目的 通过研究早期暴露于氟西汀的斑马鱼,探索氟西汀对斑马鱼五羟色胺系统及远期社交功能的影响。方法 用氟西汀早期慢性处理斑马鱼(3-6dpf),通过高效液相色谱法(HPLC)检测斑马鱼脑部的主要神经递质及部分代谢产物水平;用社交偏好实验评估斑马鱼社交行为的远期发展(30dpf)。结果 随氟西汀剂量的增加,五羟吲哚乙酸(5-HIAA)水平不断升高,而五羟色胺(5-HT)、多巴胺(DA)及3,4-二羟苯酰乙酸(DOPAC)在幼鱼(7dpf)脑内水平先增后减。在社交偏好实验结果中,对照组在毗邻鱼群的区域内总游动距离显著高于4 μM组和8 μM处理组(P均<0.01);游动时间的比较显示,对照组高于4 μM组和8 μM组(P均<0.05)。结论 斑马鱼早期暴露于氟西汀,可能通过改变5-HT水平和功能,对神经发育过程产生持续作用,继而影响到其社交能力。
Abstract
Objectives To expolore the effects toserotonin level and long-term social-related behaviour via a transient early postnatal fluoxetine exposure on zebarafish larves.Methods The level of neurotransmitters were exmained and their respective metabolites were quantified by HPLC from whole brain of larves (3~6 days post fertization)exposure to fluoxetine as well as tested the long-term social-related behaviour on zebrafish (30 days post fertization)quantified by social preference test.Results The level of 5-HIAA increased by enhancing dosage of fluoxetine,whlie the level of 5-HT,DA,DOPAC increased in low does and deceased in high dose.In social preference test,compared to the control group (1 255.50±117.95)cm,the 4 μM group (718.20±135.48)cm and 8 μM group (604.66±81.16) cm swam more distance in the area adjacent to the fish school(P<0.01);compared to the control group (1 005.61±54.86)s,the 4 μM group(754.21±85.63)s and 8 μM group(678.58±55.31)s had more time to swim in the area adjacent to the fish school(P<0.05). Conclutions The early-life exposed zebrafish shows the impaired long-term social-related behavior which may lead to sustained effect onneural development possibly via the changed level and function of the serotonin system.
关键词
斑马鱼 /
氟西汀 /
高效液相色谱法 /
社交相关行为 /
孤独谱系障碍
Key words
zebrafish /
fluoxetine /
high precision liquid chromatography /
social-related behaviour /
autism spectrum disorder
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参考文献
[1] Moutil A,Reddihough D,Marraffa C,et al.Fluoxetine for Autistic Behaviors ( FAB trial ):study protocol for a randomized controlled trial in children and adolescents with autism[J].Trials,2014,15(2):230.
[2] Williams K,Brignell A,Randall M,et,al.Selective serotonin reuptake inhibitors (SSRIs) for autism spectrum disorders ( ASD ) [J].The Cochrane Library,2013,8.CD004677.doi:10.1002114651858.CD004677.pub3.
[3] Langworthy-Lam KS,Aman MG,Van Bourgondien ME.Prevalence and patterns of use of psychoactive autism society of North Carolina[J].J Child Adolesc Psychopharmacol,2002,12(4):311-321.
[4] Oswald D,Sonenklar N.Medication use among children with autism spectrum disorder[J].J Child Adolesc Psychopharmacol,2007,17(4):348-355.
[5] Andersen SL.Trajectories of brain development:point of vulnerability or window of opportunity?[J].Neurosci Biobehav Rev,2003,27(1):3-18.
[6] Karpova NN,Lindholm J,Pruunsild P,et al.Long-lasting behavioural and molecular alterations induced by early postnatal fluoxetine exposure are restored by chronic fluoxetine treatment in adult mice[J].Eur Neuropsychopharmacol.2009,19(1):97-108.
[7] Daubert EA,Condron BG.Serotonin:a regulator of neuronal morphology and circuitry[J].Trends Neurosci,2010,33:424-434.
[8] Zimmerberg B,Germeyan SC.Effects of neonatal fluoxetine exposure on behavior across development in rats selectively bred for an infantile affective trait[J].Dev Psychobiol,2015,57(2):141-152.
[9] Wong RY,Oxendine SE,Godwin J.Behavioral and neurogenomic transcriptome changes in wild-derived zebrafish with fluoxetine treatment[J].BMC Genomics,2013,14(1):348.
[10] Kalueff AV,Stewart AM,Gerlai R.Zebrafish as an emerging model for studying complex brain disorders[J].Trends Pharmacol Sci,2014,35(1):63-75.
[11] Schnrr SJ,Steenbergen PJ,Richardson MK,et al.Measuring thigmotaxis in larval zebrafish[J].Behav Brain Res,2012,228(4):367-374.
[12] Olivier JD,Akerud H,Kaihola H,et al.The social zebrafish:Behavioral responses to conspecific,heterospecific,and computer animated fish[J].Behav Brain Res,2008,191(1):77-87.
[13] Oliveira RF.Mind the fish:zebrafish as a model in cognitive social neuroscience [J].Front Neural Circuits,2013,7(1):131.
[14] Engeszer RE,Ryan MJ,Parichy DM.Learned social preference in zebrafish[J].Curr Biol,2004,14(8):881-884.
[15] Buske C,Gerlai R.Shoaling develops with age in zebrafish (Danio rerio) [J].Prog NeuroPsychopharm Biol Psych,2011,35(12):1409-1415.
[16] Olivier JD,Valles A,Heesch F,et al.Fluoxetine administration to pregnant rats increases anxiety-related behavior in the offspring[J].Psychopharmacology (Berl),2011,217:419-432.
[17] Rodriguez-Porcel F,Green D,Khatri N,et al.Neonatal exposure of rats to antidepressants affects behavioral reactions to novelty and social interactions in a manner analogous to autistic spectrum disorders[J].Anat Rec (Hoboken),2011,294(12):1726-1735.
[18] Alwan S,Friedman J.Safety of Selective Serotonin Reuptake Inhibitors in Pregnancy[J].CNS Drugs,2009,23:493-509.
[19] Bock N,Quentin DJ,Moll G,et,al.Very early treatment with fluoxetine and reboxetine causing long-lasting change of the serotonin but not the noradrenaline transporter in the frontal cortex of rats[J].World J Biol Psychiatry,2005,6(2):107-112.
[20] Booij L,Tremblay RE,Szyf M,et,al.Genetic and early environmental influences on the serotonin system?:consequences for brain development and risk for psychopathology[J].J Psychiatry Neurosci,2015,40(1):5-18.
[21] McDougle CJ,Naylor ST,Cohen DJ,et al.EFfects of tryptophan depletion in drug-free adults with autistic disorder[J].Arch Gen Psychiatry,1996,53(9):993-1000.
[22] Sugie Y,Sugie H,Fukuda T,et al.Clinical efficacy of fluvoxamine and functional polymorphism in a serotonin transporter gene on childhood autism[J].J Autism Dev Disord,2005,35(4):377-385.
[23] Croen LA,Grether JK,Yoshida CK,et al.Antidepressant use during pregnancy and childhood autism spectrum disorders[J].Arch Gen Psychiatry,2011,68(11):1104-1112.
基金
上海交通大学“医工交叉研究基金”项目(YG20132D0503)
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