疏肝和胃汤对抑郁模型大鼠PFC-NAc-VTA神经环路DA含量的影响
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摘要
目的:观察疏肝和胃汤对抑郁模型大鼠脑部前额叶皮层(PFC)-伏隔核(NAc)-腹侧被盖区(VTA)神经环路多巴胺(DA)含量的影响,探讨疏肝和胃汤的抗抑郁作用机制。方法:120只大鼠随机分成空白组,模型组,疏肝和胃汤低、中、高剂量组,氟西汀组,每组20只,慢性不可预知性温和应激结合孤养法制作抑郁大鼠模型,共计造模4周后,疏肝和胃汤低、中、高剂量组分别予3.67、7.34、14.68g·kg-1·d-1给药,氟西汀组按1.58mg·kg-1·d-1给药,空白组及模型组给予等体积0.9%氯化钠溶液,每天灌胃1次,共计7d。在第5周结束后,根据大鼠脑立体定位图取大鼠脑PFC区、NAc区及VTA区组织,采用高效液相色谱法检测各脑区DA的含量。结果:与空白组比较,模型组大鼠PFC区、NAc区及VTA区DA含量均明显降低(P<0.01);治疗1周后,疏肝和胃汤中、高剂量组及氟西汀组大鼠PFC区DA含量升高,疏肝和胃汤各剂量组及氟西汀组NAc区DA含量升高,疏肝和胃汤低、中剂量组及氟西汀组大鼠VTA区DA含量升高,与模型组比较均有显著性差异(P<0.05,P<0.01);其中,PFC区疏肝和胃汤高剂量组与氟西汀组比较,NAc区疏肝和胃汤中剂量组与氟西汀组比较,无显著性差异,而VTA区疏肝和胃汤低、中剂量组与氟西汀组比较,差异有统计学意义(P<0.01)。结论:疏肝和胃汤可能是通过增加PFC区、NAc区及VTA区DA的表达,整体调节PFC-NAc-VTA神经环路中DA的含量,达到改善抑郁样行为的作用。
Objective: To observe the effects of Shugan Hewei Decoction on dopamine(DA) content in prefrontal cortex(PFC)-nucleus accumbens(NAc)-ventral tegmental area(VTA) neural circuit of depression model rats, and to explore the possible anti-depression mechanism of Shugan Hewei Decoction. Methods: One hundred and twenty rats were randomized divided into the blank control group, the model group, the low, middle and high dose Shugan Hewei Decoction group, and the fluoxetine group, with twenty rats in each group. The depression rats model was established with chronic unpredictable mild stress(CUMS) combined with social isolation. Four weeks after modeling, the low, middle and high dose Shugan Hewei Decoction groups were respectively intervened with Shugan Hewei Decoction with a dosage of 3.67, 7.34, 14.68 g/kg, the fluoxetine group was intervened with fluoxetine with a dosage of 1.58 mg/kg, the blank control group and model group were given the same volume normal saline. Each group was given intragastric administration for seven days, once a day. At the end of the fifth week, the rat brain tissues in PFC, NAc and VTA were taken out based on rat brain stereogram, and the method of high performance liquid chromatography(HPLC) was used to detect the DA content in PFC, NAc and VTA. Results: Compared with the blank control group, the DA content of PFC, NAc and VTA were all decreased obviously in model group(P<0.01). One week after treatment, the DA content of PFC in the middle and high dose Shugan Hewei Decoction group and fluoxetine group increased, and DA content of NAc in the low, middle,high dose Shugan Hewei Decoction group and fluoxetine group increased, and DA content of VAT in the low, middle dose Shugan Hewei Decoction group and fluoxetine group increased. There were all significant differences, comparing with the model group(P<0.05, P<0.01). There was no significant difference in DA content of PFC between the high dose Shugan Hewei Decoction group and the fluoxetine group, and the same in DA content of NAc between the middle dose Shugan Hewei Decoction group and the fluoxetine group. While there was significant difference of DA content among the low, middle dose Shugan Hewei Decoction group and the fluoxetine group in VTA(P<0.01). Conclusion: Shugan Hewei Decoction playing a role of improving depression behavior may be by increasing the expression of DA in PFC, NAc and VTA, and it integrally regulates the DA content in PFC-NAc-VTA neural circuit.
Objective: To observe the effects of Shugan Hewei Decoction on dopamine(DA) content in prefrontal cortex(PFC)-nucleus accumbens(NAc)-ventral tegmental area(VTA) neural circuit of depression model rats, and to explore the possible anti-depression mechanism of Shugan Hewei Decoction. Methods: One hundred and twenty rats were randomized divided into the blank control group, the model group, the low, middle and high dose Shugan Hewei Decoction group, and the fluoxetine group, with twenty rats in each group. The depression rats model was established with chronic unpredictable mild stress(CUMS) combined with social isolation. Four weeks after modeling, the low, middle and high dose Shugan Hewei Decoction groups were respectively intervened with Shugan Hewei Decoction with a dosage of 3.67, 7.34, 14.68 g/kg, the fluoxetine group was intervened with fluoxetine with a dosage of 1.58 mg/kg, the blank control group and model group were given the same volume normal saline. Each group was given intragastric administration for seven days, once a day. At the end of the fifth week, the rat brain tissues in PFC, NAc and VTA were taken out based on rat brain stereogram, and the method of high performance liquid chromatography(HPLC) was used to detect the DA content in PFC, NAc and VTA. Results: Compared with the blank control group, the DA content of PFC, NAc and VTA were all decreased obviously in model group(P<0.01). One week after treatment, the DA content of PFC in the middle and high dose Shugan Hewei Decoction group and fluoxetine group increased, and DA content of NAc in the low, middle,high dose Shugan Hewei Decoction group and fluoxetine group increased, and DA content of VAT in the low, middle dose Shugan Hewei Decoction group and fluoxetine group increased. There were all significant differences, comparing with the model group(P<0.05, P<0.01). There was no significant difference in DA content of PFC between the high dose Shugan Hewei Decoction group and the fluoxetine group, and the same in DA content of NAc between the middle dose Shugan Hewei Decoction group and the fluoxetine group. While there was significant difference of DA content among the low, middle dose Shugan Hewei Decoction group and the fluoxetine group in VTA(P<0.01). Conclusion: Shugan Hewei Decoction playing a role of improving depression behavior may be by increasing the expression of DA in PFC, NAc and VTA, and it integrally regulates the DA content in PFC-NAc-VTA neural circuit.
引文
[1]邢颖.抑郁模型大鼠行为学和胃肠激素变化及疏肝和胃汤干预作用的实验研究.武汉:湖北中医药大学,2012
[2]李明珠.疏肝和胃汤对抑郁模型大鼠胃粘膜肥大细胞及感觉神经递质影响的研究.武汉:湖北中医药大学,2013
[3]岳滢滢.从抑郁模型大鼠脑和脊髓敏感性脑肠肽变化研究肝胃不和证的发生机制.武汉:湖北中医药大学,2014
[4]刘松林,岳滢滢,邢颖,等.疏肝和胃汤对抑郁模型大鼠延髓、脊髓及胃黏膜组织P物质表达的影响.中华中医药杂志,2015,30(9):3116-3120
[5]Scott J Russo,Eric J Nestler.The brain reward circuitry in mood disorders.Nature Reviews Neuroscience,2013,9(14):609-622
[6]Tran A H,Tamura R,Uwano T,et al.Dopamine D1 receptors involved in locomotor activity and accumbens neural responses to prediction of reward associated with place.Proc Natl Acad Sci USA,2005,102(6):2117-2122
[7]Shirayama Y,Chaki S.Neurochemistry of the nucleus accumbens and its relevance to depression and antidepressant action in rodents.Curr Neuropharmacol,2006,4(4):277-291
[8]Cacciapaglia F,Wightman R M,Carelli R M.Rapid dopamine signaling differentially modulates distinct microcircuits within the nucleus accumbens during sucrose directed behavior.J Neurosci,2011,31(39):13860-13869
[9]魏伟,吴希美,李元建.药理实验方法学.4版.北京:人民卫生出版社,2010:1136
[10]Willner P,Towell A,Sampson D,et al.Reduction of sucrose preference by chronic unpredictable mild stressand its restoration by a tricycle antidepressant.Psychopharmacology,1987,93(3):358
[11]许晶,李晓秋.慢性应激抑郁模型的建立及其评价.中国行为医学科学,2003,12(1):14-17
[12]Paxinos G,Watson C.The Rat Brain in Stereotaxic Coordinates.Netherlands:Elsevier Academic Press,2007
[13]许乐思,刘松林,岳滢滢,等.基于抑郁症PFC-NAc-VTA神经环路与摄食相关信号的中枢外周效应观察“肝郁犯胃”发生机制.中华中医药杂志,2017,32(11):4914-4917
[14]Mittal V A,Walker E F.Diagnostic and statistical manual of mental disorders.Psychiatry Res,2011,189(1):158-159
[15]Watson D,Weber K,Assenheimer J S,et al.Testing atripartite model:Evaluating the convergent and discriminant validity of anxiety and depression symptom scales.J Abnorm Psychol,1995,104(1):3-14
[16]Ramnani N,Owen A M.Anterior prefrontal cortex:insights into func-tion from anatomy and neuroimaging.Nature Reviews Neuroscience,2004,5(3):184-194
[17]Myers-Schulz B,Koenigs M.Functional anatomy of ventromedial prefrontal cortex:implications for mood and anxiety disorders.Molecular Psychiatry,2011,17(2):132
[18]Barr A M,Markou A,Phillips A G.A‘crash’course on psychostimulant withdrawal as a model of depression.Trends Pharmacol Sci,2002,23(10):475-482
[19]Hee-Dae Kim,Jennifer Hesterman,Deveroux Ferguson.SIRT1mediates depression-like behaviors in the nucleus accumbens.The Journal of Neuroscience,2016,36(32):8441-8452
[20]Di C G,Loddo P,Tanda G.Reciprocal changes in prefrontal and limbic dopamine responsiveness to aversive and rewarding stimuli after chronic mild stress:implications for the psychobiology of depression.Biol Psychiatry,1999,46(12):1624-1633
[21]Soetanto A,Wilson R S,Talbot K,et al.Association of anxiety and depression with microtubule-associated protein 2-and synaptopodin immunolabeled dendrite and spine densities in hippocampal CA3of older humans.Arch Gen Psychiatry,2010,67(5):448-457
[22]Mazeirobison M S,Nestler E J.Opiate-induced molecular and cellular plasticity of ventral tegmental area and locus coeruleus catecholamine neurons.Cold Spring Harbor Perspectives in Medicine,2012,2(7):a012070
[23]Nair-Roberts R G,Chatelain-Badie S D,Benson E,et al.Stereological estimates of dopaminergic,GABAergic and glutamatergic neurons in the ventral tegmental area,substantia nigra and retrorubral field in the rat.Neuroscience,2008,152(4):1024-1031
[24]Sesack S R,Grace A A.Cortico-basal ganglia reward network:microcircuitry.Neuropsychopharmacology Official Publication of the American College of Neuropsychopharmacology,2010,35(1):27-47
[25]Mao L M,Wang W,Chu X P,et al.Stability of surface NMDA receptors controls synaptic and behavioral adaptations to amphetamine.Nat Neurosci,2009,12(5):602-610
[26]Hosseini S B,Sahraei H,Mohammadi A,et al.Inactivation of the Nucleus Accumbens,core exerts no effect on nicotine induced conditioned place preference.Neurophysiology,2015,47(4):295-301
[27]刘文华,陈楚侨,黄敏儿.抑郁症的内表现型:快感缺失及其测量方法.心理科学进展,2010,18(2):271-281
[28]孙晖.调节Kv7通道对VTA区DA神经元兴奋性及动物抑郁样行为的作用及机制.石家庄:河北医科大学,2016
[29]白玫.慢性应激诱发抑郁的多巴胺能神经通路异常机制.长沙:中南大学,2013
[30]Nathan P J,O’Neill B V,Mogg K,et al.The effects of the dopamine D3receptor antagonist GSK598809 on attentional bias to palatable food cues in overweight and obese subjects.Int J Neuropsychopharmacol,2012,15(2):149-161
[31]Scheggi S,Leggio B,Masi F,et al.Selective modifications in the nucleus accumbens of dopamine synaptic transmission in rats exposed to chronic stress.J Neurochem,2002,83(4):895-903
[32]刘丹丹.伏隔核中型多棘神经元兴奋性及海马长时程增强在抑郁症发病中的作用.上海:上海交通大学,2013
[33]杨怡.茶氨酸对抑郁模型大鼠行为学、神经递质的影响.长沙:中南大学,2013
[2]李明珠.疏肝和胃汤对抑郁模型大鼠胃粘膜肥大细胞及感觉神经递质影响的研究.武汉:湖北中医药大学,2013
[3]岳滢滢.从抑郁模型大鼠脑和脊髓敏感性脑肠肽变化研究肝胃不和证的发生机制.武汉:湖北中医药大学,2014
[4]刘松林,岳滢滢,邢颖,等.疏肝和胃汤对抑郁模型大鼠延髓、脊髓及胃黏膜组织P物质表达的影响.中华中医药杂志,2015,30(9):3116-3120
[5]Scott J Russo,Eric J Nestler.The brain reward circuitry in mood disorders.Nature Reviews Neuroscience,2013,9(14):609-622
[6]Tran A H,Tamura R,Uwano T,et al.Dopamine D1 receptors involved in locomotor activity and accumbens neural responses to prediction of reward associated with place.Proc Natl Acad Sci USA,2005,102(6):2117-2122
[7]Shirayama Y,Chaki S.Neurochemistry of the nucleus accumbens and its relevance to depression and antidepressant action in rodents.Curr Neuropharmacol,2006,4(4):277-291
[8]Cacciapaglia F,Wightman R M,Carelli R M.Rapid dopamine signaling differentially modulates distinct microcircuits within the nucleus accumbens during sucrose directed behavior.J Neurosci,2011,31(39):13860-13869
[9]魏伟,吴希美,李元建.药理实验方法学.4版.北京:人民卫生出版社,2010:1136
[10]Willner P,Towell A,Sampson D,et al.Reduction of sucrose preference by chronic unpredictable mild stressand its restoration by a tricycle antidepressant.Psychopharmacology,1987,93(3):358
[11]许晶,李晓秋.慢性应激抑郁模型的建立及其评价.中国行为医学科学,2003,12(1):14-17
[12]Paxinos G,Watson C.The Rat Brain in Stereotaxic Coordinates.Netherlands:Elsevier Academic Press,2007
[13]许乐思,刘松林,岳滢滢,等.基于抑郁症PFC-NAc-VTA神经环路与摄食相关信号的中枢外周效应观察“肝郁犯胃”发生机制.中华中医药杂志,2017,32(11):4914-4917
[14]Mittal V A,Walker E F.Diagnostic and statistical manual of mental disorders.Psychiatry Res,2011,189(1):158-159
[15]Watson D,Weber K,Assenheimer J S,et al.Testing atripartite model:Evaluating the convergent and discriminant validity of anxiety and depression symptom scales.J Abnorm Psychol,1995,104(1):3-14
[16]Ramnani N,Owen A M.Anterior prefrontal cortex:insights into func-tion from anatomy and neuroimaging.Nature Reviews Neuroscience,2004,5(3):184-194
[17]Myers-Schulz B,Koenigs M.Functional anatomy of ventromedial prefrontal cortex:implications for mood and anxiety disorders.Molecular Psychiatry,2011,17(2):132
[18]Barr A M,Markou A,Phillips A G.A‘crash’course on psychostimulant withdrawal as a model of depression.Trends Pharmacol Sci,2002,23(10):475-482
[19]Hee-Dae Kim,Jennifer Hesterman,Deveroux Ferguson.SIRT1mediates depression-like behaviors in the nucleus accumbens.The Journal of Neuroscience,2016,36(32):8441-8452
[20]Di C G,Loddo P,Tanda G.Reciprocal changes in prefrontal and limbic dopamine responsiveness to aversive and rewarding stimuli after chronic mild stress:implications for the psychobiology of depression.Biol Psychiatry,1999,46(12):1624-1633
[21]Soetanto A,Wilson R S,Talbot K,et al.Association of anxiety and depression with microtubule-associated protein 2-and synaptopodin immunolabeled dendrite and spine densities in hippocampal CA3of older humans.Arch Gen Psychiatry,2010,67(5):448-457
[22]Mazeirobison M S,Nestler E J.Opiate-induced molecular and cellular plasticity of ventral tegmental area and locus coeruleus catecholamine neurons.Cold Spring Harbor Perspectives in Medicine,2012,2(7):a012070
[23]Nair-Roberts R G,Chatelain-Badie S D,Benson E,et al.Stereological estimates of dopaminergic,GABAergic and glutamatergic neurons in the ventral tegmental area,substantia nigra and retrorubral field in the rat.Neuroscience,2008,152(4):1024-1031
[24]Sesack S R,Grace A A.Cortico-basal ganglia reward network:microcircuitry.Neuropsychopharmacology Official Publication of the American College of Neuropsychopharmacology,2010,35(1):27-47
[25]Mao L M,Wang W,Chu X P,et al.Stability of surface NMDA receptors controls synaptic and behavioral adaptations to amphetamine.Nat Neurosci,2009,12(5):602-610
[26]Hosseini S B,Sahraei H,Mohammadi A,et al.Inactivation of the Nucleus Accumbens,core exerts no effect on nicotine induced conditioned place preference.Neurophysiology,2015,47(4):295-301
[27]刘文华,陈楚侨,黄敏儿.抑郁症的内表现型:快感缺失及其测量方法.心理科学进展,2010,18(2):271-281
[28]孙晖.调节Kv7通道对VTA区DA神经元兴奋性及动物抑郁样行为的作用及机制.石家庄:河北医科大学,2016
[29]白玫.慢性应激诱发抑郁的多巴胺能神经通路异常机制.长沙:中南大学,2013
[30]Nathan P J,O’Neill B V,Mogg K,et al.The effects of the dopamine D3receptor antagonist GSK598809 on attentional bias to palatable food cues in overweight and obese subjects.Int J Neuropsychopharmacol,2012,15(2):149-161
[31]Scheggi S,Leggio B,Masi F,et al.Selective modifications in the nucleus accumbens of dopamine synaptic transmission in rats exposed to chronic stress.J Neurochem,2002,83(4):895-903
[32]刘丹丹.伏隔核中型多棘神经元兴奋性及海马长时程增强在抑郁症发病中的作用.上海:上海交通大学,2013
[33]杨怡.茶氨酸对抑郁模型大鼠行为学、神经递质的影响.长沙:中南大学,2013