酸枣仁汤抗焦虑作用的实验研究
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摘要
酸枣仁汤（SZRT）源于《金匮要略》，主治肝血不足、虚热内扰之虚烦证。现代临证除治疗失眠症外，还用于以情绪或神志障碍为主要表现的精神系统疾病。焦虑症是一种以广泛和持续的焦虑或者反复发作的惊恐不安为主要特征的神经症，常伴以头晕、胸闷、心悸、呼吸急促、口干、尿频尿急、震颤等植物神经功能症状和运动性紧张，其状态并非由实际威胁或危险引起，与现实处境很不相称。本病大致属于中医学“心神不宁”的范畴，可从调神角度辨治。SZRT具有养心安神，清热除烦的功效，与目前本病中医治法相吻合。
论文分两部分。理论部分分别从中、西医学两个方面对焦虑症研究情况进行了回顾。首先从流行病学、病因病理学、西医治疗学三方面对焦虑症的现代研究作了总结；继之，从试验研究角度回顾了焦虑动物模型研究方面取得的进展，并对其中的高架+形迷宫的应用研究进行了评述；最后对近10余年来国内外运用中医药防治本病的研究进展进行了概述和评价。
实验研究部分分别观察了口服SZRT对大、小鼠焦虑模型的行为学影响、对两种模型动物大脑相关脑区中单胺类神经递质及其代谢产物含量的影响以及对小鼠免疫功能的调节作用。
高架+形迷宫实验中，SZRT水煎液组大鼠进入开放臂次数比和在开放臂停留时间比均显著高于对照组（P<0.05），大鼠在开放臂和中央平台中head-dipping次数显著增加（P<0.05），但是大鼠开放臂和封闭臂总的进入次数与对照组比没有显著差异(P>0.05)；小鼠Holeboard探究实验中，SZRT高剂量组小鼠探究圆孔的次数(P<0.01)和时间(P<0.001)均显著少于对照组；SZRT低剂量组小鼠探究圆孔的时间明显少于正常组(P<0.05)，小鼠低头探究圆孔的潜伏期显著延长(P<0.01)，但是后腿直立的次数以及运动活力没有明显差异（P>0.05）。结果表明本方确有一定的抗焦虑作用，且与镇静催眠作用无关。
小鼠免疫试验中，高剂量SZRT组小鼠脾脏B淋巴细胞的增殖反应显著提高(P<0.05),低剂量组T淋巴细胞增殖率的显著下降(P<0.01)，而腹腔巨噬细胞的吞噬功能显著增强(P<0.001)。提示本方对正常小鼠免疫功能具有复杂的调节作用。
单胺递质的检测表明：SZRT治疗组大鼠海马内NE含量明显降低(P<0.05)，分析是通过降低海马中NE的释放而实现；SZRT治疗组小鼠大脑皮质区内DA以及其代谢物HVA含量显著低于正常组(P<0.05)，其作用效果与DZP的一致，表明SZRT能抑制该脑区DA能纤维DA的释放，推测SZRT可调节（降低）皮质DA传入神经的兴奋性，抑制DA的合成和释放。
研究结果表明：SZRT具有一定的抗焦虑效应，这种效应可能与其作用于中枢神经系统海马NE和皮质区DA的调节作用有关；SZRT还对免疫系统具有调节作用。提示SZRT通过多系统、多层次及多靶点产生效用。
Suanzaoren Tang（SZRT）, one of a traditional Chinese herbal medicine ,was mainly used to treat the agitation syndrome caused by the blood of Gan failing to nourish the mind in the ancient times.In modern clinical practice, it is successfully used in anxiety，as well as many other psychological disorders，such as neurasthenia，phobia，depression，insomnia and so on. In man, anxiety neurosis is perceived as an unpleasant affect，characterized by a tense and physically exhaustively alertness, focused on an impending and inevitable, although not objectively apparent, danger or emergency along with a painful awareness of uncertainty about the possibility of resolving the situation. in this paper, we investigated the possiblely potential anxiolytic effect of SZRT in laboratory.
To investigate the anxiolytic activity of SZRT, the characteristics of the behavioral effects of SZRT on exploration and on spontaneous locomotor activity both in rats and in mice were studied after oral administration of SZRT for 7 days. In the elevated plus-maze（EPM）test,which is currently one of the most widely used animal models in evaluation of novel anxiolytic agents and to investigate psychological and neurochemical basis of anxiety, the results showed that the animals had a significantly greater interest for the open arm exploration, both does of SZRT(7.5g/kg、15.0g/kg) significantly increased both the number and the ratio of open arm entries ,furthermore,the high does of SZRT could markedly raised the proportion of total time spent on the open arm .At the same time, analysis of spontaneous locomotor activity showed that no significant change took place in the total arm entry in the rats. We also found that more head－dipping could be observed in the unprotected areas of the EPM in rats received SZRT-treatment than normal rats. The holeboard apparatus, as it permits an independent measurement of exploration and locomotion, was used in this test. Head-dipping，locomotor activity, rearing and latency to the first head-dipping were measured in mice. It was found that the latency to the first head-dipping was significantly prolonged in SZRT-treated mouse. Moreover, both the frequency and the duration of head-dipping, which was recorded as a measure of anxiety, obviously decreased. As the indices of locomotion, both the number of rearing and the duration of the mouse moving around in the holeboard were not altered by the treatment of SZRT.These results told us that SZRT was a potentially efficient Anxiolytic.
In order to assess the influence of SZRT on immune system in mice, experiments were performed on the 10th day of treatment. The results showed that SZRT (20.0 g/kg) obviously raised the B lymphocyte proliferative response to LPS and a mild rising trend of the production of IL-1 by peritoneal macrophages.on the other hand, the
lower does of SZRT (10.0 g/kg) markedly inhibited the proliferation of T lymphocyte induced by ConA and potentiated the phagoctic ability of peritoneal macrophages compared with vehicle-treated group. Our work suggested that SZRT could have played a role in the regulation of immune function in normal mice.
To study the changes of central monoamine transmitters and their metabolites induced by SZRT,rats were decapitated and the brains were removed, and two regions of hippocampus and brains cortex of each rat were isolated as soon as the EPM test had been finished.for the mice,the cerebal cortex and the brain stem in each mouse were obtained on the last day of chronic SZRT treatment and the tissue was stored for subsequent determination. Nor-epinephrine (NE) , dopamine(DA), serotonin(5-HT) and their metabolites,3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindole-3-acetic acid (5-HIAA) were measured by high performance liquid chromatography coupled with electrochemical detection (HPLC-ECD)．The levels of NE within hippocampus decreased in rats that had been chronicaly pretreated with SZRT relative to vechile-treated mice,obvious reducing in DA and HVA concentration of
论文分两部分。理论部分分别从中、西医学两个方面对焦虑症研究情况进行了回顾。首先从流行病学、病因病理学、西医治疗学三方面对焦虑症的现代研究作了总结；继之，从试验研究角度回顾了焦虑动物模型研究方面取得的进展，并对其中的高架+形迷宫的应用研究进行了评述；最后对近10余年来国内外运用中医药防治本病的研究进展进行了概述和评价。
实验研究部分分别观察了口服SZRT对大、小鼠焦虑模型的行为学影响、对两种模型动物大脑相关脑区中单胺类神经递质及其代谢产物含量的影响以及对小鼠免疫功能的调节作用。
高架+形迷宫实验中，SZRT水煎液组大鼠进入开放臂次数比和在开放臂停留时间比均显著高于对照组（P<0.05），大鼠在开放臂和中央平台中head-dipping次数显著增加（P<0.05），但是大鼠开放臂和封闭臂总的进入次数与对照组比没有显著差异(P>0.05)；小鼠Holeboard探究实验中，SZRT高剂量组小鼠探究圆孔的次数(P<0.01)和时间(P<0.001)均显著少于对照组；SZRT低剂量组小鼠探究圆孔的时间明显少于正常组(P<0.05)，小鼠低头探究圆孔的潜伏期显著延长(P<0.01)，但是后腿直立的次数以及运动活力没有明显差异（P>0.05）。结果表明本方确有一定的抗焦虑作用，且与镇静催眠作用无关。
小鼠免疫试验中，高剂量SZRT组小鼠脾脏B淋巴细胞的增殖反应显著提高(P<0.05),低剂量组T淋巴细胞增殖率的显著下降(P<0.01)，而腹腔巨噬细胞的吞噬功能显著增强(P<0.001)。提示本方对正常小鼠免疫功能具有复杂的调节作用。
单胺递质的检测表明：SZRT治疗组大鼠海马内NE含量明显降低(P<0.05)，分析是通过降低海马中NE的释放而实现；SZRT治疗组小鼠大脑皮质区内DA以及其代谢物HVA含量显著低于正常组(P<0.05)，其作用效果与DZP的一致，表明SZRT能抑制该脑区DA能纤维DA的释放，推测SZRT可调节（降低）皮质DA传入神经的兴奋性，抑制DA的合成和释放。
研究结果表明：SZRT具有一定的抗焦虑效应，这种效应可能与其作用于中枢神经系统海马NE和皮质区DA的调节作用有关；SZRT还对免疫系统具有调节作用。提示SZRT通过多系统、多层次及多靶点产生效用。
Suanzaoren Tang（SZRT）, one of a traditional Chinese herbal medicine ,was mainly used to treat the agitation syndrome caused by the blood of Gan failing to nourish the mind in the ancient times.In modern clinical practice, it is successfully used in anxiety，as well as many other psychological disorders，such as neurasthenia，phobia，depression，insomnia and so on. In man, anxiety neurosis is perceived as an unpleasant affect，characterized by a tense and physically exhaustively alertness, focused on an impending and inevitable, although not objectively apparent, danger or emergency along with a painful awareness of uncertainty about the possibility of resolving the situation. in this paper, we investigated the possiblely potential anxiolytic effect of SZRT in laboratory.
To investigate the anxiolytic activity of SZRT, the characteristics of the behavioral effects of SZRT on exploration and on spontaneous locomotor activity both in rats and in mice were studied after oral administration of SZRT for 7 days. In the elevated plus-maze（EPM）test,which is currently one of the most widely used animal models in evaluation of novel anxiolytic agents and to investigate psychological and neurochemical basis of anxiety, the results showed that the animals had a significantly greater interest for the open arm exploration, both does of SZRT(7.5g/kg、15.0g/kg) significantly increased both the number and the ratio of open arm entries ,furthermore,the high does of SZRT could markedly raised the proportion of total time spent on the open arm .At the same time, analysis of spontaneous locomotor activity showed that no significant change took place in the total arm entry in the rats. We also found that more head－dipping could be observed in the unprotected areas of the EPM in rats received SZRT-treatment than normal rats. The holeboard apparatus, as it permits an independent measurement of exploration and locomotion, was used in this test. Head-dipping，locomotor activity, rearing and latency to the first head-dipping were measured in mice. It was found that the latency to the first head-dipping was significantly prolonged in SZRT-treated mouse. Moreover, both the frequency and the duration of head-dipping, which was recorded as a measure of anxiety, obviously decreased. As the indices of locomotion, both the number of rearing and the duration of the mouse moving around in the holeboard were not altered by the treatment of SZRT.These results told us that SZRT was a potentially efficient Anxiolytic.
In order to assess the influence of SZRT on immune system in mice, experiments were performed on the 10th day of treatment. The results showed that SZRT (20.0 g/kg) obviously raised the B lymphocyte proliferative response to LPS and a mild rising trend of the production of IL-1 by peritoneal macrophages.on the other hand, the
To study the changes of central monoamine transmitters and their metabolites induced by SZRT,rats were decapitated and the brains were removed, and two regions of hippocampus and brains cortex of each rat were isolated as soon as the EPM test had been finished.for the mice,the cerebal cortex and the brain stem in each mouse were obtained on the last day of chronic SZRT treatment and the tissue was stored for subsequent determination. Nor-epinephrine (NE) , dopamine(DA), serotonin(5-HT) and their metabolites,3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindole-3-acetic acid (5-HIAA) were measured by high performance liquid chromatography coupled with electrochemical detection (HPLC-ECD)．The levels of NE within hippocampus decreased in rats that had been chronicaly pretreated with SZRT relative to vechile-treated mice,obvious reducing in DA and HVA concentration of
引文
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