可卡因戒断对小鼠焦虑样行为以及海马神经再生的影响
刘明菲, 李娟, 顾晶晶, 崔梦卿, 李良平, 张璐
中国临床解剖学杂志 ›› 2013, Vol. 31 ›› Issue (5) : 551-554.
可卡因戒断对小鼠焦虑样行为以及海马神经再生的影响
The effect of cocaine withdrawal on anxiety-like behavior and hippocampal neurogenesis of mice
目的 观察重复给予可卡因并戒断后对小鼠焦虑样行为以及小鼠海马区齿状回区（dentate gyrus，DG）神经再生（neurogenesis）的影响。 方法 将19只昆明小鼠随机分为两组，生理盐水组9只，可卡因组10只，腹腔注射生理盐水或可卡因(20 mg·kg-1·d-1)，连续注射14 d，戒断48 h，通过旷场实验（OFT）、高架十字迷宫（EPM）观察小鼠焦虑样行为学变化。免疫荧光实验时，生理盐水组和可卡因组分别5只，给药方法同行为学实验，最后一次注射生理盐水或可卡因同时，腹腔注射BrdU（20 mg/kg per 12 hr）,连续注射48 h。最后一次注射BrdU 24 h后，通过BrdU/Dcx双标的免疫荧光技术观察小鼠海马神经再生情况。 结果 可卡因组旷场实验中央停留时间(center-time）明显少于生理盐水组（P<0.01）。可卡因组高架十字迷宫开臂进入次数（open arm-entries）和开臂停留时间（open arm -time）明显少于生理盐水组（P<0.01）。免疫荧光实验显示可卡因组小鼠海马DG区BrdU+/Dcx+细胞明显少于生理盐水组（P<0.01）。 结论 可卡因反复给药并戒断后，能诱导焦虑样行为的产生以及降低海马DG区神经再生，而海马区神经再生降低可能参与了焦虑样行为的发生。
Objective To observe the effect of cocaine withdrawal after repeated cocaine administration on anxiety-like behavior and hippocampal neurogenesis in the dentate gyrus. Method The Kuming mice were divided into two groups, with 9 in Group saline and 10 in Group cocaine. All mice received daily intraperitoneal injections of saline or cocaine (20 mg/kg) for 14 consecutive days, then all mice were subject to abstinence for 48 hours after the final injection of cocaine or saline. The Open Field Test (OFT) and the Elevated Plus Maze (EPM) were used to observe the level of anxiety-like behavior. For immuno?覲uorescence, mice were also divided into two groups, 5 in each group. After the final injection of cocaine or saline, mice received intraperitoneal injections of BrdU（20 mg/kg, per 12 hours）for 48 hours. 24 hours after the last injection of BrdU, mice were dissected and BrdU+/Dcx+ double labeled immuno?uorescence was carried out to observe the hippocampal neurogenesis in the dentate gyrus. Result The center-time in the OFT was significantly reduced in Group cocaine compared with Group saline(P<0.01). Mice received withdrawal from cocaine showed less open arm-entries and open arm-time in the EPM compared with that received withdrawal from saline(P<0.01). Immuno?覲uorescence revealed that the number of BrdU+/Dcx+ cells significantly decreased in Group cocaine compared with Group saline (P<0.01). Conclusion Cocaine withdrawal after repeated cocaine administration can induce anxiety-like behavior and inhibit neurogenesis, and the inhibited neurogenesis may play important role in cocaine withdrawal-induced anxiety-like behavior.
可卡因戒断 / 焦虑 / 神经再生 / 旷场实验 / 高架十字迷宫
Cocaine withdrawal / Anxiety; / Neurogenesis / The Open Field Test / The Elevated Plus Maze
[1] Kelley AE. Memory and addiction: shared neural circuitry and molecular mechanisms
[J]. Neuron, 2004, 44(1): 161-179.
[2] Schultz W. Neural coding of basic reward terms of animal learning theory, game theory, microeconomics and behavioural ecology
[J]. Curr Opin Neurobiol,2004,14(2): 139-147.
[3] Wise RA, Kiyatkin EA. Differentiating the rapid actions of cocaine
[J].Nat Rev Neurosci, 2011, 12(8):479-484.
[4] Leshner AI. Molecular mechanisms of cocaine addiction. The New England Journal of medicine
[J],1996,335(2):128-129.
[5] Buffalari DM, Baldwin CK, See RE. Treatment of cocaine withdrawal anxiety with guanfacine: relationships to cocaine intake and reinstatement of cocaine seeking in rats
[J]. Psychopharmacology (Berl), 2012, 223(2):179-190.
[6] MCO Citó, FCC da Silva, MIG da Silva,et al. Reversal of Cocaine withdrawal-induced anxiety by ondansetron, buspirone and propranolol
[J]. Behavioural Brain Research, 2012, 231(1):116-123
[7] Mu Y, Lee SW, Gage FH. Signaling in adult neurogenesis
[J]. Current Opinion in Neurobiology,2010, 20(4):416-423.
[8] 陈振中, 顾晶晶, 李娟, 等.不同剂量可卡因对昆明小鼠成瘾行为学的影响
[J]. 中国临床解剖学杂志,2013,?31(3):325-327.
[9] 罗雁威, 曹文宇, 徐杨, 等.大鼠配对前经历吗啡成瘾及戒断对子代焦虑样行为产生的机制
[J].中华行为医学与脑科学杂志,2012,21(6):500-504.
[10] DA Kupferschmidt, AE Newman, R Boonstra, et al. Antagonism of cannabinoid 1 receptors reverses the anxiety-like behavior induced by central injections of corticotropin-releasing factor and cocaine withdrawal
[J]. Neuroscience, 2012, 204:125-33
[11]Kalivas PW, O'Brien C. Drug addiction as a pathology of staged neuroplasticity
[J]. Neuropsychopharmacology. 2008,33(1):166-1680.
[12] Zhang L, Li J, Liu N, et al. Signaling via dopamine D1 and D3 receptors oppositely regulates cocaine-induced structural remodeling of dendrites and spines
[J]. Neurosignals,2012, 20(1):15-34.
[13]Li J, Liu N, Lu K, et al. Cocaine-induced dendritic remodeling occurs in both D1 and D2 dopamine receptor-expressing neurons in the nucleus accumbens
[J]. Neurosci Lett,2012, 517(2):118-22.
[14]Mesulam MM．Neuroplasticity failure in Alzheimer’s diease: Bridging the gap between plaques and tangles
[J]．Neuron，1999，24(3)：521-529.
[15]Kheirbek MA, Klemenhagen KC, Sahay A, et al. Neurogenesis and generalization: a new approach to stratify and treat anxiety disorders
[J]. Nat Neurosci, 2012 ,15(12):1613-1620.
[16]David DJ, Samuels BA, Rainer Q, et al. Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression
[J]. Neuron,2009,62(4):479-493.
[17]Revest JM, Dupret D, Koehl M, et al. Adult hippocampal neurogenesis is involved in anxiety-related behaviors
[J]. Mol Psychiatry, 2009,14(10):959-967.
国家自然科学基金(81071120, 81371509)；教育部科学技术研究重点项目(21132)；粤港关键领域重点突破项目(2011A011304001)；广东省产学研合作重大科技专项(2011A090100025)；广州市科技计划项目(7411832133935)；广东省自然科学基金（10151022001000003）。
京ICP备08002354号-3/
| 〈 |
|
〉 |
