高剂量长时程金刚烷胺对小鼠行为学和脑内c-Fos表达的影响  

Ethological changes and the expression of c - Fos in mice brain induced by amantadine of high dose and long - term

作　　者：刘阳[1,2] 宋亮[3] 吴宇[1] 陈幽婷[3] 王德广[3] 马传响[3] 

机构地区：[1]徐州医学院神经生物学实验室,江苏徐州221002 [2]常州卫生高等职业技术学校,江苏常州213002 [3]徐州医学院解剖学教研室

出　　处：《徐州医学院学报》2012年第5期290-294,共5页Acta Academiae Medicinae Xuzhou

基　　金：基金项目：徐州市科技计划项目（XM07C057）

摘　　要：目的 探讨临床高剂量长时程使用金刚烷胺 （amantadine,AMA） 治疗疾病时导致患者出现精神症状副作用的中枢机制.方法 雄性昆明小鼠,随机分成对照组和AMA组（每组n=20）.AMA组小鼠腹腔注射高剂量金刚烷胺 （60 mg/kg,qd×10天）,对照组小鼠注射等量生理盐水.在第9 天注射后20 min,分别用Sams-Dodd的刻板行为评分、自主活动观察和一次性被动回避反应 （OPAR） 对2组小鼠的行为学进行检测;在第10 天注射后2 h,用免疫组织化学法检测2组小鼠脑内c-Fos蛋白的表达.结果 ①AMA组小鼠刻板行为评分明显高于对照组 （P〈0.01）,尤以头部的背腹方向运动增多显著;②AMA组小鼠的自主行为活动明显少于对照组（P〈0.01）;③ AMA组小鼠的记忆能力较对照组明显下降（P〈0.01）;④AMA组小鼠在边缘皮质、海马、基底前脑、间脑的中线核和板内核、脑桥基底部以及延髓的外侧网状核等脑区c-Fos蛋白的表达数量明显高于对照组.结论 ①高剂量长时程AMA可致小鼠出现明显的精神分裂症样行为学变化,并影响了学习记忆功能;②与精神行为、情绪和内脏活动密切相关的前额皮质、扣带皮质、海马、杏仁核和隔外侧核等脑区的神经元功能活动明显改变,可能是高剂量长时程AMA导致出现精神病样副作用的解剖学基础.Objective To evaluate the underlying mechanisms of the side effets of psychiatric symptoms induced by high dose and long - term amantadine in clinical treatment of diseases. Methods Male Kunming mice were divided into normal saline group （0.9% NaC1, i.p. , qd × 10 d） and AMA group （60 mg/kg, i. p. , qd × 10 d） at random （n = 20 each） , and their ethological changes were determined by Sams -Dodd stereotyped behavior scores, spontaneous activity observation and once passive avoidance response （OPAR） respectively in 20 minutes after the injection on the 9th day. Meanwhile, immunohistochemical method was used to detect and evaluate the expression of c - Fos in mice brain of the two groups at 2 hours after the injection on the 10th day. Results （2） Compared with normal saline group, the scores of stereotyped behaviors of AMA group were significantly increased particularly in dorsal - ventral movement of head （ P 〈 0. 01 ）. （2） The spontaneous activities of AMA group of mice were significantly less than normal saline group （P 〈 0.01 ）. （3） Memory ability of AMA group of mice declined in OPAR （ P 〈 0.01 ）. （4） c - Fos positive neurons of AMA groups were obviously more than normal saline group in limbic cortex, hippocampus, basal forebrain, diencephalic midline nu- clear group and intralaminar nuclear group, basilar part of pons and oblongatal lateral reticular nucleus. Conclusion （1） High dose and long - term of amantadine can induce schizophrenia - like behavioral changes in mice, and affect learning and memory function ; （2） The functional activity of neurons apparently change in prefrontal cortex, cingulate cortex, hippocampus, amygdala and lateral septal necleus that is closely related to the psychoactivity, emotions and visceral motility. That may be the anatomical basis of psychiatric - like side effects induced by high dose and long - term of amantadine.

关 键 词：金刚烷胺 精神症状 行为学 脑 C-FOS 小鼠 

分 类 号：R749.38[医药卫生—神经病学与精神病学]