cell patch clamp technique we found that NS1619, theBK_(Ca)agonist, increasd the peak of the fAHP in the NAc neurons of addiction mice. The function of BK_(Ca)channels was decreased in thenicotine-addiction mice.
Conclusions
1. BK_(Ca)channels were expressed in both excitatory and inhibitory neurons andthe expression of BK_(Ca)was decreased after nicotine treatment.
2. Expression of BK_(Ca)channels was decreased in NAc of nicotine-addictionmice. Increase of BK_(Ca)channel function (using agonist NS1619) coulddecrease drug-seeking behavior, however, inhibition of BK_(Ca)expressionby shRNA caused enhancement of drug-seeking behavior.
3. Whole-cell patch-clamp recordings reveal that BK_(Ca)channels involve in thedevelopment of nicotine-addiction by regulating the excitability of thenetwork. Modulation of the BK_(Ca)channels may be the potential target forthe treatnment of drug addition.
PartⅡ
Objective: Gentiopicroside (Gent) is one of the secoiridoid compoundisolated from Gentiana lutea. This compound exhibits analgesic activities andinhibits the expression of GluN2B-containing N-methyl-D-aspartate (NMDA)receptors in the anterior cingulate cortex in mice. Nucleus accumbens (NAc) is aforebrain structure known for its role in drug addiction. However, little is knownabout the role of Gent on morphine dependence and synaptic transmissionchanges in the NAc.
Methods: Conditioned place preference (CPP) test and behavioralsensitization of locomotor activity were used to investigate drug-seeking relatedbehaviors. Brain slices containing NAc were prepared, and whole-cell patch-clamp recordings were performed to record the excitatory postsynapticcurrents (EPSCs). Expression of proteins was detected by Western blot analysis.
Results: Systemic administration of Gent attenuated the CPP effect inducedby morphine, but had no effect on morphine-induced behavioral sensitization.Gent significantly reversed overexpression of GluN2B-containing NMDAreceptors and dopamine D2receptors in NAc during the first week of morphinewithdrawal. However, the compound did not affect the overexpression ofGluN2A-containing NMDA receptors, GluA1, and dopamine D1receptors.Lastly, Gent significantly reduced NMDA receptors-mediated EPSCs in theNAc.
Conclusions: Our study provides strong evidence that Gent inhibitsmorphine dependence through downregulation of GluN2B-containing NMDAreceptors in the NAc.
引文
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