慢性应激大鼠抑郁症模型奖赏系统多巴胺受体功能及中西抗抑郁药作用的研究
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摘要
抑郁症（major depressive disorder, MDD）是临床上很常见的一种精神心理疾病，以持续性的情绪低落为主要特征，快感缺乏、动力低下是其主要核心症状，病程迁延，容易复发，自杀率高，严重地威胁着人们的生活质量和生命健康。抑郁症的发病机制非常复杂，到目前为止仍然不十分清楚，需要进一步深入的研究和探索。本实验采用慢性不可预见性轻度应激大鼠抑郁模型，来了解奖赏系统相关脑区在应激前后及用药不同阶段的神经生化改变，以期能为临床治疗提供新的认识和方法。
第一部分抑郁症奖赏系统多巴胺D2、D3受体功能障碍的研究
实验一慢性不可预见性轻度应激抑郁症模型的建立
目的：大鼠抑郁模型是抑郁症研究中最为关键的研究媒介，稳定可靠的动物模型是研究工作成果是否可靠的重要基础条件。本实验采用慢性不可预见性轻度应激（chronic unpredictable mild stress, CUMS）结合孤养的方法，以期获得稳定、可靠、重复性强的大鼠抑郁模型，为进一步的研究打下良好的基础。
方法：选用成年雄性Sprague-Dawley大鼠，共16只，随机分为正常组和模型组各8只，采用慢性不可预见性轻度应激结合孤养的方法，制作大鼠抑郁模型，进行21天应激干预，分别于应激干预前后进行强迫游泳实验（The forced swimmingtest，FST）和液体消耗实验（Fluid consumption test）测量，并定期监测大鼠体重变化，用以上三项指标来评估大鼠快感缺乏和行为绝望的程度。模型制作结束后，应用高效液相色谱质谱连用方法（HPLC-MS）分析大鼠前额叶、海马、伏隔核各脑区单胺类神经递质及其代谢产物多巴胺（DA）、3,4-二羟基苯乙酸（DOPAC）、高香草酸（HVA）、5-羟色胺（5-HT）、5-羟吲哚乙酸（5-HIAA）在应激前后含量的变化，进一步评估大鼠抑郁模型的有效性。
结果：
1.行为学结果显示，相对于正常组大鼠，模型组大鼠在接受应激干预后液体消耗实验的糖水偏爱指数下降显著；强迫游泳实验静止不动时间明显延长；体重增长值显著下降。各项结果均差异显著，有统计学意义。
2. HPLC-MS检测结果显示，模型组在应激后大鼠前额叶、海马、伏隔核各脑区DA、DOPAC、HVA、5-HT、5-HIAA含量均比正常组有明显减少，有统计学意义。
结论：慢性不可预见性轻度应激结合孤养制做的大鼠抑郁模型，能够很好的模拟人类抑郁症的核心症状，模型大鼠快感缺乏，行为绝望，体重下降三项指标均改变明显，且脑内神经递质变化符合目前抑郁症的神经生化改变。模型症状稳定，可重复性强，持续时间长，是非常可靠的动物抑郁模型，可以作为良好的媒介进性下一步的实验。
实验二5-羟色胺再摄取抑制剂对抑郁症模型大鼠奖赏系统的影响
目的：抑郁症核心症状快感缺乏是奖赏系统功能障碍的直接体现。通过大鼠抑郁模型进一步了解奖赏系统重要脑区多巴胺D2受体、多巴胺D3受体的在应激干预前后含量变化，明确奖赏系统功能障碍的确切依据，并通过对比大鼠应用5-羟色胺再摄取抑制剂西酞普兰用药前后不同阶段神经递质及其代谢产物、D2DR、D3DR的变化，来探讨5-羟色胺再摄取抑制剂对奖赏系统的可能影响。
方法：将依照实验一部分制作的抑郁模型大鼠随机分组，分别为盐水对照早期组、盐水对照晚期组、西酞普兰早期组、西酞普兰晚期组各6只。分别给予盐水及西酞普兰用药干预，另外有随机分组的对照组及模型组大鼠各6只，分别正常饲养及仅按照前述模型制作方法制作成模型大鼠。分别于应激干预前、后及用药1天后及用药14天后对各组大鼠进行行为学检测，包括强迫游泳实验、液体消耗实验及体重监测。然后通过HPLC-MS方法检测大鼠单胺类神经递质及其代谢产物在应激前后、用药前后及用药不同阶段的变化，通过蛋白质免疫印迹（Western-Blotting，WB）方法检测D2DR、D3DR的含量改变，来进一步了解西酞普兰用药不同时期对奖赏系统的影响。
结果：
1.西酞普兰晚期用药组出现了明显的行为学改善，糖水偏爱指数升高、强迫游泳不动时间缩短及体重增长值增加，有统计学意义，用药早期无明显改变。
2.西酞普兰组早期组用药1天后伏隔核DA、海马DOPAC及海马5-HT就有明显增加，其余各组早期未见明显有统计学意义的差别；晚期组用药14天后西酞普兰组各脑区DA、DOPAC、HVA、5-HT、5-HIAA均较盐水对照组有明显增加,有统计学意义。
3.模型组大鼠在应激后与对照组大鼠比较，在前额叶、海马、伏隔核各脑区D2DR及D3DR的表达均明显下降，有统计学意义。在前额叶、海马、伏隔核西酞普兰早期组D2DR的表达较模型盐水组有显著增加，西酞普兰晚期组D2DR的表达均比模型盐水组有明显增加，三个脑区内西酞普兰晚期组D2DR的表达仍较空白对照组明显减少；在三个脑区内西酞普兰早期组及西酞普兰晚期组D3DR表达均较模型盐水组有明显增加，用药14天后西酞普兰晚期组比西酞普兰早期组D3DR表达又均有明显减少；三个脑区内D3DR表达西酞普兰早期及晚期组均比空白对照组均有明显减少，有统计学意义。
结论：
1.大鼠抑郁模型存在奖赏系统功能障碍，主要表现在奖赏系统重要脑区多巴胺及其代谢产物及D2DR、D3DR的表达的下降。
2. D3DR的表达在用药的早期出现一过性升高后，继之又下降，到晚期组下降显著，提示西酞普兰对D3DR受体功能存在一定程度的抑制，表现在长期用药后D3DR的表达减少，D2DR的表达虽然有所上升，但与正常组比较仍有较大差距，提示奖赏系统功能并未得到有效恢复。
第二部分柴胡加龙骨牡蛎汤抗抑郁作用的研究
目的：中医中药是中华民族的瑰宝，但因作用机制复杂不清而难以被广泛认可和接受，通过慢性应激大鼠抑郁模型了解柴胡加龙骨牡蛎汤的抗抑郁作用，并通过与西酞普兰对比探索其抗抑郁的作用机制。
方法：制作完成的大鼠抑郁模型，随机分组为盐水对照早期组、盐水对照晚期组、西酞普兰早期组、西酞普兰晚期、中药方剂早期组、中药方剂晚期组各6只，分别于用药1天后及用药14天后进行强迫游泳实验、液体消耗实验及体重变化的行为学检测。然后通过HPLC-MS方法检测大鼠脑内单胺类神经递质及其代谢产物的变化，通过蛋白质免疫印迹（Western-Blotting，WB）方法检测D2DR、D3DR的含量改变，通过与西酞普兰比较，进一步了解柴胡加龙骨牡蛎汤的抗抑郁作用，以及对奖赏系统的影响。
结果：
1.行为学结果的对比发现，柴胡加龙骨牡蛎汤与西酞普兰在改善抑郁症状的糖水偏爱指数及对体重的影响方面作用效果相当，但柴胡加龙骨牡蛎汤比西酞普兰能更为显著的缩短强迫游泳的不动时间，差异显著。
2.柴胡加龙骨牡蛎汤组单胺类神经递质DA、DOPAC、HVA、5-HT、5-HIAA在用药早期就开始出现，到用药晚期各脑区均增加显著，有统计学意义，但较西酞普兰组增加幅度相对较小，有统计学意义。
3.柴胡加龙骨牡蛎汤对D2DR、D3DR的影响趋势与西酞普兰相同，但幅度相对西酞普兰较小，有统计学意义。
结论：
1.从行为学检测结果来看，柴胡加龙骨牡蛎汤对抑郁模型大鼠的抑郁症状行为学表现改善更加突出，其对强迫游泳不动时间的显著缩短，提示柴胡加龙骨牡蛎汤对奖赏系统功能损害的行为绝望、动力低下的方面改善更为明显，提示其对奖赏系统有一定保护作用。
2.通过与西酞普兰的比较，提示柴胡加龙骨牡蛎汤有类似5-羟色胺再摄取抑制剂的抗抑郁效果，但对神经递质及D2DR、D3DR的影响均较西酞普兰弱，提示柴胡加龙骨牡蛎汤还有其他方面的抗抑郁机制在同时发挥作用，值得我们深入研究。
Major depressive disorder(MDD) is a very common mental disease, characterizedas the continued depressed mood. The core symptoms of MDD are anhedonia and lossof motivation. The course of MDD is usually very long and easily to relapse. Thepatients of MDD have very high suicide rate. It seriously threats the people’s life healthand life quality. The pathogenesis of MDD is very complicated and remains uncoverednowadays. Therefore, it is of great significance to perform a thorough investigation onMDD. In this work, we explored the change of the neurological biochemistry in thereward system before and after taken medicine in deferent period of time.
Part Ⅰ: Research of the dysfunction of dopaminereceptor2and dopamine receptor3in the dopamine rewardsystem
Experiment1: establishment of chronic unpredictablemild stress rat model
Objective: Rat model of depression is a very important means for the researchwork. A stable and reliable model is the necessary for good results. Our research usedchronic unpredictable mild stress combined with Solitary support to establish a stableand reliable model of depression to lay a solid foundation for the further research.
Methods:16adult Sprague-Dawley (SD) rats were randomly divided into thecontrol group and the model group. We used long-term variety of chronic unpredictablemild stress combine to solitary support to establish the rat model of depression. We usedvariety of chronic unpredictable mild stress combine to solitary support for21days toestablish the rat model of depression. The fluid consumption test, the forced swimmingtest and the body weight were compared before and after the process of stress. Theseresults were used to investigate the degree of anhedonia and behavioral despair. Afterthe accomplishment of the model, we used HPLC-MS to analysis changes ofmonoamine neurotransmitter of DA, DOPAC, HVA,5-HT,5-HIAA in the prefrontallobe, hippocampus and nucleus accumbens to verify the validity of the model.
Results:
1. The results of behavioral experiments: Compared with rats in control group, thesucrose preference index of rats after stress procedure in model group decreasedsignificantly; the swimming test static time of the model group rats extended greatly;the growth rate of rats in model group was significantly less than those in the controlgroup.
2. The HPLC-MS analysis results showed: Significantly reduction of DA, DOPAC,HVA,5-HT,5-HIAA in the prefrontal lobe, hippocampus and nucleus accumbens wasfounded in model group.
Conclusion:
1. The rat model of depression of chronic unpredictable mild stress combinedwith solitary support can imitate the core symptoms of depression. Afterthe model was established, the index of anhedonia, behavioral despair andweight loss changed dramatically. The changes of monoamineneurotransmitter of DA, DOPAC, HVA,5-HT,5-HIAA were accord withthe current knowledge on the neurological biochemistry change indepression. Our rat model of depression was reliable, repeated easily, stableand prolonged enough for the further research.
Experiment2: Slective serotonin (5-HT) reuptakeinhibitors (SSRIs) has influence on the reward system in therat model of depression
Objective: The core symptom of depression anhedonia is a direct reflection ofdysfunction of the reward system. We used rat model of depression to explore theevidence of changes of the dopamine receptor2(D2DR) and dopamine receptor3(D3DR) in the important area of the reward sysmem. We want to estimate the exactlychanges of D2DR and D3DR after usage of antidepressant drug’s of dopamine and itmetabolites, D2DR、D3DR, to get a further understand of the act of SSRIs on the rewardsystem.
Methods: The depressed rats made according to experiment1were randomlydivided into4groups, namely the acutely controlled saline group, the chronic controlledsaline group, the acutely citaloplam group and the chronic citalopram group. We alsoset up a control group where the rats were raised normally and the model group thatonly received stress intervention but no medicine. The fluid consumption test, theforced swimming test and the body weight were all accomplished before and after thestress interventions and the medicine interventions. HPLC-MS and Western Blottingmethod were used to analysis changes of monoamine neurotransmitter of DA, DOPAC,HVA,5-HT,5-HIAA and changes of D2DR、D3DR in the prefrontal lobe, hippocampusand nucleus accumbens to verify the act of SSRIs on the reward system after acutelyand chronic use of drugs.
Results:
1. The chronic group showed significantly behavioral promotion with the distinctlypromoted sucrose preference index; the distinctly shortened swimming test static timeand the significantly increased growth body weight rate of rats in the chronic controlcitaloplam group. Such promotion effect was not discovered in saline group or theacutely citaloplam group.
2. The DA in nucleus accumbens, the DOPAC in hippocampus and the5-HTincreased remarkably after the acutely use of citaloplam, but this increase was notdiscovered in the acutely saline group. The DA, DOPAC, HVA,5-HT,5-HIAA in allthree area increased remarkably after chronic use of citaoplam, but this effect was notobserved in the chronic saline group.
3. After the stress interventions, the model rats’ D2DR、D3DR expression decreasedsignificantly compared with the control group in all areas of the prefrontal lobe,hippocampus and nucleus accumbens. There were significantly increase of D2DR、D3DR expression in all three areas in the acutely group of citaloplam. However, thisphenomenon was not observed in the saline group. The D2DR expression increasedmore in chronic use of citaloplam, but D3DR expression were decreased after chronicuse of citaloplam vs. saline. The D2DR、D3DR expression in all three area were notrecovered as controlled group.
Conclusion:
1. The rat model of depression had dysfunction in reward system as the decrease inthe dopamine and its metabolites and the decrease of expression of D2DR、D3DR.
2. The expression of D3DR had a transitory increase after acutely use of citaloplam,but decreased significantly after chronic use of citaloplam, indicated that citaloplam hada kind of inhibition on the reward system. Although the expression of D2DR wereincreased, but did not reach the normal level, indicated that the reward system was notrecovery after use of drugs.
Part Ⅱ: The Chaihu-jia-longgu-muli decoction (CJLMD)’sact as an antidepressant
Objective: The Chinese traditional medicine is the treasure of China history. But itis not very popular in today because of its complex mechanism. We used the rat modelto explore the antidepressive act of CJLMD and the mechanism of it by comparing itseffect with those of citaloplam.
Methods: The depressed rats made accord to experiment1were randomlydivided into6groups, namely the acutely controlled saline group, the chronic controlledsaline group, the acutely citaloplam group, the chronic citalopram group, the acutelyCJLMD group and the chronic CJLMD group. The fluid consumption test, the forcedswimming test and body weight were all accomplished before and after the medicineintervention. HPLC-MS and Western Blotting method were used to analysis change ofin concentration of monoamine neurotransmitter of DA, DOPAC, HVA,5-HT,5-HIAA and change of concentration of D2DR、D3DR in the prefrontal lobe, hippocampus andnucleus accumbens to verify the act of SSRIs on the reward system after acutely andchronic use of drugs.
Results:
1. The CJLMD group had the same antidepressive acts as the citalopram groupafter chronic use of drugs in the changes of depressive behaviors of sucrose preferenceindex and the growth rate of body weight, and had even more distinctly shorten time inswimming test static time than the citalopram group.
2. The concentration of DA, DOPAC, HVA,5-HT,5-HIAA of all three area in theCJLMD group increased weaker than the citaloplam group in all aspects, but increasedmore the saline group.
3. There were same trend of changes in the expression of D2DR、D3DR as thecitaloplam group in all three area but more weaker the citaloplam group.
Conclusion:
1. From the point of view of the depressive behaviors change of rats, the CJLMDhad more valid antidepressive act than the citalopram group especially in the aspect ofswimming test static time. We postulated that CJLMD can cure behavioral despair andloss of motivation which are the results of damaged reward system. The resultsindicated that CJLMD had a protectable act on reward system.
2. Comparing with citaloplam, we postulated that CJLMD had a similarantidepressive act like citaloplam, but is more weaker in the aspect of change inmonoamine neurotransmitter and D2DR、 D3DR. According to the better behaviorchange we postulated that CJLMD might had other mechanisms of antidepressive actother than SSRIs, such as protection the reward system. We will address this issue in thefuture.
第一部分抑郁症奖赏系统多巴胺D2、D3受体功能障碍的研究
实验一慢性不可预见性轻度应激抑郁症模型的建立
目的：大鼠抑郁模型是抑郁症研究中最为关键的研究媒介，稳定可靠的动物模型是研究工作成果是否可靠的重要基础条件。本实验采用慢性不可预见性轻度应激（chronic unpredictable mild stress, CUMS）结合孤养的方法，以期获得稳定、可靠、重复性强的大鼠抑郁模型，为进一步的研究打下良好的基础。
方法：选用成年雄性Sprague-Dawley大鼠，共16只，随机分为正常组和模型组各8只，采用慢性不可预见性轻度应激结合孤养的方法，制作大鼠抑郁模型，进行21天应激干预，分别于应激干预前后进行强迫游泳实验（The forced swimmingtest，FST）和液体消耗实验（Fluid consumption test）测量，并定期监测大鼠体重变化，用以上三项指标来评估大鼠快感缺乏和行为绝望的程度。模型制作结束后，应用高效液相色谱质谱连用方法（HPLC-MS）分析大鼠前额叶、海马、伏隔核各脑区单胺类神经递质及其代谢产物多巴胺（DA）、3,4-二羟基苯乙酸（DOPAC）、高香草酸（HVA）、5-羟色胺（5-HT）、5-羟吲哚乙酸（5-HIAA）在应激前后含量的变化，进一步评估大鼠抑郁模型的有效性。
结果：
1.行为学结果显示，相对于正常组大鼠，模型组大鼠在接受应激干预后液体消耗实验的糖水偏爱指数下降显著；强迫游泳实验静止不动时间明显延长；体重增长值显著下降。各项结果均差异显著，有统计学意义。
2. HPLC-MS检测结果显示，模型组在应激后大鼠前额叶、海马、伏隔核各脑区DA、DOPAC、HVA、5-HT、5-HIAA含量均比正常组有明显减少，有统计学意义。
结论：慢性不可预见性轻度应激结合孤养制做的大鼠抑郁模型，能够很好的模拟人类抑郁症的核心症状，模型大鼠快感缺乏，行为绝望，体重下降三项指标均改变明显，且脑内神经递质变化符合目前抑郁症的神经生化改变。模型症状稳定，可重复性强，持续时间长，是非常可靠的动物抑郁模型，可以作为良好的媒介进性下一步的实验。
实验二5-羟色胺再摄取抑制剂对抑郁症模型大鼠奖赏系统的影响
目的：抑郁症核心症状快感缺乏是奖赏系统功能障碍的直接体现。通过大鼠抑郁模型进一步了解奖赏系统重要脑区多巴胺D2受体、多巴胺D3受体的在应激干预前后含量变化，明确奖赏系统功能障碍的确切依据，并通过对比大鼠应用5-羟色胺再摄取抑制剂西酞普兰用药前后不同阶段神经递质及其代谢产物、D2DR、D3DR的变化，来探讨5-羟色胺再摄取抑制剂对奖赏系统的可能影响。
方法：将依照实验一部分制作的抑郁模型大鼠随机分组，分别为盐水对照早期组、盐水对照晚期组、西酞普兰早期组、西酞普兰晚期组各6只。分别给予盐水及西酞普兰用药干预，另外有随机分组的对照组及模型组大鼠各6只，分别正常饲养及仅按照前述模型制作方法制作成模型大鼠。分别于应激干预前、后及用药1天后及用药14天后对各组大鼠进行行为学检测，包括强迫游泳实验、液体消耗实验及体重监测。然后通过HPLC-MS方法检测大鼠单胺类神经递质及其代谢产物在应激前后、用药前后及用药不同阶段的变化，通过蛋白质免疫印迹（Western-Blotting，WB）方法检测D2DR、D3DR的含量改变，来进一步了解西酞普兰用药不同时期对奖赏系统的影响。
结果：
1.西酞普兰晚期用药组出现了明显的行为学改善，糖水偏爱指数升高、强迫游泳不动时间缩短及体重增长值增加，有统计学意义，用药早期无明显改变。
2.西酞普兰组早期组用药1天后伏隔核DA、海马DOPAC及海马5-HT就有明显增加，其余各组早期未见明显有统计学意义的差别；晚期组用药14天后西酞普兰组各脑区DA、DOPAC、HVA、5-HT、5-HIAA均较盐水对照组有明显增加,有统计学意义。
3.模型组大鼠在应激后与对照组大鼠比较，在前额叶、海马、伏隔核各脑区D2DR及D3DR的表达均明显下降，有统计学意义。在前额叶、海马、伏隔核西酞普兰早期组D2DR的表达较模型盐水组有显著增加，西酞普兰晚期组D2DR的表达均比模型盐水组有明显增加，三个脑区内西酞普兰晚期组D2DR的表达仍较空白对照组明显减少；在三个脑区内西酞普兰早期组及西酞普兰晚期组D3DR表达均较模型盐水组有明显增加，用药14天后西酞普兰晚期组比西酞普兰早期组D3DR表达又均有明显减少；三个脑区内D3DR表达西酞普兰早期及晚期组均比空白对照组均有明显减少，有统计学意义。
结论：
1.大鼠抑郁模型存在奖赏系统功能障碍，主要表现在奖赏系统重要脑区多巴胺及其代谢产物及D2DR、D3DR的表达的下降。
2. D3DR的表达在用药的早期出现一过性升高后，继之又下降，到晚期组下降显著，提示西酞普兰对D3DR受体功能存在一定程度的抑制，表现在长期用药后D3DR的表达减少，D2DR的表达虽然有所上升，但与正常组比较仍有较大差距，提示奖赏系统功能并未得到有效恢复。
第二部分柴胡加龙骨牡蛎汤抗抑郁作用的研究
目的：中医中药是中华民族的瑰宝，但因作用机制复杂不清而难以被广泛认可和接受，通过慢性应激大鼠抑郁模型了解柴胡加龙骨牡蛎汤的抗抑郁作用，并通过与西酞普兰对比探索其抗抑郁的作用机制。
方法：制作完成的大鼠抑郁模型，随机分组为盐水对照早期组、盐水对照晚期组、西酞普兰早期组、西酞普兰晚期、中药方剂早期组、中药方剂晚期组各6只，分别于用药1天后及用药14天后进行强迫游泳实验、液体消耗实验及体重变化的行为学检测。然后通过HPLC-MS方法检测大鼠脑内单胺类神经递质及其代谢产物的变化，通过蛋白质免疫印迹（Western-Blotting，WB）方法检测D2DR、D3DR的含量改变，通过与西酞普兰比较，进一步了解柴胡加龙骨牡蛎汤的抗抑郁作用，以及对奖赏系统的影响。
结果：
1.行为学结果的对比发现，柴胡加龙骨牡蛎汤与西酞普兰在改善抑郁症状的糖水偏爱指数及对体重的影响方面作用效果相当，但柴胡加龙骨牡蛎汤比西酞普兰能更为显著的缩短强迫游泳的不动时间，差异显著。
2.柴胡加龙骨牡蛎汤组单胺类神经递质DA、DOPAC、HVA、5-HT、5-HIAA在用药早期就开始出现，到用药晚期各脑区均增加显著，有统计学意义，但较西酞普兰组增加幅度相对较小，有统计学意义。
3.柴胡加龙骨牡蛎汤对D2DR、D3DR的影响趋势与西酞普兰相同，但幅度相对西酞普兰较小，有统计学意义。
结论：
1.从行为学检测结果来看，柴胡加龙骨牡蛎汤对抑郁模型大鼠的抑郁症状行为学表现改善更加突出，其对强迫游泳不动时间的显著缩短，提示柴胡加龙骨牡蛎汤对奖赏系统功能损害的行为绝望、动力低下的方面改善更为明显，提示其对奖赏系统有一定保护作用。
2.通过与西酞普兰的比较，提示柴胡加龙骨牡蛎汤有类似5-羟色胺再摄取抑制剂的抗抑郁效果，但对神经递质及D2DR、D3DR的影响均较西酞普兰弱，提示柴胡加龙骨牡蛎汤还有其他方面的抗抑郁机制在同时发挥作用，值得我们深入研究。
Major depressive disorder(MDD) is a very common mental disease, characterizedas the continued depressed mood. The core symptoms of MDD are anhedonia and lossof motivation. The course of MDD is usually very long and easily to relapse. Thepatients of MDD have very high suicide rate. It seriously threats the people’s life healthand life quality. The pathogenesis of MDD is very complicated and remains uncoverednowadays. Therefore, it is of great significance to perform a thorough investigation onMDD. In this work, we explored the change of the neurological biochemistry in thereward system before and after taken medicine in deferent period of time.
Part Ⅰ: Research of the dysfunction of dopaminereceptor2and dopamine receptor3in the dopamine rewardsystem
Experiment1: establishment of chronic unpredictablemild stress rat model
Objective: Rat model of depression is a very important means for the researchwork. A stable and reliable model is the necessary for good results. Our research usedchronic unpredictable mild stress combined with Solitary support to establish a stableand reliable model of depression to lay a solid foundation for the further research.
Methods:16adult Sprague-Dawley (SD) rats were randomly divided into thecontrol group and the model group. We used long-term variety of chronic unpredictablemild stress combine to solitary support to establish the rat model of depression. We usedvariety of chronic unpredictable mild stress combine to solitary support for21days toestablish the rat model of depression. The fluid consumption test, the forced swimmingtest and the body weight were compared before and after the process of stress. Theseresults were used to investigate the degree of anhedonia and behavioral despair. Afterthe accomplishment of the model, we used HPLC-MS to analysis changes ofmonoamine neurotransmitter of DA, DOPAC, HVA,5-HT,5-HIAA in the prefrontallobe, hippocampus and nucleus accumbens to verify the validity of the model.
Results:
1. The results of behavioral experiments: Compared with rats in control group, thesucrose preference index of rats after stress procedure in model group decreasedsignificantly; the swimming test static time of the model group rats extended greatly;the growth rate of rats in model group was significantly less than those in the controlgroup.
2. The HPLC-MS analysis results showed: Significantly reduction of DA, DOPAC,HVA,5-HT,5-HIAA in the prefrontal lobe, hippocampus and nucleus accumbens wasfounded in model group.
Conclusion:
1. The rat model of depression of chronic unpredictable mild stress combinedwith solitary support can imitate the core symptoms of depression. Afterthe model was established, the index of anhedonia, behavioral despair andweight loss changed dramatically. The changes of monoamineneurotransmitter of DA, DOPAC, HVA,5-HT,5-HIAA were accord withthe current knowledge on the neurological biochemistry change indepression. Our rat model of depression was reliable, repeated easily, stableand prolonged enough for the further research.
Experiment2: Slective serotonin (5-HT) reuptakeinhibitors (SSRIs) has influence on the reward system in therat model of depression
Objective: The core symptom of depression anhedonia is a direct reflection ofdysfunction of the reward system. We used rat model of depression to explore theevidence of changes of the dopamine receptor2(D2DR) and dopamine receptor3(D3DR) in the important area of the reward sysmem. We want to estimate the exactlychanges of D2DR and D3DR after usage of antidepressant drug’s of dopamine and itmetabolites, D2DR、D3DR, to get a further understand of the act of SSRIs on the rewardsystem.
Methods: The depressed rats made according to experiment1were randomlydivided into4groups, namely the acutely controlled saline group, the chronic controlledsaline group, the acutely citaloplam group and the chronic citalopram group. We alsoset up a control group where the rats were raised normally and the model group thatonly received stress intervention but no medicine. The fluid consumption test, theforced swimming test and the body weight were all accomplished before and after thestress interventions and the medicine interventions. HPLC-MS and Western Blottingmethod were used to analysis changes of monoamine neurotransmitter of DA, DOPAC,HVA,5-HT,5-HIAA and changes of D2DR、D3DR in the prefrontal lobe, hippocampusand nucleus accumbens to verify the act of SSRIs on the reward system after acutelyand chronic use of drugs.
Results:
1. The chronic group showed significantly behavioral promotion with the distinctlypromoted sucrose preference index; the distinctly shortened swimming test static timeand the significantly increased growth body weight rate of rats in the chronic controlcitaloplam group. Such promotion effect was not discovered in saline group or theacutely citaloplam group.
2. The DA in nucleus accumbens, the DOPAC in hippocampus and the5-HTincreased remarkably after the acutely use of citaloplam, but this increase was notdiscovered in the acutely saline group. The DA, DOPAC, HVA,5-HT,5-HIAA in allthree area increased remarkably after chronic use of citaoplam, but this effect was notobserved in the chronic saline group.
3. After the stress interventions, the model rats’ D2DR、D3DR expression decreasedsignificantly compared with the control group in all areas of the prefrontal lobe,hippocampus and nucleus accumbens. There were significantly increase of D2DR、D3DR expression in all three areas in the acutely group of citaloplam. However, thisphenomenon was not observed in the saline group. The D2DR expression increasedmore in chronic use of citaloplam, but D3DR expression were decreased after chronicuse of citaloplam vs. saline. The D2DR、D3DR expression in all three area were notrecovered as controlled group.
Conclusion:
1. The rat model of depression had dysfunction in reward system as the decrease inthe dopamine and its metabolites and the decrease of expression of D2DR、D3DR.
2. The expression of D3DR had a transitory increase after acutely use of citaloplam,but decreased significantly after chronic use of citaloplam, indicated that citaloplam hada kind of inhibition on the reward system. Although the expression of D2DR wereincreased, but did not reach the normal level, indicated that the reward system was notrecovery after use of drugs.
Part Ⅱ: The Chaihu-jia-longgu-muli decoction (CJLMD)’sact as an antidepressant
Objective: The Chinese traditional medicine is the treasure of China history. But itis not very popular in today because of its complex mechanism. We used the rat modelto explore the antidepressive act of CJLMD and the mechanism of it by comparing itseffect with those of citaloplam.
Methods: The depressed rats made accord to experiment1were randomlydivided into6groups, namely the acutely controlled saline group, the chronic controlledsaline group, the acutely citaloplam group, the chronic citalopram group, the acutelyCJLMD group and the chronic CJLMD group. The fluid consumption test, the forcedswimming test and body weight were all accomplished before and after the medicineintervention. HPLC-MS and Western Blotting method were used to analysis change ofin concentration of monoamine neurotransmitter of DA, DOPAC, HVA,5-HT,5-HIAA and change of concentration of D2DR、D3DR in the prefrontal lobe, hippocampus andnucleus accumbens to verify the act of SSRIs on the reward system after acutely andchronic use of drugs.
Results:
1. The CJLMD group had the same antidepressive acts as the citalopram groupafter chronic use of drugs in the changes of depressive behaviors of sucrose preferenceindex and the growth rate of body weight, and had even more distinctly shorten time inswimming test static time than the citalopram group.
2. The concentration of DA, DOPAC, HVA,5-HT,5-HIAA of all three area in theCJLMD group increased weaker than the citaloplam group in all aspects, but increasedmore the saline group.
3. There were same trend of changes in the expression of D2DR、D3DR as thecitaloplam group in all three area but more weaker the citaloplam group.
Conclusion:
1. From the point of view of the depressive behaviors change of rats, the CJLMDhad more valid antidepressive act than the citalopram group especially in the aspect ofswimming test static time. We postulated that CJLMD can cure behavioral despair andloss of motivation which are the results of damaged reward system. The resultsindicated that CJLMD had a protectable act on reward system.
2. Comparing with citaloplam, we postulated that CJLMD had a similarantidepressive act like citaloplam, but is more weaker in the aspect of change inmonoamine neurotransmitter and D2DR、 D3DR. According to the better behaviorchange we postulated that CJLMD might had other mechanisms of antidepressive actother than SSRIs, such as protection the reward system. We will address this issue in thefuture.
引文
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[1]杨洁，翟荣.基于抗抑郁作用的柴胡加龙骨牡蛎汤的研究进展.2012,34（6）：39-40.
[2]孟海彬，瞿融，马世平．柴胡加龙骨牡蛎汤抗抑郁作用研究．中药药理与临床，2003，19(I)：3．
[3]南晋生等,实用中医药杂志，1998,14（7）：36
[4]翁黄念慈，刘继林．中药复方治疗抑郁状态的述评．四川中医，2005，23(10)：40．
[5]邓暖繁．柴胡龙骨牡蛎汤治疗恶性肿瘤化疗后并发抑郁症临床观察：Jj．光明中医，2012，27(1)：76—78．
[6]尚俊平．柴胡加龙骨牡蛎汤治疗老年抑郁症30例[Jj．甘肃中医，2010，23(2)：247—48．
[7]金子善彦.柴胡加龙骨牡蛎汤治疗抑郁状态[J]日本医学介绍，1981,11:31.
[8]张有志，聂惠民，张徳昌，何维。柴胡加龙骨牡蛎汤治疗抑郁症的动物行为学研究。中国中医基础医学杂志，2001,7（7）：31-32
[9]瞿融，孟海彬，褚蔚，关新军，徐斌，顾武军，等，柴胡加龙骨牡蛎汤对抑郁模型大鼠脑内单胺递质的影响[J]中药药理与临床，2003；19：1-3
[10]任鹏姣，马世平，瞿融等.柴胡加龙骨牡蛎汤组方配伍研究（III）-对慢性应激大鼠的抗抑郁作用[J]药学与临床研究，2008，16（2）：86-89.
[11]Weili Zhu, Qu Rong, Dangli Wang, Shiping Ma. Antidepressant-like effect ofsaponins extracted from Chaihu-jia-longgu-muli-tang and its possiblemechanism[M] Life sciences,2006:79,749.
[12]孟海彬，瞿融，马世平，等.柴胡加龙骨牡蛎汤抗抑郁作用研究[J]中药药理与临床，2003,19（1）：3.
[13]张有志，聂惠民，张德昌，等.柴胡加龙骨牡蛎汤等经方治疗抑郁症的动物行为学研究[J]中国中医基础医学杂志，2005,7（7）：30.
[14]康大力，瞿融，朱维莉，等.柴胡加龙骨牡蛎汤对抑郁动物下丘脑-垂体-肾上腺素轴的影响[J]中国临床药理学与治疗学，2005,10（11）：1231.
[15]张有志.柴胡加龙骨牡蛎汤等经方治疗抑郁症的动物行为学研究[J]中国中医基础医学杂志，2001,7（7）：30
[1] Kessler RC, Berglund P, Demler O, et al. The epidemiology of majordepressive disorder: results from the National Comorbidity Survey Replication(NCS-R). JAMA2003;289:3095-105.
[2] Nemeroff CB. Prevalence and management of treatment-resistant depression. JClin Psychiatry2007;68(Suppl8):17-25.
[3] Nestler EJ, Carlezon WA Jr. The mesolimbic dopamine reward circuit indepression. Biol Psychiatry2006;59:1151-9.
[4] McClung CA, Nestler EJ. Neuroplasticity mediated by altered gene expression.Neuropsychopharmacology2008;33:3-17.
[5] Lescia K. Tremblay, BSc; Claudio A. Naranjo, MD et al.Probing brain rewardsystem function in major depressive disorder, Arch Gen Psychiatry2002;59:409-16
[6] Spanagel R, Weiss F. The dopamine hypothesis of reward: past and currentstatus. Trends Neurosci,1999,22:521～527.
[7] Zarate CA Jr, Singh JB, Carlson PJ, et al. A randomized trial of anN-methyl-Daspartate antagonist in treatment-resistant major depression. ArchGen Psychiatry2006;63:856-64.
[8] Fiorillo CD, Tobler PN, et al. Discrete coding of reward probability anduncertainty by dopamine neurons. Science2003;299(5614):1898–902.
[9] Volkow ND, Wang GJ, et al. Profound decreases in dopamine release instriatum in detoxified alcoholics: possible orbitofrontal involvement. JNeurosci2007;27:12700-6.
[10]余化霖,叶雯睿,马以骝,等.多巴胺D2受体拮抗剂/激动剂对SD大鼠条件化位置偏好的影响[J]动物学研究2006;27(1):54-62.
[11] Drevets WC, Furey ML. Emotional disorders: depression and the brain. InNew Encyclopedia of Neuroscience (Squire, L., ed.), Elsevier, Amsterdam, inthe press2009.
[12] Lambert G, Johansson M, et al. Reduced brain norepinephrine and dopaminerelease in treatment-refractory depressive illness: evidence in support of thecatecholamine hypothesis of mood disorders. Arch. Gen. Psychiatry2000;57:787–93.
[13]Zarate Jr, CA, et al. Pramipexole for bipolar II depression: aplacebo-controlled proof of concept study.Biol. Psychiatry2004;56:54–60.
[14] Meyer JH, McNeely HE, et al. Elevated putamen D2receptor bindingpotential in major depression with motor retardation:an [11C]raclopridepositron emission tomography study.Am J Psychiatry2006;163:1594–602.
[15]Henriques JB, Glowacki JM, et al. Reward fails to alter response bias indepression. Journal ofAbnormal Psychology1994;103(3):460–6.
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[19]Mitterschiffthaler MT, Kumari V, et al. Neural response to pleasant stimuli inanhedonia: an fMRI study. Neuroreport2003;14(2):177–82.
[20]Pizzagalli DA, Sherwood RJ, et al. Frontal brain asymmetry and rewardrespon-siveness: a source-localization study. Psychological Science2005;16(10):805–13.
[21] Guiard BP, El Mansari M, Merali Z, et al. Functional interactions betweendopamine, serotonin and norepinephrine neurons: an invivoelectrophysiological study in rats with monoaminergic lesions. Int JNeuropsychopharmacol2008;11:625-39.
[22] Lanzenberger RR, Hahn A, Windischberger C, Wadsak W, Holik A, Gerstl F,Savli M, Moser U, Mien LK, Akimova E, Mitterhauser M, Kletter K, Moser E,Kasper S (2009) Serotonin-1A receptor binding and reward-dependentactivation are associated within the human dorsal raphe nucleus as revealedby PET-fMRI. Neuroimage47(S1):S176.
[23] Eliyahu Dremencov, Mostafa El Mansari, Pierre Blier, Effects of sustainedserotonin reuptake inhibition on the firing of dopamine neurons in the ratventral tegmental area, J Psychiatry Neurosci2009;34(3):223-9.
[24] Jani P, Jaana K, Sargo, Jussi H, et al. Effects of fluoxetine on dopamine D2receptors in the human brain: a positron emission tomography study with
[11C]raclopride, International Journal of Neuropsychopharmacology (2004),7,431–439.
[25] Guiard BP, El Mansari M, Merali Z, et al. Functional interactions betweendopamine, serotonin and norepinephrine neurons: an invivoelectrophysiological study in rats with monoaminergic lesions. Int JNeuropsychopharmacol2008;11:625-39.
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[20]. Lanzenberger RR, Hahn A, Windischberger C, Wadsak W, Holik A, Gerstl F,Savli M, Moser U, Mien LK, Akimova E, Mitterhauser M, Kletter K, Moser E,Kasper S (2009) Serotonin-1A receptor binding and reward-dependentactivation are associated within the human dorsal raphe nucleus as revealedby PET-fMRI. Neuroimage47(S1):S176.
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[1]杨洁，翟荣.基于抗抑郁作用的柴胡加龙骨牡蛎汤的研究进展.2012,34（6）：39-40.
[2]孟海彬，瞿融，马世平．柴胡加龙骨牡蛎汤抗抑郁作用研究．中药药理与临床，2003，19(I)：3．
[3]南晋生等,实用中医药杂志，1998,14（7）：36
[4]翁黄念慈，刘继林．中药复方治疗抑郁状态的述评．四川中医，2005，23(10)：40．
[5]邓暖繁．柴胡龙骨牡蛎汤治疗恶性肿瘤化疗后并发抑郁症临床观察：Jj．光明中医，2012，27(1)：76—78．
[6]尚俊平．柴胡加龙骨牡蛎汤治疗老年抑郁症30例[Jj．甘肃中医，2010，23(2)：247—48．
[7]金子善彦.柴胡加龙骨牡蛎汤治疗抑郁状态[J]日本医学介绍，1981,11:31.
[8]张有志，聂惠民，张徳昌，何维。柴胡加龙骨牡蛎汤治疗抑郁症的动物行为学研究。中国中医基础医学杂志，2001,7（7）：31-32
[9]瞿融，孟海彬，褚蔚，关新军，徐斌，顾武军，等，柴胡加龙骨牡蛎汤对抑郁模型大鼠脑内单胺递质的影响[J]中药药理与临床，2003；19：1-3
[10]任鹏姣，马世平，瞿融等.柴胡加龙骨牡蛎汤组方配伍研究（III）-对慢性应激大鼠的抗抑郁作用[J]药学与临床研究，2008，16（2）：86-89.
[11]Weili Zhu, Qu Rong, Dangli Wang, Shiping Ma. Antidepressant-like effect ofsaponins extracted from Chaihu-jia-longgu-muli-tang and its possiblemechanism[M] Life sciences,2006:79,749.
[12]孟海彬，瞿融，马世平，等.柴胡加龙骨牡蛎汤抗抑郁作用研究[J]中药药理与临床，2003,19（1）：3.
[13]张有志，聂惠民，张德昌，等.柴胡加龙骨牡蛎汤等经方治疗抑郁症的动物行为学研究[J]中国中医基础医学杂志，2005,7（7）：30.
[14]康大力，瞿融，朱维莉，等.柴胡加龙骨牡蛎汤对抑郁动物下丘脑-垂体-肾上腺素轴的影响[J]中国临床药理学与治疗学，2005,10（11）：1231.
[15]张有志.柴胡加龙骨牡蛎汤等经方治疗抑郁症的动物行为学研究[J]中国中医基础医学杂志，2001,7（7）：30
[1] Kessler RC, Berglund P, Demler O, et al. The epidemiology of majordepressive disorder: results from the National Comorbidity Survey Replication(NCS-R). JAMA2003;289:3095-105.
[2] Nemeroff CB. Prevalence and management of treatment-resistant depression. JClin Psychiatry2007;68(Suppl8):17-25.
[3] Nestler EJ, Carlezon WA Jr. The mesolimbic dopamine reward circuit indepression. Biol Psychiatry2006;59:1151-9.
[4] McClung CA, Nestler EJ. Neuroplasticity mediated by altered gene expression.Neuropsychopharmacology2008;33:3-17.
[5] Lescia K. Tremblay, BSc; Claudio A. Naranjo, MD et al.Probing brain rewardsystem function in major depressive disorder, Arch Gen Psychiatry2002;59:409-16
[6] Spanagel R, Weiss F. The dopamine hypothesis of reward: past and currentstatus. Trends Neurosci,1999,22:521～527.
[7] Zarate CA Jr, Singh JB, Carlson PJ, et al. A randomized trial of anN-methyl-Daspartate antagonist in treatment-resistant major depression. ArchGen Psychiatry2006;63:856-64.
[8] Fiorillo CD, Tobler PN, et al. Discrete coding of reward probability anduncertainty by dopamine neurons. Science2003;299(5614):1898–902.
[9] Volkow ND, Wang GJ, et al. Profound decreases in dopamine release instriatum in detoxified alcoholics: possible orbitofrontal involvement. JNeurosci2007;27:12700-6.
[10]余化霖,叶雯睿,马以骝,等.多巴胺D2受体拮抗剂/激动剂对SD大鼠条件化位置偏好的影响[J]动物学研究2006;27(1):54-62.
[11] Drevets WC, Furey ML. Emotional disorders: depression and the brain. InNew Encyclopedia of Neuroscience (Squire, L., ed.), Elsevier, Amsterdam, inthe press2009.
[12] Lambert G, Johansson M, et al. Reduced brain norepinephrine and dopaminerelease in treatment-refractory depressive illness: evidence in support of thecatecholamine hypothesis of mood disorders. Arch. Gen. Psychiatry2000;57:787–93.
[13]Zarate Jr, CA, et al. Pramipexole for bipolar II depression: aplacebo-controlled proof of concept study.Biol. Psychiatry2004;56:54–60.
[14] Meyer JH, McNeely HE, et al. Elevated putamen D2receptor bindingpotential in major depression with motor retardation:an [11C]raclopridepositron emission tomography study.Am J Psychiatry2006;163:1594–602.
[15]Henriques JB, Glowacki JM, et al. Reward fails to alter response bias indepression. Journal ofAbnormal Psychology1994;103(3):460–6.
[16]Pizzagalli DA, Jahn AL, et al. Toward an objective characterization of ananhedonic phenotype: a signal-detection approach. Biological Psychiatry2005;57(4):319–27.
[17]Keedwell PA, Andrew C, et al. The neural correlates of anhedonia in majordepressive disorder. Biological Psychiatry2005;58(11):843–53.
[18]Epstein J, Pan H, et al. Lack of ventral striatal response to positive stimuli indepressed versus normal subjects. American Journal of Psychiatry2006;163(10):1784–90.
[19]Mitterschiffthaler MT, Kumari V, et al. Neural response to pleasant stimuli inanhedonia: an fMRI study. Neuroreport2003;14(2):177–82.
[20]Pizzagalli DA, Sherwood RJ, et al. Frontal brain asymmetry and rewardrespon-siveness: a source-localization study. Psychological Science2005;16(10):805–13.
[21] Guiard BP, El Mansari M, Merali Z, et al. Functional interactions betweendopamine, serotonin and norepinephrine neurons: an invivoelectrophysiological study in rats with monoaminergic lesions. Int JNeuropsychopharmacol2008;11:625-39.
[22] Lanzenberger RR, Hahn A, Windischberger C, Wadsak W, Holik A, Gerstl F,Savli M, Moser U, Mien LK, Akimova E, Mitterhauser M, Kletter K, Moser E,Kasper S (2009) Serotonin-1A receptor binding and reward-dependentactivation are associated within the human dorsal raphe nucleus as revealedby PET-fMRI. Neuroimage47(S1):S176.
[23] Eliyahu Dremencov, Mostafa El Mansari, Pierre Blier, Effects of sustainedserotonin reuptake inhibition on the firing of dopamine neurons in the ratventral tegmental area, J Psychiatry Neurosci2009;34(3):223-9.
[24] Jani P, Jaana K, Sargo, Jussi H, et al. Effects of fluoxetine on dopamine D2receptors in the human brain: a positron emission tomography study with
[11C]raclopride, International Journal of Neuropsychopharmacology (2004),7,431–439.
[25] Guiard BP, El Mansari M, Merali Z, et al. Functional interactions betweendopamine, serotonin and norepinephrine neurons: an invivoelectrophysiological study in rats with monoaminergic lesions. Int JNeuropsychopharmacol2008;11:625-39.
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