茶氨酸对抑郁模型大鼠行为学、神经递质的影响
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摘要
目的：
观察茶叶提取物茶氨酸及氟西汀对抑郁模型大鼠行为学及前额叶皮质(PFC)、伏隔核(NAC)、纹状体(ST)、杏仁核(AM)和海马(HIP)等边缘系统—皮层—纹状体—苍白球—丘脑(LCSPT)回路相关脑区单胺递质及谷氨酸递质的影响,探讨茶氨酸可能的抗抑郁机制。
研究方法：
1.动物模型：选取雄性SD大鼠66只,随机分为模型组(17只)、氟西汀组(17只)、茶氨酸组(17只)、对照组(15只),前三组采用连续21天慢性轻度不可预见性应激(CUMS)结合孤养的方法建立慢性抑郁大鼠模型,茶氨酸组和氟西汀组分别给予2mg/kg/Qd茶氨酸和1.54mg/kg/Qd氟西汀灌胃21天,模型组和对照组给予同体积溶剂灌胃21天。
2.行为学指标：实验第1天,第22天,各组取9只大鼠,记录实验过程中各组大鼠的体重、旷场试验的活动总路程、糖水偏爱试验的糖水偏爱值、和强迫游泳试验的不动时间,研究茶氨酸及氟西汀对上述指标的影响。
3.神经递质指标：实验第22天,各组取8只大鼠(对照组6只),处死大鼠,取出PFC、NAC、ST、AM和HIP等脑组织,用库仑阵列电化学高效液相色谱法测定各组抑郁模型大鼠上述脑区单胺递质(NE、5-HT、HIP)的浓度及其代谢产物和谷氨酸(GLU)递质及谷氨酰胺(GLN)的浓度。
结果：
1.与对照组相比,模型组大鼠反应迟钝,体重增加减慢,在规定时间内自主水平活动减少,糖水消耗量、糖水偏爱百分比降低,强迫游泳试验的不动时间增长(P<0.05)。与模型组相比,茶氨酸组和氟西汀组大鼠体重增加速度正常、自主运动能力增强,糖水消耗量、糖水偏爱百分比显著增加,强迫游泳试验的不动时间减少(P<0.05)。
2.与对照组相比,模型组大鼠PFC、NAC、ST (NE阴性)、AM (NE、5-HT阴性)、HIP等脑区单胺神经递质NE、DA和5-HT及部分代谢产物的浓度明显降低,GLU(GLN)浓度明显升高(P<0.05)。
3.与模型组相比,氟西汀组PFC、NAC、ST (NE阴性)、AM(NE\5HT阴性)、HIP(NE阴性)等脑区单胺神经递质浓度及部分代谢产物的浓度显著升高,GLU (GLN)的浓度显著降低(P<0.05)。
与模型组相比,茶氨酸组PFC、NAC、ST (NE阴性)、AM(5HT阴性)、HIP等脑区单胺神经递质浓度及部分代谢产物的浓度显著升高,GLU (GLN)的浓度显著降低(P<0.05)
结论：
1.抑郁模型大鼠各项行为学指标异常,前额叶、伏隔核、海马、纹状体(NE阴性)、杏仁核(NE、5-HT阴性)等脑区NE、5-HT、 DA浓度下降,GLU浓度上升,表明抑郁模型大鼠存在抑郁行为和不同脑区神经递质改变,说明模型建立成功。
2.茶氨酸和氟西汀均可以有效改善抑郁模型大鼠的抑郁行为,并提高PFC、NAC、HIP、AM、ST等脑区单胺神经递质NE、5-HT、 DA及部分代谢产物的浓度,降低GLU及其前体GLN的浓度,说明茶氨酸抗抑郁作用与可能机制和氟西汀类似。
Objective:
To investigate the changes of the depression model rats' behavior and the monoamines and glutamate neurotransmitter in prefrontal cortex (PFC), nucleus accumbens (NAC), striatum (ST), amygdala (AM) and hippocampus (HIP), and to explore the antidepressive effect and the possible mechanisms related to the tea extract theanine and the antidepressant fluoxetine.
Method:
1. Animal model:The Sprague-Dawley male rats were randomly divided into four groups including normal control group, model control group, fluoxetine group and theanine group. To establish chronic depression model rats by the chronic unpredictable mild stress (CUMS) and separation after21days.
2. Behavioral index:recorded the weight changes, the total movement distance in the open-field test, the sucrose preference values in the sucrose consumption test, and the immobility time of the force swimming test during the experiments.to discuss the effects of theanine and fluoxetine.
3. Neurotransmitter index:recorded the concentration of the monoamine neurotransmitters (NE,5-HT, HIP)its metabolites and the glutamate (GLU) and glutamine (GLN) in the four depression model group rat, by using coularray HPLC., to discuss the possible mechanisms of Theanine and fluoxetine.
Results:
1. Compared with the control group, the body weight, the total movement distance, the volume and percentage of the sucrose consumption test, were significantly decreased.the immobility time in FST was growth remarkably in the model group P<0.05).
Compared with the model group, the body weight, the total movement distance, the volume and percentage of the sucrose consumption test, were significantly enhanced.the immobility time in FST was decreased remarkably, suggested interest improved, pleasure enhanced, the hopeless and helpless reduced in the theanine group and fluoxetine group(P<0.05).
2. Compared with the control group, monoamine neurotransmitter NE, DA and5-HT and some of its metabolites in the brain region PFC, NAC, ST (except NE), AM (except NE\5-HT) and HIP decreased significantly, GLU and GLN both increased significantly in the model group (P<0.05).
Compared with the model group, monoamine neurotransmitter NE, DA and5-HT and some of its metabolites in the brain region PFC, NAC, ST (except NE), AM (except NE\5-HT), HIP (except NE) increased significantly, GLU and GLN both decreased significantly in the fluoxetine group(P<0.05).
Compared with the model group, monoamine neurotransmitter NE, DA and5-HT and some of its metabolites in the brain region PFC、NAC、 ST (except NE)、AM(except5-HT)、increased significantly, GLU and GLN both decreased significantly in the theanine group(P<0.05).
Conclusion:
1. The indexes of depressive behavior of model group is reduced, The changes of NE,5-HT, DA and GLU in PFC,NAC,ST,AM, HIP, which is related to the indexes of behaviors, and antidepressant fluoxetine treatment can improve them, which means the chronic unpredictable mild stress (CUMS) and separation is an effective method to establish depression animal model, and the changes of the monoamines and glutamate neurotransmitter in different brain regions that may be one of the pathogenesis mechanisms of depression.
2. Theanine and fluoxetine can effectively improve the depressive behavior of the depression model rats, increase the content of monoamine neurotrans-mitter NE,5-HT, DA and its metabolites, and reduce the content of GLU and its precursor GLN,in the PFC,NAC, AM, ST and HIP brain regions. suggested that the antidepressant effect and possible mechanism of theanine may be related to the neurotransmitters. Compared with fluoxetine, the antidepressant mechanism of theanine is more extensive, specificity is more weak than fluoxetine.
观察茶叶提取物茶氨酸及氟西汀对抑郁模型大鼠行为学及前额叶皮质(PFC)、伏隔核(NAC)、纹状体(ST)、杏仁核(AM)和海马(HIP)等边缘系统—皮层—纹状体—苍白球—丘脑(LCSPT)回路相关脑区单胺递质及谷氨酸递质的影响,探讨茶氨酸可能的抗抑郁机制。
研究方法：
1.动物模型：选取雄性SD大鼠66只,随机分为模型组(17只)、氟西汀组(17只)、茶氨酸组(17只)、对照组(15只),前三组采用连续21天慢性轻度不可预见性应激(CUMS)结合孤养的方法建立慢性抑郁大鼠模型,茶氨酸组和氟西汀组分别给予2mg/kg/Qd茶氨酸和1.54mg/kg/Qd氟西汀灌胃21天,模型组和对照组给予同体积溶剂灌胃21天。
2.行为学指标：实验第1天,第22天,各组取9只大鼠,记录实验过程中各组大鼠的体重、旷场试验的活动总路程、糖水偏爱试验的糖水偏爱值、和强迫游泳试验的不动时间,研究茶氨酸及氟西汀对上述指标的影响。
3.神经递质指标：实验第22天,各组取8只大鼠(对照组6只),处死大鼠,取出PFC、NAC、ST、AM和HIP等脑组织,用库仑阵列电化学高效液相色谱法测定各组抑郁模型大鼠上述脑区单胺递质(NE、5-HT、HIP)的浓度及其代谢产物和谷氨酸(GLU)递质及谷氨酰胺(GLN)的浓度。
结果：
1.与对照组相比,模型组大鼠反应迟钝,体重增加减慢,在规定时间内自主水平活动减少,糖水消耗量、糖水偏爱百分比降低,强迫游泳试验的不动时间增长(P<0.05)。与模型组相比,茶氨酸组和氟西汀组大鼠体重增加速度正常、自主运动能力增强,糖水消耗量、糖水偏爱百分比显著增加,强迫游泳试验的不动时间减少(P<0.05)。
2.与对照组相比,模型组大鼠PFC、NAC、ST (NE阴性)、AM (NE、5-HT阴性)、HIP等脑区单胺神经递质NE、DA和5-HT及部分代谢产物的浓度明显降低,GLU(GLN)浓度明显升高(P<0.05)。
3.与模型组相比,氟西汀组PFC、NAC、ST (NE阴性)、AM(NE\5HT阴性)、HIP(NE阴性)等脑区单胺神经递质浓度及部分代谢产物的浓度显著升高,GLU (GLN)的浓度显著降低(P<0.05)。
与模型组相比,茶氨酸组PFC、NAC、ST (NE阴性)、AM(5HT阴性)、HIP等脑区单胺神经递质浓度及部分代谢产物的浓度显著升高,GLU (GLN)的浓度显著降低(P<0.05)
结论：
1.抑郁模型大鼠各项行为学指标异常,前额叶、伏隔核、海马、纹状体(NE阴性)、杏仁核(NE、5-HT阴性)等脑区NE、5-HT、 DA浓度下降,GLU浓度上升,表明抑郁模型大鼠存在抑郁行为和不同脑区神经递质改变,说明模型建立成功。
2.茶氨酸和氟西汀均可以有效改善抑郁模型大鼠的抑郁行为,并提高PFC、NAC、HIP、AM、ST等脑区单胺神经递质NE、5-HT、 DA及部分代谢产物的浓度,降低GLU及其前体GLN的浓度,说明茶氨酸抗抑郁作用与可能机制和氟西汀类似。
Objective:
To investigate the changes of the depression model rats' behavior and the monoamines and glutamate neurotransmitter in prefrontal cortex (PFC), nucleus accumbens (NAC), striatum (ST), amygdala (AM) and hippocampus (HIP), and to explore the antidepressive effect and the possible mechanisms related to the tea extract theanine and the antidepressant fluoxetine.
Method:
1. Animal model:The Sprague-Dawley male rats were randomly divided into four groups including normal control group, model control group, fluoxetine group and theanine group. To establish chronic depression model rats by the chronic unpredictable mild stress (CUMS) and separation after21days.
2. Behavioral index:recorded the weight changes, the total movement distance in the open-field test, the sucrose preference values in the sucrose consumption test, and the immobility time of the force swimming test during the experiments.to discuss the effects of theanine and fluoxetine.
3. Neurotransmitter index:recorded the concentration of the monoamine neurotransmitters (NE,5-HT, HIP)its metabolites and the glutamate (GLU) and glutamine (GLN) in the four depression model group rat, by using coularray HPLC., to discuss the possible mechanisms of Theanine and fluoxetine.
Results:
1. Compared with the control group, the body weight, the total movement distance, the volume and percentage of the sucrose consumption test, were significantly decreased.the immobility time in FST was growth remarkably in the model group P<0.05).
Compared with the model group, the body weight, the total movement distance, the volume and percentage of the sucrose consumption test, were significantly enhanced.the immobility time in FST was decreased remarkably, suggested interest improved, pleasure enhanced, the hopeless and helpless reduced in the theanine group and fluoxetine group(P<0.05).
2. Compared with the control group, monoamine neurotransmitter NE, DA and5-HT and some of its metabolites in the brain region PFC, NAC, ST (except NE), AM (except NE\5-HT) and HIP decreased significantly, GLU and GLN both increased significantly in the model group (P<0.05).
Compared with the model group, monoamine neurotransmitter NE, DA and5-HT and some of its metabolites in the brain region PFC, NAC, ST (except NE), AM (except NE\5-HT), HIP (except NE) increased significantly, GLU and GLN both decreased significantly in the fluoxetine group(P<0.05).
Compared with the model group, monoamine neurotransmitter NE, DA and5-HT and some of its metabolites in the brain region PFC、NAC、 ST (except NE)、AM(except5-HT)、increased significantly, GLU and GLN both decreased significantly in the theanine group(P<0.05).
Conclusion:
1. The indexes of depressive behavior of model group is reduced, The changes of NE,5-HT, DA and GLU in PFC,NAC,ST,AM, HIP, which is related to the indexes of behaviors, and antidepressant fluoxetine treatment can improve them, which means the chronic unpredictable mild stress (CUMS) and separation is an effective method to establish depression animal model, and the changes of the monoamines and glutamate neurotransmitter in different brain regions that may be one of the pathogenesis mechanisms of depression.
2. Theanine and fluoxetine can effectively improve the depressive behavior of the depression model rats, increase the content of monoamine neurotrans-mitter NE,5-HT, DA and its metabolites, and reduce the content of GLU and its precursor GLN,in the PFC,NAC, AM, ST and HIP brain regions. suggested that the antidepressant effect and possible mechanism of theanine may be related to the neurotransmitters. Compared with fluoxetine, the antidepressant mechanism of theanine is more extensive, specificity is more weak than fluoxetine.
引文
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[65]夏军,叶慧,周义成.慢性应激大鼠抑郁模型的建立及其有效性的探讨.中国科技大学学报(医学版).2005,34(4)：493—495
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[70]MacQueen G, Frodl T. The hippocampus in major depression:evidence for the convergence of the bench and bedside in psychiatric research[J]? Mol Psychiatry. 2011; 16(3):252-64.
[71]Sheline YI, Mittler BL, Mintun MA. The hippocampus and depression [J],Eur Psychiatry,2002,17(Suppl3):300-305.
[72]Wamer-Schmidt JL, Duman RS. Hippocampal neurogenesis:opposing effects of stress and antidepressant treatment [J]. Hippocampus,2006,16(3):239-249.
[73]YanJ,Wang CA,Ye AL,et al.The effect of stress on behaviors and glutamate levels of four brain regions[J].Acta Psychol Sin,1995,27(4):422-427.
[74]Mc Ewen BS,Magarinos A M,.Stress and hippocampal plasticity:implications for the pathophysiology of affective disorders[J].Hum Psychophramacol, 2001,16(S1):S7-S19.
[75]Manahan-Vaughan D,WIIdfErster V,Thomsen C.et al.Rescue of hippocampal LTP and learning deficits in a rat model of psychosis by inhibition of glycine transporter-1(GlyT1)[J].Eur J Neurosci,2008,28(7):1342-1350.
[76]Altar CA, Laeng P, Jurata LW, et al. Electroconvu lsive seizures regulate gene expression of distinct neurotrophic signaling path ways[J]. JN euro sci,2004, 24(11):2667-2677.
[1]Desai MJ, Gill MS, Hsu WH, et al. Pharmacokinetics of theanine enantiomers in rats [J]. Chirality,2005,17:154-162.
[2]龚雨顺,李勤,黄建安,等.茶氨酸制备方法研究进展[J].湖南农业大学学报：自然科学版,2008,34(2)：232—235.
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[11]林雪玲,程朝辉,黄才欢等.茶氨酸对小鼠学习记忆能力的影响[J].食品科学2004,Vol.25,No.5
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[53]林雪玲,程朝辉,黄才欢等.茶氨酸对小鼠学习记忆能力的影响[J].食品科学2004,Vol.25,No.5
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[1]Desai MJ, Gill MS, Hsu WH, et al. Pharmacokinetics of theanine enantiomers in rats [J]. Chirality,2005,17:154-162.
[2]龚雨顺,李勤,黄建安,等.茶氨酸制备方法研究进展[J].湖南农业大学学报：自然科学版,2008,34(2)：232—235.
[3]Sugiyama T,et al. Enhancing effects of green tea components on the ntitumor activity of adriamycin against M5076 ovarian sarcoma[J]. Cancer Lett,2008,133 (1):19-26.
[4]Yokogoshi H,et al. Reduction effect of theanine on blood pressure and brain 5-hy droxyindoles in spontaneously hypertensiverats rats[J]. Biosci Biotech Biochem,2005,59(4):615-619.
[5]Zhang QMiura Y, Yagasaki K. Effects of dietary powdered green tea and theanine on tumor growth and endogenous hyperlipidemia in hepatoma bearing rats [J]. Biosci Biotechnol Biochem,2002,66:711-716.
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