论著
神经类固醇在阿普唑仑抗大鼠焦虑样行为效应中的作用研究
梁钰华 黎少英 陈淑华
【摘要】 【摘要】目的 在本研究中,我们通过行为学实验检测阿普唑仑抗大鼠的焦虑行为与部分脑区(如海马体和前额皮层)中神经类固醇(如四氢孕酮,孕酮和孕烯醇酮)水平的联系。方法 在本研究中,我们采用动物为SD大鼠,应用阿普唑仑对大鼠进行腹腔给药(剂量为0.5,1,2 mg/kg)。给药7日以后,每只大鼠分别通过一系列行为学实验进行研究,如在第8日进行大鼠Vogel饮水冲突实验,在第10日进行高架十字迷宫实验,在第12日进行开场实验。研究过程中,相关实验的检测指标如下:
【关键字】 阿普唑仑,焦虑症,行为学,四氢孕酮,孕酮,孕烯醇酮
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[Abstract] Objective In the present study, we examined the association of anxiety behavior of apazolam-resistant rats with levels of neurosteroids (e.g., allopregnanolone, progesterone, and progesterone) in some brain regions (e.g., hippocampus and prefrontal cortex) through behavioral experiments. Methods In this study, we used SD rats as animals, and applied alprazolam to rats for intraperitoneal administration (dose of 0.5, 1, 2 mg/kg). After 7 days of administration, each rat was studied through a series of behavioral experiments, such as Vogel drinking water conflict experiment on the 8th day, elevated cross maze experiment on the 10th day and opening experiment on the 12th day. In the research process, the detection indicators of relevant experiments are as follows: in the Vogel drinking water conflict experiment of rats, the number of licking in 3 min was detected; in the elevated cross maze experiment, the total number of times of entering the arm, the time of entering the arm, the number of times of entering the arm and the time of staying in the arm were detected respectively in 5 min; in the opening experiment, the number of fecal particles, the number of cross lattice and the number of standing were detected respectively in 5 min. After the completion of all behavioral experiments, we further explored the mechanism of alprazolam's anti anxiety behavior at the histological level. We extract brain regions (such as the hippocampus and prefrontal cortex) that are associated with anxiety. Then, enzyme-linked immunosorbent assay (ELISA) was used to evaluate the changes of the levels of neurosteroids (such as allopregnanolone, progesterone and pregnenolone) in the above brain regions. Results In the Vogel drinking water conflict experiment, the number of licking was significantly increased after alprazolam (1 and 2 mg/kg) treatment; in the elevated plus maze experiment, the number of arm opening entry and arm opening dwell time were significantly increased after alprazolam (1 and 2 mg/kg) treatment. However, there was no significant change in the total number of entering arms and the total time of entering arms. In the opening experiment, the number of fecal pellets, the number of crossings and rears were not affected by alprazolam treatment. In the aspect of mechanism research, the levels of progesterone and allopregnanolone in hippocampus and prefrontal cortex of rats increased significantly in the dose range of alprazolam (1 and 2 mg / kg), while the levels of pregnenolone did not change significantly. Conclusion The antianxiety effects of alprazolam in rats were related to the increase of allopregnanolone and progesterone levels in hippocampus and prefrontal cortex.
焦虑症是一种社会性精神性障碍疾病。其发病影响着发病者的日常行为,目前,该疾病已成为全球关注和研究的精神性卫生难题。流行病学分析显示全球患者中约有20%的患者可能终身性患有焦虑症。焦虑症患者主要有以下症状,如神经失常和不安,机体方面可能有自主性肌肉紧张等。其发病给国家,家庭和个人都带来极大的负面影响[1-2]。据此,焦虑症的研究和治疗收到越来越多学者的关注。
目前尚未明确焦虑症的发病机制,研究显示焦虑症的发病涉及多种因素。其中传统研究的影响因素为脑区单胺功能和水平的紊乱。而在单胺递质系统中,去甲肾上腺素,多巴胺,5-羟色胺(serotonin,5-HT)等递质水平的异常是焦虑的发病机制重要影响因素[3]。根据焦虑症的发病机制,5-HT再摄取抑制剂是临床上常用的抗焦虑药物之一,具体代表药有舍曲林和帕罗西汀等[4]。该类药物的作用机制是通过作用于机体中5-HT受体,使5-HT水平正常化而产生抗焦虑作用。然而,5-HT再摄取抑制剂在临床上抗焦虑须慎用,这体现在其具有起效较慢,有效率不高,可导致服用者自杀倾向等毒副作用[5]。根据以上该类药物在临床使用中的种种不足,挖掘强效低毒的抗焦虑药物对临床防治焦虑症具有重要意义。
研究显示神经类固醇与焦虑症的发病有关,其体现在焦虑症患者中,部分脑区(如前额平层和海马体)的神经类固醇(如四氢孕酮,孕酮和孕烯醇酮等)水平的紊乱可能导致焦虑症的发生[6]。而神经类固醇水平的正常化具有显著的抗精神性疾病的作用,如抗惊恐,抗应激,抗抑郁,抗焦虑等。其作用靶点是γ-氨基丁酸(γ-aminobutyric acid,GABA)受体。阿普唑仑是传统的抗焦虑药物,其起效途径是作用于GABAA受体,提高GABA能中神经传递和突触后抑制作用,使脑区多巴胺的释放降低。然而,阿普唑仑的作用途径是否与神经类固醇有联系还在研究。而本研究也尝试通过动物行为学实验,评价神经类固醇(如四氢孕酮,孕酮和孕烯醇酮)在阿普唑仑抗焦虑效应中所扮演的角色。