摘要
茶叶是具有多种保健作用的世界性饮料之一。本研究的目的是以茶组四种植物为研究对象，在对所含的嘌呤类生物碱和茶多酚类成分比较的基础上，选择具有特征组成的可可茶(Camellia ptilophylla Chang)和苦茶(Camellia assamica var．kucha Chang et Wang)为原料，探讨富含可可碱的广东特产资源—可可茶的研究开发利用前途以及苦茶中含有的特殊嘌呤生物碱—theacrine对中枢神经系统的作用。
本文采用高效液相色谱法建立了对茶叶水提取物中嘌呤生物碱及茶多酚类化合物的快速分析方法，并对可可茶、苦茶、绿茶(Camellia sinensis(L．)O．Ktze)及普洱茶(Camellia assamica(Mast．)Chang)四种茶组植物中4种嘌呤生物碱类物质和9种茶多酚类物质同时进行了定量检测。实验结果证明，与普通绿茶、普洱茶不同，可可茶中以可可碱为优势生物碱，含量高达茶叶干重的5.8％，且咖啡碱含量很低或不含咖啡碱。在确定分析方法的基础上，对173株野生可可茶植株进行了采样分析，共检测出29株完全不含咖啡碱的纯种可可茶植株，作为母本通过扦插繁殖建立纯种可可茶种苗基地，扩大天然无咖啡碱茶树的种质资源。
高效液相分析结果显示苦茶中特异性嘌呤生物碱theacrine含有为1.78％，而在其他三种茶中均未检出该生物碱。通过对42g干燥苦茶样品的提取与分离，富集得到了部分theacrine(1，3，7，9-tetramethyluric acid，1)以供药理活性研究。同时，还从苦茶水提取物中分离得到caffeine(2)，theobromine(3)，(+)-catechin(4)，(-)-epigallocatechin(5)，(-)-gallocatechin(6)，(-)-epigallocatechin 3-O-gallate(7)，(-)-gallocatechin 3-O-gallate(8)，1，2，6-tri-O-galloyl-β-D-glucose(9)和gallic acid(10)。其中，化合物4～10为首次从该种中分离得到。
茶叶中含有的嘌呤生物碱类物质具有显著的中枢神经药理活性，其中咖啡碱、茶碱、可可碱在临床治疗中应用广泛，但药用领域却有所不同，它们化学结构上的区别仅在于该类化合物嘌呤母核上甲基取代基的数量和位置不同。Theacrine也具有相似的嘌呤母核化学结构，但其上取代的甲基数目最多，推测其可能具有明显的药理作用，也可能与其它嘌呤类生物碱在作用上存在较大的差别。由于theacrine天然来源稀少，化学合成又比较困难，其中枢神经药理活性未见任何研究报道。苦茶的发现为研究theacrine的药理活性提供了前提条件。本文重点研究了theacrine对中枢神经系统的药理作用，包括对小鼠自主活动、强迫游泳运动、睡眠、学习记忆能力以及应激状态下实验动物脑内单胺类神经递质的影响，并将其与caffeine和theobromine进行对比，旨在探讨theacrine的中枢神经系统作用及其机制，为苦茶及其特异性生物碱theacrine的开发利用提供实验依据。
研究发现，在自主活动及强迫游泳实验中，caffeine(10～30 mg／kg)显示出一定的中枢兴奋作用，而theobromine(10 mg／kg)相反具有中枢安定作用，theacrine在10 mg／kg具有微弱的中枢安定作用，而30 mg／kg下对动物行为改变作用不明显，未显示出与caffeine相似的中枢神经兴奋作用。
在戊巴比妥诱导小鼠睡眠实验中，对于正常及急、慢性拘束应激小鼠，theacrine(10-30 mg／kg)均能在一定程度上延长戊巴比妥诱导的小鼠睡眠时间，而caffeine和theobromine在相同条件下显示出对睡眠时间的缩短作用。
在避暗及Morris水迷宫实验中，三种受试药物均对实验动物的学习记忆能力显示出一定的增强作用，但theacrine与caffeine和theobromine相比在作用程度上没有显著差异。
小鼠拘束应激实验结果显示，急性拘束应激能够普遍提高小鼠各脑区单胺类神经递质的合成与代谢。三种嘌呤生物碱类物质对正常及应激状态下小鼠脑内的单胺类递质水平有一定的升高作用，但受到剂量和脑区等多种因素显著的影响。转轮应激能够导致大鼠与临床神经厌食症和强迫症相似的行为改变以及脑内多巴胺能神经功能亢进和5-羟色胺能神经功能低下。除30 mg／kg caffeine外，三种嘌呤生物碱类化合物均对大鼠的强迫运动行为具有一定的缓解作用。三种生物碱还能够显著提高大鼠脑内5-HT含量，可能是其缓解大鼠应激状态的原因之一。但三种嘌呤生物碱对应激状态下实验动物中枢神经系统的作用以及作用的机制还有待于进一步实验证实。
综合以上结果可以看出，在本实验剂量条件下theacrine对中枢神经系统没有显示出与caffeine相似的兴奋作用，但却可以显著延长戊巴比妥诱导的睡眠时间。Theacrine具有一定的增强实验动物学习记忆能力的作用。三种生物碱均能够升高正常和急性拘束应激状态下小鼠脑内的单胺类递质水平，并对转轮应激大鼠的强迫行为有一定的缓解作用，该作用可能与其提高中枢5-HT水平有关。
本研究工作在化学和生物活性研究的基础上，证实了茶组植物可可茶不含caffeine的特性，并首次揭示了茶组植物苦茶中特异性嘌呤生物碱theacrine的中枢神经药理作用。本文的实验结果将为今后对茶组植物可可茶与苦茶的研究与开发提供初步的实验依据，并为系统研究和开发其他茶组植物提出了良好的思路。
Tea is the most popular beverage known to have beneficial effects on health in the world. On basis of comparison of chemical constituents of purine alkaloids and catechins in four species of Camellia Sect. Thea, the research discussed the future of development and utilization to C. ptilophylla, a special tea plant abundant in theobromine, and investigated the effects of theacrine, a peculiar purine alkaloid in C. assamica var. kucha, on central nervous system.
In this paper, a RP-HPLC method was established to analyze the purine alkaloids and catechins in water extract of tea leaves. Four purine alkaloids and nine catechins in C. assamica var. kucha, C. ptilophylla, C. sinensis and C. assamica were identified and quantified at the same time. The results indicated theobromine, different from C. sinensis and C. assamica, is the major alkaloid (5.8 %) present in dry leaves of C. ptilphylla, which contains no or a small amount of caffeine. Furthermore, the HPLC method was used to detect caffeine content of 173 wild grown trees of C. ptilphylla, 29 caffeine-free tea trees obtained which could be cutting propagated and resolve the problem of commercial production of caffeine free tea.
A large content substance was isolated from C. assamica var. kucha. Its structure was elucidated as theacrine (1, 3, 7, 9-tetramethyluric acid, 1) through spectroscopic analysis. Meanwhile, other 9 compounds were obtained from the extract of kucha leaves, which were caffeine (2), theobromine (3), (+)-catechin (4), (-)-epigallocatechin (5), (-)-gallocatechin (6), (-)-epigallocatechin 3-O-gallate (7), (-)-gallocatechin 3-O-gallate (8), 1, 2, 6-tri-O-galloyl-β-D-glucose (9) and gallic acid (10). Among these, compounds 4～10 were isolated from the plant for the first time.
Purine alkaloids present in tea have significant effects on CNS. Caffeine, theophylline and theobromine are all widely used in clinical therapy. Even though these kinds of compounds have similar chemical structures, their effects on CNS may be much different. Compared with caffeine, the effects of theacrine on CNS have never been studied since its scarcity in nature and difficulty of artificial synthesis. Therefore, we investigated some behavioral and CNS effects of theacrine including ambulatory activity, forced swimming test, pentobarbital-induced sleep time, step-through test and Morris water maze test. The effects of theacrine on monoamine transmitters in brain of animals were also studied by animal models of restraint stress and activity stress. By comparison with caffeine and theobromine, the effects of theacrine on CNS could be illustrated.
In the ambulatory activity and forced swimming tests, caffeine (10-30 mg/kg) could produce a remarkable increase in activity, but theobromine (10 mg/kg) responded with a reversed effect compared with caffeine. Theacrine at the dose of 10 mg/kg also showed some weakly sedative effect, whereas did not process significant effect at 30 mg/kg. In test of pentobarbital induced sleep time, theacrine at 10 or 30 mg/kg could reliably prolong the sleep time of mice in either normal or acute and chronic stress condition, whereas caffeine and theobromine increased the arousal level of mice at the same time. The step-through task and Morris water maze test results revealed that theacrine, caffeine and theobromine all could improve the learning and momory abilities.
The results of restraint stress suggested that the levels of monoamine transmitters in brain of mice generally increased after restraint stress. Three purine alkaloids could increase NE, 5-HT and 5-HIAA levels in brain cortex and NE in hypothalamus in both normal and stress mice, but the action of theacrine and theobromine were much weaker than caffeine at the same dose. The activity stress paradigm could make rats have abnormal behaviors such as anorexia nervosa and compulsive behavior similar to those observed in humans. Except for 30 mg/kg caffeine, all three purine alkaloids could ameliorate the abnormal behaviors of activity stress rats. Neurochemical results showed that administration of three purine alkaloids could increase 5-HT levels in brain of activity stress rats which may account for their protective effect on behavior of stress rats. The difference of effects of three alkaloids on central nonoamine transmitters and the mechanisms involved still required further study.
The chemical and bioactive studies in this academic dissertation confirmed caffeine-free characters of C. ptilophylla, and firstly revealed effects of theacrine obtained from C. assamica var. kucha on central nervous system. Our findings will provide faithful theoretical and experimental evidences for research and development of C. ptilophylla and C. assamica var. kucha in future, and also inaugurate a new way to explore systemically the other plants' resources of Camellia Sect. Thea.
引文
[1] 林清平．中国茶魂．清明，2005，5，195-200
[2] 陈炳环．茶树分类研究的历史和现状．中国茶叶，1983，5，14-15
[3] 中国科学院．中国植物志，北京：科学出版社．1998，Vol．49(3)：115
[4] 杨贤强，王岳飞，陈留记，等．茶多酚化学．上海：上海科学技术出版社．2003，1-3
[5] 葛圣蕾，谢鼎华．儿茶素对拟衰老大鼠大脑皮层及肾组织MDA、SOD的影响，中国老年学杂志，2003，23(9)：607-608
[6] 方芳，崔志清，韩永晶．茶儿茶素的研究概况，中草药．2000，31(5)：396-398
[7] 龚志华，仇灿红，肖文君．茶多酚降血脂研究进展．福建茶叶，2002，4，39-40
[8] 刘敏．茶多酚与动脉粥样硬化．实用临床医学，2000，1(1)：83-86
[9] 林宏．茶多酚对心血管系统的药理作用．天津药学，1999，11(2)：11-12
[10] Takahashi H, Nomata K, Mori KI, et al. The preventive effect of green tea on the gap junction intercellular communication in renal epithelial cells treated with a renal carcinogen. Anticancer Res., 2004, 24(6): 3757-3762
[11] 罗非君，胡智，赵晓荣，等．茶多酚诱导鼻咽cyclin D1表达下调．癌症，2001，20(4)：358-362
[12] 张星海，郭碧花，杨贤强．茶多酚诱导肿瘤细胞凋亡及其机理探讨．福建茶叶，2003，1，39-41
[13] 刘军权，陈复兴，巩新建，等．茶多酚增强T淋巴细胞杀伤肿瘤细胞的作用研究．陕西医学杂志，2003，32(4)：355-357
[14] 梁文红．茶多酚抗菌作用的研究概况．国外医学口腔医学分册，2004，31(增刊)，26-28
[15] 徐竺婷，李鸣宇．10种中药有效成分抑制口腔主要致病菌比较．中国现代应用药学杂志，2000，17(4)：277-279
[16] 丁苑，徐伟健．以茶多酚为盖髓剂临床治疗观察．J．Comprehensive Stomatology，2001，17(4)：314
[17] 唐明，肖晓蓉，章锦才等．茶多酚对牙周主要致病菌的抗菌活性研究．重庆医学，2004，33(3)：410-411
[18] 彭慧琴，蔡卫民，项哨．茶多酚体外抗流感病毒A3的作用，茶叶科学，2003，23(1)：79-81
[19] 张国营，李彦勇，何丽娜，等．绿茶及茶多酚抗人轮状病毒的实验．茶叶科学，1994，14(2)：155-158
[20] 金性江，高敏芬，罗荣喜，等．茶多酚对化疗癌症病人血象的保护作用．茶叶，1994，20(4)：45-46
[21] 王岳飞，唐德松，朴宰日，等．茶多酚对荷瘤小鼠辐射损伤的影响．中华放射医学与防护杂志，2004，24(3)：263-264
[22] Ashihara, H., Monteiro, A. M., Gillies, F. M., et al. Caffeine biosynthesis in leaves of coffee(Coffea Arabica L.). Plant Physiol., 1996, 111, 747-753
[23] Ashihara, H., Monterio, A. M., Moritz, T., et al. Catabolism of caffeine and related purine alkaloids in leaves of Coffea Arabica L. Planta, 1996, 198, 334-339
[24] Ashihara, H. Gillies, F. M., Crozier, A., et al. Metabolism of Caffeine and Related Purine Alkaloids in Leaves of Tea(Camellia sinensis L.). Plant Cell Physiol. 1997, 38(4): 413-419
[25] Koshiishi, C., Kato, A., Yama, S., et al. A new caffeine biosynthetic pathway in tea leaves: utilization of adenosine released from the S-adenosyl-L-methionine cycle. FEBS Lett., 2001, 499, 50-54
[26] Suzuki, T., Ashihara, H., Waller, G. T., Purine and purine alkaloid metabolism in Camellia and Coffea plants. Phytochemistry, 1992, 31, 2575-2584
[27] 曾晓雄，谭淑宜．茶树体内咖啡碱的生物合成．茶叶通讯，1992，4：12-15
[28] Negishi, O., Ozawa, T., Imagawa, H.. Conversion of xanthosinc into caffeine in tea plants. Agric. Biol. Chem. 1985, 49(1): 251-253
[29] Suzuki, T., Ashihara, H., Waller, G. R.. Purine and purine alkaloid metabolism in Camellia and Coffca plants. Phytochemistry, 1992, 31(8): 2575-2584
[30] Ashihara, H., Kubota, H.. Patterns of adenine metabolism and caffeine biosynthesis in different parts of tea seedlings. Physiol. Plant. 1986, 6, 275-281
[31] Fujimori, N., Suzuki, T., Ashihara, H.. Seasonal variations in biosynthetic capacity for the synthesis of caffeine in tea leaves. Phytochemistry, 1991, 30, 2245-2248
[32] Fujimori, N., Ashihara, H.. Adenine metabolism and the synthesis of purine alkaloids in flowers of Camellia plants. Phytochemistry, 1990, 29, 3513-3516
[33] Terrasaki, Y., Suzuki, T., Ashihara, H.. Purine metabolism and the biosynthesis of purine alkaloids in tea fruits during development. Life Sci. Adv. (Plant Physiol.). 1994, 13, 134-142
[34] Kalberer, P.. Breakdown of caffeine in leaves of Coffea Arabica L. Nature, 1965, 205, 597-598
[35] Ito, E. A.. Contribution of purine nucleotide biosynthesis de novo to the formation of caffeine in young tea(Camellia sinensis) leaves. J. Plant Physiol., 1999, 154, 145-151
[36] Ashihara, H., Kato, M., Ye, C. X.. Biosynthesis and metabolism of purine alkaloids in leaves of cocoa tea(Camellia ptilophylla). J. Plant Res., 1998, 111, 599-604.
[37] 张宏达．山茶属植物的系统研究．中山大学学报论丛，1981，1，1-180
[38] 张宏达，叶创兴，张润梅，等．中国发现新的茶叶资源—可可茶，中山大学学报(自然科学版)，1988，3，131-133
[39] 叶创兴，林永成，同海云，等．可可茶嘌呤生物碱的分离和分析．中山大学学报(自然科学版)，1997，36(6)：30-33
[40] 叶创兴，林永成，苏建业，等．苦茶Camellia assamica var．kucha Chang et Wang的嘌呤生物碱．中山大学学报(自然科学版)．1999．38(5)：82-86
[41] Zheng, X. Q., Ye, C. X., Kato, M., et al.. Theacrine (1, 3, 7, 9-tetramethyluric acid) synthesis in leaves of a Chinese tea, kucha(Camellia assamica var. kucha). Phytochemistry, 2002, 60, 129-134.
[42] 孙威江，张翠香．茶资源利用及产品开发现状与趋势．福建茶叶，2004，1，35-37
[43] 许实波，王向谊，郭文成，等．毛叶茶提取物的药理作用．中山大学学报(自然科学版)，1990，29(增刊)，185-190
[44] 许实波，王向谊，郭文成，等．毛叶茶提取物急性毒性、降血脂、降胆固醇和减肥作用的研究．中山大学学报(自然科学版)，1990，29(增刊)，190-194
[45] Lin. J. K., Lin, C. L., Liang, Y. C., et al. Survey of catechins, gallic acid, and methylxanthines in green, oolong, pu-erh, and black teas. J Agric Food Chem. 1998, 46(9): 3635-3642
[46] Shao W, Powell C, Clifford M N. The analysis of HPLC of green, black and Pu'er teas produced in Yunan. J. Sci. Food Agric. 1995, 69(4): 535-540
[47] Yao, L. H., Jiang, Y. M., Datta, N., et al. HPLC analyses of flavanols and phenolic acids in the fresh young shoots of tea(Camellia sinensis) grown in Australia. Food Chem., 2004, 84, 253-263.
[48] Kinugasa, H., Takeo, T., Yano, N.. Differences of flavor components found in green tea canned drinks made from tea leaves plucked on different matured stage. Nippon Shokuhin Kagaku Kogaku Kaishi. 1997, 44 (2): 112-118
[49] Sakata, I., lkeuchi, M., Maruyama, I., et al.. Quantitative analysis of (-)-epigallocatechin gallate in tea leaves by high-performance liquid chromatography. Yakugaku zasshi: J. Pharmac. Soc. Japan. 1991, 111(12): 790-793
[50] Goto, T., Yoshida, Y., Kiso, M., et al. Simutaneous analysis of individuall catechins and caffeine in green tea. J. Chromatogr. A. 1996, 749(2): 295-299
[51] Axel, M., Tharcisse, N., Gunter, H.. Determination of adenine, caffeine, theophylline and theobromine by HPLC with amperometric detection. Fresenius Chin. J. Aria, Chem., 1996, 356, 284-287.
[52] Ye, C. X., Lin, Y. C., Zhou, H. Y., et al. Isolation and analysis of purine alkaloids from Camellia ptilophylla Chang. Acta Scientiarum Naturalium Universitatis Sunyatseni, 1997, 36, 30-33.
[53] Ye, C. X., Lin, Y. C., Su, J. Y., et al. Purine alkaloids in Camellia assamica var. kucha Chang et Wang. Acta Scientiarum Naturalium Universitatis Sunyatseni. 1999, 38, 82-86
[54] 罗龙新．国内外制茶工业多样化产品生产现状及发展趋势(续)．中国茶叶，1998，1，32-33
[55] 叶勇，周军勇，朱伯荣．茶制品去咖啡因方法的比较研究．中国食品添加剂，1999，1，40-42
[56] 叶创兴，郑新强，袁长春，等．无咖啡因茶树新资源可可茶的研究综述．广东农业科学，2001，2，12-15
[57] 张雯洁，刘玉清，李兴从，等．云南“生态茶”的化学成分研究．云南植物研究，1995，17(2)：204-208
[58] Shen, C. C., Chang, Y. S., Hott, L. K.. Nuclear magnetic resonance studies of 5, 7-dihydroxyflavonoids. Phytochemistry, 1993, 34(3): 843-845
[59] Cecile, C. O., Jean-Michel, W., Emmanuel, M., et al. Catechin and epicatechin deprotonation followed by ~(13)C NMR. Tetrahedron Lett. 2002, 43, 4545-4549
[60] 贾志胜，周波，杨立，等．绿茶中茶多酚的2D NMR研究．波谱学杂志，1998，15(1)：23-30
[61] 周志宏，杨崇仁．云南普洱茶原料晒青毛茶的化学成分．云南植物研究，2000，22(3)：343-350
[62] Kyoji, Y., Kenjiro, O., Toshio, M., et al. Inhibitory effects of the C-2 epimeric isomers of tea catechins on mouse type Ⅳ allergy. J. Agri. Food Chem., 2004, 52, 4660-4663
[63] Lee, M. W., Tanaka, T., Nonaka, G. I., et al. Hirsunin, an ellagitannin with a diarylheptanoid moiety, from Alnus hirsute var. microphylla. Phytochemistry, 1992, 31(3): 967-970
[64] Yang, X. F., Fu, H. Z., Lei, H. M., et al. Chemical constituents from the leaves of koelreuteria panichlata Laxm. Acta Pharmaceutica Sinica(药学学报). 1999, 34(6): 457-462
[65] Griffiths, R. R., Evans, S. M., Heishman, S. J., et al. Low-dose caffeine discrimination in humans. J. Pharmacol. Exp. Ther., 1990, 252, 970-978
[66] Silverman, K., Evans, S. M., Strain, E. C., et al. Withdrawal syndrome after the double-blind cessation of caffeine consumption. N. Engl. J. Med., 1994, 327, 1109-1114
[67] Griffiths, R. R., Mumford, G. K.. Caffeine-A drug of abuse? In Psychopharmacology: The Fourth Generation of Progress, Raven Press, New York 1995, pp 1699-1713
[68] Rusted, J.. Caffeine and cognitive performance: effects on mood or mental processing? Pharmacopsychoecologia, 1994, 7, 49-54
[69] Warburton, D. M.. Effects of caffeine on cognition and mood without caffeine abstinence. Psychopharmacol., 1995, 119, 66-70
[70] Smith, A. P., Kendrick, A. M., Maben, A. L.. Effects of breakfast and caffeine on performance and mood in the late morning and after lunch. Neuropsychobiol., 1992, 26, 198-204
[71] Smith, A. P., Brockman, B., Flynn, R., et al. Investigation of the effects of coffee on alertness and performance during the day and night. Neuropsychobiol., 1993, 27, 217-223
[72] Smith, A. P., Thomas, M., Perry, K., et al. Caffeine and the common cold. J. Psychopharmacol., 1997, 11, 319-324
[73] Bonnet, M. H., Gomez, S., Wirth, O., et al. The use of caffeine versus prophylactic naps in sustained performance. Sleep, 1995, 18, 97-104
[74] Loke, W. H., Hinrichs, J. V., Ghoneim, M. M.. Caffeine and diazepam: separate and combined effect on mood, memory, and psychomotor performance. Psychopharmacol., 1985, 87, 344-350
[75] Sicard, B. A., Perault, M. C., Enslen, M., et al. The effects of 600 mg of slow release caffeine on mood and alertness. Aviation, Space, and Environmental Medicine, 1996, 67, 859-862
[76] Green, P. J., Suls, J.. The effects of caffeine on ambulatory blood pressure, heart rate, and mood in coffee drinkers. J. Behavi. Med., 1996, 19, 111-128
[77] Daly, J. W., Padgett, W. L., Secunda, S. I., et al. Structure-activity relationship for 2-substituted adenosines at A1 and A2 adenosine receptors. Pharmacol., 1993, 46, 91-100
[78] Kaplan, G. B., Greenblatt, D. J., Ehrenberg, B. L., et al. Dose-dependent pharmacokinetics and psychomotor effects of caffeine in humans. J. Clin. Pharmacol. 1997, 37, 693-703
[79] Phillis, J. W., Kostopoulos, G. K.. Adenosine as a putative transmitter in the cerebral cortex: Studies with potentiators and antagonists. Life Sci., 1975, 17, 1085-1094
[80] Arushanian, E. B., Belozertsev, Y. B.. The effect of amphetamine and caffeine on neuronal activity in the neocortex of the cat. Neuropharmacol., 1978, 17, 1-6
[81] Dunwiddie, T. V., Hoffer, B. J., Fredholm, B. B.. Alkylxanthines elevate hippocampal excitability. Evidence for a role of endogenous adenosine. Naunyn-Schmiedebergs Arch Pharmacol., 1981, 316, 326-330
[82] Greene, R. W., Haas, H. L., Hermann, A.. Effects of caffeine on hippocampal pyramical cells in vitro. Br. J. Pharmacol., 1985, 85, 163-169
[83] Arai, A., Kessler, M., Lynch, G.. The effects of adenosine on the development of long-term potentiation. Neurosci. Lett., 1990, 119, 41-44
[84] Tanaka, Y., Sakurai, M., Goto, M., et al., Effect of xanthine derivatives on hippocampal long-term potentiation. Brain Res., 1990, 522, 63-68
[85] Zwyghuizen-Doorenbos, A., Roehrs, T. A., Lipschutz, L., et al. Effects of caffeine on alertness. Psychopharmacol., 1990. 100,36-39
[86] Hicks, R. A., Hicks, G. J., Reyes, J. R., et al. Daily caffeine use and the sleep of college students. Bull. Psychonomic Soci., 1983, 21, 24-25
[87] Levy, M., Zylber-Katz, E.. Caffeine metabolism and coffee-attributed sleep disturbances. Clin. Pharmacol. Ther., 1983, 33, 770-775
[88] Smellie, F. W., Davis, C. W., Daly, J. W., et al., Alkylxanthines: Inhibition of adenosine-elicited accumulation of cyclic AMP in brain slices and of brain phosphodiesterase activity. Life Sci., 1979, 24, 2475-2482
[89] Fredholm, B. B.. Are methylxanthine effects due to antagonism of endogenous adenosine? Trends Pharmacol. Sci., 1980, 1, 129-132
[90] McPherson, P. S., Kim, Y. K., Valdivia, H., et al. The brain ryanodine receptor: a caffeine-sensitive calcium release channel. Neuron, 1991, 7, 17-25
[91] Fredholm, B. B.. Adenosine, adenosine receptors and the actions of caffeine. Pharmacol. Toxicol. 1995, 76,93-101
[92] Nehlig, A.. Daval, J. L., Debry, G.. Caffeine and the central nervous system: mechamisms of action, biochemical, metabolic and psychostimulant effects. Brain Res. Rev., 1992, 17, 139-170
[93] Fredholm, B. B., Battig, K., Holmen, J., et al. Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol. Rev., 1999, 51, 83-133
[94] Fredholm, B. B., Abbracchio, M. P., Burnstock, G., et al. Nomenclature and classification of purinoceptors. Pharmacol. Rev., 1994, 46, 143-156
[95] Dunwiddie, T. V., Masino, S. A.. The role and regulation of adenosine in the central nervous system. Annu. Rev. Neurosci., 2001,24, 31-55
[96] Jacobson, K. A.. Adenosine A3 receptors: novel ligands and paradoxical effects. Trends Pharmacol. Sci., 1998, 19, 184-191
[97] Feoktistov, I., Biaggioni, I.. Adenosine A2B receptors. Pharmacol. Rev. 1997,49, 381-402
[98] Dunwiddie, T. V., Diao, L. H.. Extracellular adenosinein hippocampal brain slices and the tonic inhibitory modulation of evoked excitatory responses. Pharmacol. Exp. Ther., 1994, 268, 537-545
[99] Goodman, R. R., Snyder, S. H.. Autoradiographic localization of adenosine receptors in rat brain using [~3H] cyclohexyladenosine. J. Neurosci. 1982, 2, 1230-1241
[100] Fastbom, J., Pazos, A., Palacios, J. M. The distribution of aenosine Al receptors and 5'-nucleotidase in the brain of some commonly used experimental animals. Neurosci., 1987, 22, 813-826
[101] Himmelheber, A. M., Sarter, M., Bruno, J. P.. Increasesin cortical acetylcholine release during sustained attention performance in rats. Cogn. Brain Res., 2000, 9, 313-325
[102] Passetti, F., Dalley, J. W., O'Connell, M. T., et al. Increased acetylcholine release in the rat medial prefrontal cortex during performance of a visual attentional task. Eur. J. Neurosci, 2000, 12 , 3051-3058
[103] Fredholm, B. B.. Activation of adenylate cyclase from rat striatum and tuberculum olfactorium by adenosine. Med. Biol., 1977, 45, 177-181
[104] Premont, J., Perez, M., Blanc, G., et al.. Adenosine-sensitive adenylate syslase in rat brain homogenates: kinetic characteristics, specificity, topographical, subcellular and cellular distribution. Mol. Pharmacol., 1979, 16, 790-804
[105] Gerfen, C. R.. The neostriatal mosaic: multiple levels of compartmental organiza-tion in the basal ganglia. Ann. Rev. Neurosci., 1992, 15, 285-320
[106] Sergi, F., Bertil, B. F., Micaela, M., et al. Adenosine-dopamine recetptor-receptor interactions as an integrative mechanism in the basal ganglia. Trends neurosci, 1997, 20, 482-487
[107] Thompson, W. R.. Influence of prenatal maternal anxiety on emotionality in young rats. Science. 1957, 125(3250), 698-699
[108] Amos, S., Kolawole, E., Akah, P., Wambebe, C., Gamaniel, K.. Behavioral effects of the aqueous extract of Guiera senegalensis in mice and rats. Phytomed., 2001, 8(5), 356-361
[109] Porsolt, R. D., Antin, G., Blavet, N., et al. Behavioral despair in rats: a new model sensitive to antidepressant treatments. Eur. J. Pharmacol., 1978, 47, 379-391
[110] Siuciak, J. A., Lewis, D. R., Wiegand, S. J., et al. Antidepressant-like effect of brain-derived neurotrophic factor(BDNF). Pharmacol. Biochem. Behav., 1997, 56, 131-137
[111] Yang, J. Y., Wu, C. F., Song, H. R.. Studies on the sedative and hypnotic effects of Oleamide in mice. Arzneim-Forsch., 1999, 49, 663-667
[112] 张垒，张均田．学习、记忆的实验方法和记忆障碍模型．药学通报，1988，23(8)：475-477
[113] 陈奇主编．中药药理研究方法学．人民卫生出版社．1993，894-895
[114] Morris, R. G. M., Garrud, P., Rawlins, J. N. P., et al. Place navigation impaired in rats with hippocampal lesions. Nature, 1982, 297, 681-683
[115] Morris, R.. Developments of a water-maze procedure for studing spatial learning in the rat. J. Neurosci. Methods., 1984, 11, 47-60
[116] MoNamara, R. K., Skelton, R. W.. The neuropharamacological and neurochemical basis of place learning in the Morris water maze. Brain. Res. Rev., 1993, 18, 33-49
[117] Sapolsky, R. M.. Why stress is bad for your brain. Science, 1996, 273(5276): 749-50
[118] Oitzl, M. S., Mulder, M., Lucassen, P. I., et al. Severe learning deficits in apolipoprotein E-knockout mice in a water maze task. Brain Res., 1997, 752(1-2): 189-196
[119] Himori, N., Tanaka, Y., Kurasawa, M., et al. Dextrophan attenuates the behavioral consequences of ischemia and the biochemical consequences of anoxia: possible role of N-methyl-d-aspartate receptor antagonist and ATP replenishing action in its cerebroprotecting profile. Psychopharmacol., 1993, 111(2): 153-162
[120] Youngblood, B. D., Zhou, J., Smagin, G. N., et al. Sleep deprivation by the 'flower pot' technique and spatial reference memory. Physiol. Behav., 1997, 61(2): 249-56
[121] D'Hooge, R., De Deyn, P. P.. Applications of the Morris water maze in the study of learning and memory. Brain. Res. Rev., 2001, 136(1): 60-90
[122] Petrie, B. F., Pinsky, C., Standish, N. M., et al. Parenteral domoic acid impairs spatial learning in mice. Pharmacol. Biochem. Behav., 1991, 41, 211-214
[123] Brioni, J. D., Arolfo, M. P.. Diazepam impairs retention of spatial information without affecting retrieval or cue learning. Pharmcol. Biochem. Behav., 1991, 41, 1-5
[124] Oritz J., Fitagerald L. W., Lane S., et al. Biochemical adaptations in the mesolimbic dopamine system in response to repeated stress. Neurochopharmacol., 1996, 14, 443-452
[125] Masashi, N., Michihiro, T., David, S., et al. Repeated stress increases catalytic TrkB mRNA in rat hippocampus. Neurosc., 1999, 267, 81-84
[126] 严灿，邓中炎，王剑．调肝方对慢性束缚应激大鼠神经内分泌免疫功能的影响．中国免疫学杂志，2000，16，488
[127] Maryam, A. -M., Arturo, C., Mohammed K.. Repeated immobilization stress increases total cytosoli glucocorticiod receptor in rat liver. Steriod, 2000, 65, 8-15
[128] Karp, J. D., Smith, J., Hawk, K.. Restraint stress augments antibody production in cyclophosphamide-treated mice. Physiol. Behave. 2000, 70(3-4): 271-278
[129] Isobe, H., Okajima, K., Harada, N., et al. Activated protein C reduces stress-induced gastricmucosal injury in rats by inhibiting the endothelial cell injury. J. Thromb. Haemost., 2004, 2(2): 313-320
[130] 徐菲菲，程罡，周晓棉，等．吡拉西坦对水浸-束缚应激大鼠脑内单胺类递质含量的影响．沈阳药科大学学报，2001，18(9)：366-369
[131] Hall, J. R., Hanford, P. V.. Activity as a function ofa retricted feeding schedule. J. Comp. Physiol. Psychol., 1954, 47, 362-363
[132] Aitemus, M., Glowa, J. R., Galliven E., et al. Effects of serotonergic agents on food-restriction-induced hyperactivity. Pharmacol. Biochem. Behav., 1996, 53, 123-131
[133] Morrow, N. S., Schall, M., Grijalva, C. V., et al. Body temperature and wheel running predict survival times in rats exposed to activity-stress. Physio. Behav., 1997, 62, 815-825
[134] Iwamoto, I., Nishihara, M., Takahashi, M.. VMH lesions reduce excessive running under the activity-stress paradigm in the rats. Physiol. Behav., 1999, 66, 803-808
[135] Endou, M., Yanai, K., Sakurai, E., et al. Food-deprived activity stress decreased the activity of the histaminergic neuron system in rats. Brain Res., 2001, 891, 32-41
[136] Lamber, K. G., Kinsley, C. H., Jones, H. E., et al. Prenatal stress attenuates ulceration in the activity stress paradigm. Physiol. Behav., 1995, 57, 989-994
[137] Nomura, K., Kaeda, N., Yoshino, T., Yamaguchi, I.. Different mechanisms mediated by dopamine D1 and D2 receptors are involved etiologically in activity-stress gastric lesion of the rat. J. Pharmacol. Exp. Ther., 1995, 273, 1001-1007
[138] Epling, W. F., Pierce, W. D., Stefan, L.. A theory of activity-based anorexia. Int. J. Eat. Disord., 1983, 3, 27-46
[139] Aravich, P. E, Rieg, T. S., Lauterio, T. J., et al. β-Endorphin and dynorphin abnormalities in rats subjected to exercise and restricted feeding: relationship to anorexia nervosa?. Brain Res., 1993, 622 (1-2): 1-8
[140] Beneke, W. M., Schulte, S. E., vander Tuig, J. G.. An analysis of excessive running in the development of activity anorexia. Physiol. Behav., 1995, 58(3): 451-457
[141] Watanabe, K., Hara, C., Ogawa, N.. Feeding conditions and estrous cycle of female rats under the activity-stress procedure from aspects of anorexia nervosa. Physiol. Behav., 1992, 51, 827-832
[142] Marazziti, D., Presta, S., Pfanner, C., et al. Immunological alterations in adult obsessive-compulsive disorder. Biol. Psychiatry, 1999, 46(6): 810-814
[143] Hirano, M., Tanaka, M., Emoto, H., et al. Recovery from activity-stress ulcer by ad lib feeding in rats. Physiol. Behav., 1998, 63, 85-89
[144] Lambert, K. G, Porter, J. H.. Pimozide mitigates excessive running in activity-stress paradigm. Physiol. Behav., 1992, 52, 299-304
[145] Rubenstein, C., Pigott, T., L'., Heureux, F., et al. A preliminary investigation of the lifetime prevalence of anorexia and bulimia nervosa in patients with obsessive-compulsive disorder. J. Clin. Psychiatry., 1993, 53, 309-314
[146] Altemus, M., Pigott, T., Kalogeras, K., et al. Abnormality in the regulation of vasopressin and corticotrophin releasing factor secretion in obsessive-compulsive disorder. Arch. Gen. Psychiatry., 1992, 49, 9-20
[147] Kaye, W., Weltzin, T., Hsu, L., Bulik, C., McConaha, C., Sobkiewicz, T.. Patients with anorexia nervosa have elevated scores on the Yale-Brown Obsessive-Compulsive Scale. Int. J. Eat. Disord., 1992
[148] Boer, D. P., Epling, W. F., Pierce, W. D., et al.. Suppression of food deprivation-induced high-rate wheel running in rats. Physiol. Behav., 1990, 48(2): 339-342
[149] Narita, K., Yokawa, T., Nishihara, M., et al. Interaction between excitatory and inhibitory amino acids in the ventromedial nucleus of the hypothalamus in inducing hyper-running. Brain Res., 1993, 603(2): 243-247
[150] Yokawa, T., Mitsushima, D., Itoh, C., et al. The ventromedial nucleus of the hypothalamus outputs long-lasting running in rats. Physiol. Behav., 1989, 46(4): 713-717
[151] Yokawa, T., Shiota, K., Takahashi, M.. Hyper-running activity originating from the hypothalamus is blocked by GABA. Physiol. Behav., 1990, 47(6): 1261-1264
[152] Kaplan, G. B., Greenblatt, D. J., Ledue, B. W., et al. Relationship of plasma and brain concentrations of caffeine and metabolites to benzodiazepine receptor binding and locomotor activity. J. Pharmacol. Exp. Ther., 1989, 248, 1078-1083
[153] Amaud, M. J., Nestle, R. C., Nestec, L., et al. The pharmacology of caffeine. Progr. Drug Res., 1987, 31, 273-313
[154] Shen, Z., Wang, G., Lin, S. Z.. Two-way shuttle box avoidance conditioning and brain NADH in rats. Physiol. and Behav., 1990, 48, 515-517
[155] Kaplan, G. B., Tai, N. T., Greenblatt, D. J., et al. Caffeine-induced behavioural stimulation is dose-and concentration-dependent. Br. J. Pharmacol. 1990, 100, 435-40
[156] Foreman, N., Barraclough, S., Moore, C., et al. High doses of caffeine impair performance of a numerical version of the stroop task in men. Pharmacol. Biochem. Behav., 1989, 32, 399-403
[157] Chou, C. C., Thomas, BVSc., Vickroy, W.. Antagonism of adenosine receptors by caffeine and caffeine metabolites in equine forebrain tissues. Am. J. Veterinary Res., 2003, 64(2): 216-224
[158] Palma, B. D., Suchecki, D., and Tufik, S.. Differential effects of acute cold and footshock on the sleep of rats. Brain Res., 2000, 861, 97-104
[159] Marinesco, S., Bonnet, C., Cespuglio, R.. Influence of stress duration on the sleep rebound induced by immobilization in the rat: a possible role for corticosterone. Neurosci., 1999, 92, 921-933
[160] Kant, G. J., Pastel, R. H., Bauman, R. A., et al. Effects of chronic stress on sleep in rats. Physiol. Behav., 1995, 57, 359-365
[161] Rampin, C., Deminiere, J. M., Le Moal, M., et al. Factors that predict individual vulnerability to amphetamine selfadministration. Science, 1989, 245, 1511-1513
[162] Shouse, M. N., Staba, R. J., Saquib, S. F. et al. Monoamines and sleep: microdialysis findings in pons and amygdala. Brain Res., 2000, 860 (1, 2): 181-189
[163] Wardas, J.. Neuroprotective role of adenosine in the CNS. Pol. J. Pharmacol., 2002, 54, 313-326
[164] Fredholm, B. B., Battig, K., Holmen, J., et al. Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol. Rev., 1999, 51, 83-133
[165] Snyder, S. H., Katims, J. J., Annau, Z., et al. Adenosine receptors and behavioral actions of methylxanthines. Proc. Natl. Acad. Sci. USA., 1981, 78, 3260-3264
[166] Daly, J. W., Butts-Lamb, P., Padjett, W.. Subclasses of adenosine receptors in the central nervous system: interaction with caffeine and related methylxanthines. Cell & Mol. Neurobiol., 1983, 3, 69-80
[167] Wei, Q.. Foreland of Pharmacology—Signal, Protein, Gene and Modem Pharmacology (药理学前沿——信号、蛋白因子、基因与现代药理). Beijing: Science Publishing House. 1999, 510
[168] McGaugh, J. L.. Drug facilitation of learning and memory. Ann. Rev. Pharmacol. 1973, 13, 229-241
[169] Gandhi, C. C., Kellyl, R. M., Wiley, R. G., et al. Impaired acquisition of a Morris water maze task following selective destruction of cerebellar purkinje cells with OX7-saporin. Behav. Brain. Res., 2000, 109, 37-47
[170] de Quervain, D. J., Roozendaal, B., McGaugh, J. L.. Stress and glucocorticoids impair retrieval of long-term spatial memory. Nature, 1998, 394, 787-790
[171] Lupien, S. J., de Leon, M., de Santi, S., et al.. Cortisol levels during human aging predict hippocampal atrophy and memory deficits. Nature Neurosci., 1998, 1, 69-73
[172] Lupien, S. J., McEwen, B. S.. The acute effects of corticosteroids on cognition: integration of animal and human model studies. Brain Res. Brain Res. Rev., 1997, 24(1): 1-27
[173] Ohl, F., Fuchs, E.. Differential effects of chronic stress on memory processes in the tree shrew. Brain Res. Cogn. Brain Res., 1999, 7, 379-387
[174] Bowman, R. E., Zrull, M. C., Luine, V. N.. Chronic restraint stress enhances radial arm maze performance in female rats. Brain Res., 2001, 904, 279-289
[175] Bowman, R. E., Beck, K. D., Luine, V. N.. Chronic stress effects on memory: sex differences in performance and monoarninergic activity. Horm. Behav., 2003, 43, 48-59
[176] Conrad, C. D., LeDoux, J. E., Magarinos, A. M., et al. Repeated restraint stress facilitates fear conditioning independently of causing hippocampal CA3 dendritic atrophy. Behav. Neurosci., 1999, 113, 902-913
[177] Luine, V., Villegas, M., Martinez, C., et al. Restraint stress causes reversible impairments of spatial memory performance. Brain Res., 1994, 639(1): 167-170
[178] McEwen, B. S.. Stress and hippocampal plasticity. Annu. Rev. Neurosci. 1999, 22, 105-122
[179] Conrad, C. D., Grote, K. R., Hobbs, R. J., et al. Sex differences in spatial and non-spatial Y-maze performance after chronic stress. Neurobiol. Learn Mere., 2003, 79, 32-40
[180] Handa, R. J., Hayaski, S., Terasawas, E., et al. Neuroplasticity, Development and Steroid Hormone Action. CRC Press, Boca Raton, FL, 2001, 202-269
[181] Kim, J. J., Yoon, K. S.. Stress: metaplastic effects in the hippocampus. Trends Neurosci., 1998, 21(2): 505-509
[182] Pavlides, C., Ogawa, S.. Role of adrenal steroid mineralocorticoid and glucocorticoid receptors in long-term potentiation in the CA1 field ofhippocampal slices. Brain Res., 1996, 738(2): 229-35
[183] Bremmer, J. D.. Does stress damage the brain? Biol. Psychiatry, 1999, 45: 797～805
[184] Zhang, Y. M., Yang, Q., Xu, C. T., et al. Effects of phenytoin on morphology and structure of hippocampal CA3 pyramidal neurons of rats in chronic stress. Acta Pharmacol. Sin. 2003, 24, 403-407
[185] Stein-Behrens, B., Mattson, M. P., Chang, I., et al. Stress exacerbates neuron loss and cytoskeletal pathology in the hippocampus. J. Neurosci., 1944, 14, 5373-538
[186] Sandi, C.. The role and mechanisms of action of glucocorticoid involvement in memory storage. Neural. Plast., 1998, 6, 41-52
[187] Pereira, G. S., Mello e Souza, T., Vinade, ERC., et al. Blockade of adenosine A1 receptors in the posterior cingulated cortex facilitates memory in rats. Eur. J. Pharmacol. 2002, 434(3): 151-154
[188] Sun, M. K., Xu, H., Alkon, D. L.. Pharmacological protection of synaptic function spatial learning and memory from transient hypoxia in rats. J. Pharmacol. Exp. Ther., 2002, 300(2): 408-416
[189] 张丹参，任雷鸣．腺苷A1受体阻断剂对学习记忆的影响及机制分析．药学学报，2003，38(6)：416-419
[190] 张丹参，任雷鸣，张力．腺苷A1受体阻断剂对学习记忆的影响与胆碱能神经的关系．中国药科大学学报，2006，37(1)：63-66
[191] 李艳，严灿，史亚飞，等．反复心理应激大鼠血浆和下丘脑单胺神经递质的变化及加味四逆散 的影响．中药药理与监床，2002．18(1)：1-3
[192] Pincomb, G. A., Lovallo, W. R., McKey, B. S., et al. Acute blood pressure elevations with caffeine in men with borderline systemic hypertension. Am. J. Cardiol., 1996, 77, 270-274
[193] Lovalio, W. R., Al'absi, M., Pincomb, G. A.. Caffeine raises blood pressure duringextended mental stress in borderline hypertensive men. Int. J. Behav. Med., 2000, 7, 183-188
[194] Al'absi, M., Lovallo, W. R.. Caffeine effects on the human stress axis. In: Nehlig A, ed. Coffee, Tea, Chocolate and the Brain. Boca Raton, FL: CRC Press LLC. 2004, 113-131
[195] Chae, H. D., Kyong, T. K.. Stimulation of A_(2A) Adenosine receptor increase expression of the tyrosine hydroxylase gene. Mol. Brain Res., 1997, 44, 31-38
[196] Ribeiro, J. A.. Adenosine A_(2A) receptor interactions with receptors for other neurotr-ansmitters and neuromodulators. Eur. J. Pharmocol., 1999, 375, 101-113
[197] Nyce, J. W. Insight into adenosine receptor function using antisense and genekno-ckout approaches. Tips, 1999, 20, 79-83
[198] Lopes, L. V, Cunha, R. A., Kull, B., et al. Adeonosine A_(2A) receptor faci-litation of hippocampal synaptic transmission is dependent on tonic A_1 receptor inhibition. Neurosci., 2002, 112, 319-329
[199] Sevenngsson, P., Moine, C. L., Fisone, G., et al. Distribution, biochemistry, and function of striatal adenosine A_(2A) receptors. Prog. in Neurobiol., 1999, 59, 355-369
[200] Garrett, B. E., Griffiths, P. R.. The role of dopamine in the behavioral effects of caffeine in animal and humans. Pharmacol. Biochem. Behav., 1997, 57, 533-541
[201] Barnes, N. M., Costall, B., et al. 5-Hydroxytryptamine and Dopamine metablism in the rat brian. Pharmacol. Biochem. Behav., 1997, 58(3): 775-783
[202] 马文涛，杨来启，武胜昔，等．急性应激对大鼠脑内5-HT_(1A)受体mRNA表达的影响．中国神经精神疾病杂志，2002，28(6)：454-455
[203] 吴兴曲，杨来启，王晓峰，等．约束应激对5-HT_(1A)和5-HT_(2A)受体表达的影响．中国临床心理学杂志，2003，11(3)：225-227
[204] Lim, B. V., Jang, M. H., Shin, M. C., et al. Caffeine inhibits exercise-induced increase in tryptophan hydroxylase expression in dorsal and median raphe of SD rats. Neurosci. Lett., 2001, 308(1): 25-28
[205] Katz, J. L., Long-distance running, anorexia nervosa, and bulimia: a report of two cases. Comp Psychiatry., 1986, 27, 74-78.
[206] Boyar, R. M., Heilman, L. D., Roffwarg, H., et al. Cortisol secretion and metabolism in anorexia nervosa. New England J. Med., 1977, 296(4): 190-193
[207] Gold, P. W., Gwirtsman, H., Avgerinos, P. C., et al. +Abnormal hypothalamic-pituitary-adrenal function in anorexia nervosa. Pathophysiologic mechanisms in underweight and weight-corrected patients. New England J. Med., 1986, 314(21): 1335-1342
[208] Counts, D. R., Gwirtsman, H., Carlsson, L. M., The effect of anorexia nervosa and refeeding on growth hormone-binding protein, the insulin-like growth factors(IGFs), and the IGF-binding proteins. J. Clin. Endocrind. Metab. 1992, 75(3): 762
[209] Gold, P., Kaye, W., Robertson, G., Ebert, M.. Abnormalities in plasma and cerebrospinal fluid arginine vasopressin in patients with anorexia nervosa. N. Engl. J. Med., 1983, 308, 1117-1123
[210] Hotta, M., Shibasaki, T., Masuda, A., et al. The response of plasma adrenocorticotropin and cortisol to corticotrophin-releasing hormone(CRH) and cerebrospinal fluid immonoreactivity CRH in anorexia nervosa patients. J. Clin. Endocrinol. Metab., 1986, 62, 319-324
[211] Surguladze, S., Russell, T., Kucharska-Pietura, K., et al. A reversal of the normal pattern of parahippocampal response to neutral and fearful faces is associated with reality distortion in schizaphrenia. Biol. Psychiatry, 2006, 65(5): 423-431
[212] Goodman, W. K., McDougle, C. J., Price, L. H.. Pharmacotherapy of obsessive-compulsive disorder. J. Clin. Psychiatry, 1992, 53, 29-37