【摘要】：研究目的:青春期抑郁癥具有其特殊性,青春期前男孩和女孩的抑郁癥發(fā)病率無明顯差別;但進(jìn)入青春期后,女孩抑郁癥發(fā)病率急劇增加,約為男孩發(fā)病的2-3倍。但目前抑郁癥的研究多集中于成年人群和雄性嚙齒類動物,針對青春期女性抑郁癥的相關(guān)研究尚不豐富,探討青春期女性抑郁癥的有效防治途徑具有深遠(yuǎn)的學(xué)術(shù)意義與臨床價值。本論文在制備青春期雌性小鼠抑郁模型基礎(chǔ)上,應(yīng)用具有快速抗抑郁效果的氯胺酮和GLYX-13兩種藥物,通過行為學(xué)研究觀察對青春期雌性抑郁小鼠的抑郁樣行為和空間記憶能力的改善作用。研究方法:1.建立青春期雌性小鼠抑郁模型C57BL/6J 18天雌性、雄性小鼠各16只,分別隨機(jī)分為:雌性對照組、雌性模型組、雄性對照組和雌性模型組,每組各8只。采用慢性輕度不可預(yù)知應(yīng)激模型(chronic unpredictable mild stress,CUMS)方法建立抑郁模型,采用水平震蕩、束縛、噪聲、禁食、禁水、晝夜顛倒、潮濕墊料、空籠飼養(yǎng)、傾斜鼠籠、陌生鼠籠等10種應(yīng)激源,模型組每天隨機(jī)不重復(fù)給予2種應(yīng)激持續(xù)3周,且程度不同的應(yīng)激源每周相應(yīng)增加。3周期間每天觀察青春期雌性小鼠的陰道口開放狀態(tài),3周后觀察比較4組小鼠的體質(zhì)量變化、糖水偏愛測試的糖水消耗百分?jǐn)?shù)、曠場實驗中的自主活動能力、運動距離和中央?yún)^(qū)時間、高架十字迷宮實驗的開放臂時間、懸尾實驗和強(qiáng)迫游泳實驗的不動時間來判斷是否出現(xiàn)抑郁樣行為。2.氯胺酮和GLYX-13對青春期雌性小鼠抑郁樣行為的藥物干預(yù)C57BL/6J 18天雌性小鼠39只,隨機(jī)分為生理鹽水對照組(Con+NS)、生理鹽水模型組(CUMS+NS)、氯胺酮對照組(Con+Ket)、氯胺酮干預(yù)組(CUMS+Ket)、GLYX-13對照組(Con+GLYX-13)和GLYX-13干預(yù)組(CUMS+GLYX-13)6組,對照組每組各6只,模型組和干預(yù)組每組各7只。比較制備3周CUMS后,各組小鼠藥物干預(yù)前后的自由活動能力。通過各組小鼠曠場實驗的運動距離和中央?yún)^(qū)時間、高架十字迷宮實驗的開放臂時間、懸尾和強(qiáng)迫游泳實驗的不動時間判斷是否表現(xiàn)抑郁樣行為。通過抑郁樣行為的改善程度比較造模后藥物干預(yù)前后各模型組小鼠的變化情況。3.青春期雌性抑郁小鼠空間記憶能力的研究主動逃避實驗可以通過小鼠在轉(zhuǎn)盤上的行為表現(xiàn)探索空間記憶能力、認(rèn)知協(xié)調(diào)能力和認(rèn)知靈活性。實驗動物分組同上2中所述,通過各組小鼠主動逃避實驗的運動軌跡、第一次進(jìn)入帶電區(qū)域的時間和進(jìn)入帶電區(qū)域的次數(shù)來判斷小鼠的空間記憶能力。通過空間記憶能力的提高程度比較造模后藥物干預(yù)前后各模型組小鼠的改善效果。研究結(jié)果:1.3周CUMS后,雌性模型組較雌性對照組的自主活動能力下降,體質(zhì)量變化、糖水消耗百分?jǐn)?shù)、運動距離、中央?yún)^(qū)時間、開放臂時間、懸尾和強(qiáng)迫游泳不動時間均有不同程度的統(tǒng)計學(xué)意義(P0.05或P0.01或P0.001);雄性模型組較雄性對照組的體質(zhì)量變化、糖水消耗百分?jǐn)?shù)、運動距離、中央?yún)^(qū)時間、強(qiáng)迫游泳不動時間均有不同程度的統(tǒng)計學(xué)意義(P0.05或P0.01或P0.001);雌性模型組較雄性模型組的自主活動能力下降更明顯,其運動距離、開放臂時間、懸尾和強(qiáng)迫游泳不動時間均有不同程度的統(tǒng)計學(xué)意義(P0.05或P0.01)。2.3周CUMS后,各模型組較相應(yīng)對照組的自主活動能力均下降,糖水偏愛測試、曠場實驗、高架十字迷宮實驗、懸尾實驗和強(qiáng)迫游泳實驗等各項行為學(xué)實驗結(jié)果有統(tǒng)計學(xué)意義(P0.05)。給藥后,氯胺酮干預(yù)組和GLYX-13干預(yù)組的自主活動能力均較給藥前改善,氯胺酮干預(yù)組與氯胺酮對照組的自主活動能力無明顯差異。氯胺酮干預(yù)組和GLYX-13干預(yù)組與各對照組比較各項結(jié)果均無統(tǒng)計學(xué)意義(P0.05);氯胺酮干預(yù)組較生理鹽水模型組的運動距離和懸尾不動時間有統(tǒng)計學(xué)意義(P0.05);GLYX-13干預(yù)組較生理鹽水模型組強(qiáng)迫游泳不動時間有統(tǒng)計學(xué)意義(P0.05)。3.3周CUMS后,主動逃避實驗中,Trial 1的運動軌跡顯示,模型組較相應(yīng)對照組空間記憶能力下降。Trial 3各模型組較生理鹽水對照組第一次進(jìn)入帶電區(qū)域的時間縮短有統(tǒng)計學(xué)意義(P0.05);Trial 6生理鹽水模型組和GLYX-13干預(yù)組較不同對照組進(jìn)入帶電區(qū)域的次數(shù)有不同程度的統(tǒng)計學(xué)意義(P0.05或P0.01)。給藥后,Trial 1的運動軌跡顯示,氯胺酮干預(yù)組和GLYX-13干預(yù)組的空間記憶能力改善不明顯。Trial 1氯胺酮干預(yù)組較生理鹽水模型組和GLYX-13干預(yù)組第一次進(jìn)入帶電區(qū)域的時間延長有統(tǒng)計學(xué)意義(P0.05或P0.01);Trial1和Trial 6中,氯胺酮干預(yù)組和GLYX-13干預(yù)組較生理鹽水模型組進(jìn)入帶電區(qū)域的次數(shù)減少有統(tǒng)計學(xué)意義(P0.05)。結(jié)論:1.青春期雌性、雄性小鼠均造模成功,但雌性模型組的行為學(xué)抑郁樣表現(xiàn)比雄性組更加明顯,相同應(yīng)激對青春期雌性小鼠的影響較雄性小鼠更加嚴(yán)重。雌性模型組與雄性模型組相比對CUMS更加易感,抑郁程度更明顯。2.氯胺酮和GLYX-13具有快速抗抑郁作用,均可改善青春期雌性抑郁小鼠的抑郁樣表現(xiàn),在不同實驗中的改善程度不同。3.氯胺酮和GLYX-13均可改善青春期雌性抑郁小鼠的空間記憶能力,但氯胺酮較GLYX-13的改善作用更快。
[Abstract]:Objectives: Adolescent depression has its particularity, and there is no significant difference in the incidence of depression between pre-adolescent boys and girls; however, after puberty, the incidence of depression in girls increases dramatically, about 2-3 times as much as in boys. However, most of the current studies on depression focus on adult populations and male rodents, targeting adolescent women. The related research of depression is not abundant, and it has far-reaching academic significance and clinical value to explore the effective prevention and treatment of adolescent female depression. Based on the preparation of adolescent female mice depression model, this paper applied ketamine and GLYX-13 with rapid antidepressant effect to observe the effect of adolescence through behavioral research. Methods: 1. Establishment of depression model C57BL/6J 18 days female mice and 16 male mice were randomly divided into female control group, female model group, male control group and female model group with 8 mice in each group. Chronic unpredictable mild stress (CUMS) was used to establish depression model. Ten stress sources, including horizontal oscillation, restraint, noise, fasting, water-fast, day-night inversion, wet mat, empty cage feeding, tilted cage, unfamiliar cage, were used. The model group was given two kinds of stress without repetition every day for three weeks, with different degrees of stress sources weekly phase. The open state of the vaginal orifice in adolescent female mice should be observed daily for 3 weeks, and the body mass changes, the percentage of sugar consumption in the sugar preference test, the autonomous activity in the open field test, the distance of movement and the time of the central area, the open arm time in the elevated cross-maze test, the tail suspension test and the strength of the four groups were observed and compared after 3 weeks. Drug intervention of ketamine and GLYX-13 on depression-like behavior in adolescent female mice C57BL/6J 18 days female mice were randomly divided into normal saline control group (Con+NS), normal saline model group (CUMS+NS), ketamine control group (Con+Ket), ketamine intervention group (CUMS+NS). Ket, GLYX-13 control group (Con+GLYX-13) and GLYX-13 intervention group (CUMS+GLYX-13) 6 groups, 6 in each control group, 7 in each model group and 7 in each intervention group. After three weeks of preparation of CUMS, the free activity of mice in each group before and after drug intervention was compared. The time of open arms, tail suspension and immobile time of forced swimming test were used to determine whether depression-like behavior was present. The changes of mice in each model group before and after drug intervention were compared by the improvement of depression-like behavior. Behavioral performance explores spatial memory, cognitive coordination, and cognitive flexibility. The experimental animals were grouped into the same groups as described in the previous 2. The spatial memory of the mice was judged by the locus of movement of each group, the time of first entering the charged area and the number of times of entering the charged area. Results: After 1.3 weeks of CUMS, the autonomic activity, body weight, percentage of sugar consumption, exercise distance, central area time, open arm time, tail suspension and forced swimming immobility time of the female model group were all decreased compared with those of the female control group. Statistical significance (P 0.05 or P 0.01 or P 0.001); body mass change, sugar consumption percentage, exercise distance, central area time, forced swimming immobility time in male model group compared with male control group were statistically significant (P 0.05 or P 0.01 or P 0.001); After 2.3 weeks of CUMS, the autonomic activity of each model group was decreased compared with that of the corresponding control group, including sugar preference test, open field test, elevated cross maze test, tail suspension test and forced swimming test. There was no significant difference between the ketamine intervention group and the ketamine control group. There was no significant difference between the ketamine intervention group and the GLYX-13 intervention group. Meaning (P 0.05); Ketamine intervention group than normal saline model group movement distance and tail suspension immobility time were statistically significant (P 0.05); GLYX-13 intervention group than normal saline model group forced swimming immobility time was statistically significant (P 0.05). 3.3 weeks after CUMS, the active escape experiment Trial 1 locus showed that the model group compared with the corresponding control group. The time of first entering the charged area in Trial-3 model group was shorter than that in normal saline control group (P 0.05), and the times of entering the charged area in Trial-6 model group and GLYX-13 intervention group were different from those in different control group (P 0.05 or P 0.01). The movement track showed that the spatial memory ability of the ketamine intervention group and GLYX-13 intervention group was not significantly improved. The time of the first entry into the charged area of the Trial-1 ketamine intervention group was significantly longer than that of the normal saline model group and GLYX-13 intervention group (P 0.05 or P 0.01); Trial-1 and Trial-6, ketamine intervention group and GLYX-13 intervention group were significantly longer than that of the normal saline model group and GLYX-13 intervention group (P 0.05 or P 0.01). Conclusion: 1. The adolescent female and male mice were successful in modeling, but the behavioral depression in the female model group was more obvious than that in the male model group. The same stress had more serious influence on the adolescent female mice than the male mice. Ketamine and GLYX-13 have a rapid antidepressant effect, both can improve the depression-like performance of adolescent female depressive mice, and the improvement degree is different in different experiments. 3. Ketamine and GLYX-13 can improve the spatial memory ability of adolescent female depressive mice, but ketamine can improve the spatial memory ability of adolescent female depressive mice. Ketones improved faster than GLYX-13.
【學(xué)位授予單位】：天津醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R749.4;R-332

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