丙咪嗪对慢性应激性抑郁易化吗啡行为敏感化的影响
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摘要
药物依赖和成瘾研究的焦点问题,是探讨诱发药物滥用及导致戒除后的复吸行为的核心因素及其机制。临床和实验研究发现:药物成瘾者存在药物依赖和抑郁共病的状态:抑郁是药物成瘾者一种典型的情绪状态;一些抗抑郁药物具有治疗药物成瘾的作用。这些发现说明药物成瘾和抑郁情绪之间存在相互联系的神经机制。但目前的研究对于药物成瘾和抑郁之间的因果关系还不慎明了。动物模型为理解抑郁与药物成瘾问题提供了一个很好的方法:行为敏感化是研究药物成瘾的公认动物模型;慢性不可预见性应激可作为建立抑郁动物模型的主要诱发因子。本实验采用慢性轻度不可预见性应激抑郁模型和吗啡行为敏感化动物模型,通过考察抑郁与吗啡行为敏感化的关系,探讨:(1)慢性应激性抑郁对吗啡滥用的诱导作用;(2)抗抑郁药丙咪嗪对这种诱导作用的影响。
实验结果发现:(1)吗啡4mg/kg急性处理,抑郁组和抑郁丙咪嗪5mg/kg处理组动物的活动量都显著高于对照组;(2)吗啡行为敏感化形成期抑郁组活动量显著高于对照组,而抑郁丙咪嗪组的动物活动量与对照组没有显著差异;(3)在吗啡激发的行为敏感化表达中,抑郁组的活动量显著高于对照组,而抑郁丙咪嗪组的动物活动量与对照组没有显著差异。
研究结果表明:(1)经历慢性应激性抑郁的大鼠,在吗啡急性处理后自主活动显著增加,而丙咪嗪对这种增加有部分抑制作用;(2)经历慢性应激性抑郁的大鼠在吗啡行为敏感化的形成和表达期自主活动显著增加,丙咪嗪的干预抑制了这种增强效应。以上结果预示慢性应激性抑郁可能对吗啡的成瘾和复吸具有诱发作用,而抗抑郁药丙咪嗪能抑制这种诱发作用,丙咪嗪对吗啡成瘾具有一定的治疗作用。
The key study of drug dependence and addiction is exploring factors and mechanism leading to drug addiction and relapse.Clinical evidence and animal experiments have found that:addicted patients frequently show the emotion of depression,depression is a common feature of various drug addicts;some antidepressant drugs has been shown to relieve drug addiction,suggesting that there is some relationship between depression and drug addiction.But current research couldn't elucidate whether the depression reflects preexisting traits,or the effects of exposure to the drug.The animal model prodives a better method to research the relationship of depression and drug addiction:the behavioral sensitization animal model is proverbially used in the study of drug addiction,the chronic mild stress procedure is an useful and reliable model of depression. This experiment was designed to explore the effect of imipramine on the morphine addiction after the performance of the chronic mild stress procedure.Based on the relationship between behavioral sensitization and addiction susceptibility,we investigate(1) the morphine behavioral sensitization in model rats treated with chronic mild stress;(2)The effect of imipramine on the morphine behavioral sensitization in model rats treated with chronic mild stress.
Our results showed that:(1)the locomotion of depression group and imipramine-depression group were significantly higher than non-depression group after treatment with 4mg/kg morphine;(2) the locomotion of depression group was significantly higher than non-depression group in the development of behavioral sensitization,no difference was observed between imipramine-depression group and non-depression group;(3) and in the expression period,the locomotion of depression group was significantly higher than non-depression group,no difference was observed between imipramine-depression group and non-depression group.
Conclusions:(1)the locomotion of depression group were significantly higher than non-depression group after treatment with 4mg/kg morphine;Imipramine inhibited this effect.(2) there is relationship between depression and addiction susceptibility,and the relapse in morphine addiction may be influenced by the emotion of depression.(3) Imipramine has an inhibition on behavioral sensitization of morphine in the chronic mild stress-depressed rats.
The effect of the chronic mild stress-depression on morphine behavioral sensitization could be inhibited by imipramine,suggesting that mild stress-depression is one of factors leading to drug addiction and relapse.Imipramine could cure drug addiction and relapse.
实验结果发现:(1)吗啡4mg/kg急性处理,抑郁组和抑郁丙咪嗪5mg/kg处理组动物的活动量都显著高于对照组;(2)吗啡行为敏感化形成期抑郁组活动量显著高于对照组,而抑郁丙咪嗪组的动物活动量与对照组没有显著差异;(3)在吗啡激发的行为敏感化表达中,抑郁组的活动量显著高于对照组,而抑郁丙咪嗪组的动物活动量与对照组没有显著差异。
研究结果表明:(1)经历慢性应激性抑郁的大鼠,在吗啡急性处理后自主活动显著增加,而丙咪嗪对这种增加有部分抑制作用;(2)经历慢性应激性抑郁的大鼠在吗啡行为敏感化的形成和表达期自主活动显著增加,丙咪嗪的干预抑制了这种增强效应。以上结果预示慢性应激性抑郁可能对吗啡的成瘾和复吸具有诱发作用,而抗抑郁药丙咪嗪能抑制这种诱发作用,丙咪嗪对吗啡成瘾具有一定的治疗作用。
The key study of drug dependence and addiction is exploring factors and mechanism leading to drug addiction and relapse.Clinical evidence and animal experiments have found that:addicted patients frequently show the emotion of depression,depression is a common feature of various drug addicts;some antidepressant drugs has been shown to relieve drug addiction,suggesting that there is some relationship between depression and drug addiction.But current research couldn't elucidate whether the depression reflects preexisting traits,or the effects of exposure to the drug.The animal model prodives a better method to research the relationship of depression and drug addiction:the behavioral sensitization animal model is proverbially used in the study of drug addiction,the chronic mild stress procedure is an useful and reliable model of depression. This experiment was designed to explore the effect of imipramine on the morphine addiction after the performance of the chronic mild stress procedure.Based on the relationship between behavioral sensitization and addiction susceptibility,we investigate(1) the morphine behavioral sensitization in model rats treated with chronic mild stress;(2)The effect of imipramine on the morphine behavioral sensitization in model rats treated with chronic mild stress.
Our results showed that:(1)the locomotion of depression group and imipramine-depression group were significantly higher than non-depression group after treatment with 4mg/kg morphine;(2) the locomotion of depression group was significantly higher than non-depression group in the development of behavioral sensitization,no difference was observed between imipramine-depression group and non-depression group;(3) and in the expression period,the locomotion of depression group was significantly higher than non-depression group,no difference was observed between imipramine-depression group and non-depression group.
Conclusions:(1)the locomotion of depression group were significantly higher than non-depression group after treatment with 4mg/kg morphine;Imipramine inhibited this effect.(2) there is relationship between depression and addiction susceptibility,and the relapse in morphine addiction may be influenced by the emotion of depression.(3) Imipramine has an inhibition on behavioral sensitization of morphine in the chronic mild stress-depressed rats.
The effect of the chronic mild stress-depression on morphine behavioral sensitization could be inhibited by imipramine,suggesting that mild stress-depression is one of factors leading to drug addiction and relapse.Imipramine could cure drug addiction and relapse.
引文
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Chiaroni P,Azorin J M,Dassa D,et al.Possible involvement of the dopamine D3 receptor locus in subtypes of bipolar affective disorder.Psychiatr Genet,2000,10:43～49.
Colpaert FC.High-efficacy 5-hydroxytryptamine 1A receptor activation counteracts opioid hyperallodynia and affective conditioning.Journal of Pharmacology and Experimental Therapeutics.2006,316 (2):892～899
Dugovic C,Solberg L C,Redei E V,et al.Sleep in the Wistar Kyoto rat,a putative genetic animal model for depression.Neuro report,2000,28(11):627～631
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Harro J,Tonissaar M,Eller M,et al.Chronic variable stress and partial 5-HT denervation by parachloroamphetamine treatment in the rat:effects on behavior and monoamine neurochemistry.Brain Research,2001,899:227～239.
Healy E,McKeon P.Dopaminergic sensitivity and prediction of antidepressant response.Psychopharmacol,2000,14:152～156.
Highfield D,Yap J,Grimm J W,et al.Repeated ofexidine treatment attenuates stress-induced,but not drug cues-induced reinstatement of a heroin-cocaine mixture (speedball) seeking in rats.Neuropsychopharmacology,2001,25(3):320～31.
Hughes,J R.Antidepressants for smoking cessation.Cochrane Database Syst Rev.2007,(1):CD000031
Hennessy M B,Deak T,Schiml Webb PA.Stress-induced sickness behaviors:an alternative hypothesis for responses during maternal separation.Dev Psychobio,2001,39:76～83
Hoplight B J.Cocaine increases 5-HT1B mRNA in rat nucleus accumbens shell neurons.Neuropharmacology.2007,52 (2):44～449
Hatsukami D K.Lack of effect of 5-HT3 antagonist in mediating subjective and behavioral responses to cocaine.Pharmacology Biochemistry and Behavior.2003,75 (1):1～7
Jay A.Gingrich.Dissecting the role of the serotonin system in neuropsychiatric disorders using knockout mice.Psychopharmacology.2001,155:1～10
Junxu li.Effects of 5-hydroxytryptophan on morphine-induced sensitization in mice Journal Of Chinese Pharmaceutical Sciences 2008,17:1
Kanof PD,Handelsman L,Aronson MJ,Ness R,Cochrane KJ,Rubinstein KJ Clinical characteristics of naloxone-precipitated withdrawal in human opioid-dependent subjects.J Pharmacol Exp Ther,1992,260:355～363
Katz RJ.Animal model of depression:Pharmacological sensitivity of a hedonic deficit,Pharmacol Biochem.Behav,1982,16,965～968
Konradi C,Cole R L,Heckers S,et al.Amphetamine regulates gene expression in rat striatum via transcription factor CREB.Journal of Neuroscience,1994,14(9):5～23.
Khantzian E L:Arch Gen Psychiatry 1985,42:1067～1071
Katz R,Hersch S.Amitriptyline and scopolamine in an anima model of depression Neurosci Biobehav Rev,1981,5:265～271
Kelly J P,Leonard B E.The effect of tianeptine and sertraline in three animal models of depression.Neuropharmacology,1994,33:1011～1016
Lucki I.The forced swimming test as a model for core and componentbehaviorl effects of antidepressant drugs.Behav Pharmacol,1997,8:523～532
Lin Z C.The human serotonin receptor 2B:coding reg polymorphisms and association with vulnerability to ill drug abuse.Pharmacogenetics.2004,14 (12):805～811
Maldonado R.The neurobiology of addiction.J Neural Transm Suppl,2003,66:1～14
Maes M,Libbrecht I,VanHunse F,et al.Pindolol andmiansenn augment the antidepressantactivity of fluoxetine in hospitalizedmajor depressed patients,including those with treatment resistance.J Clin Psychopharmaco,1999,19(2):177～182
Mateo Y.Role of serotonin in cocaine effects in mice with reduced dopamine transporter function.Proceedings of The National Academy Of Sciences of The United States of America 2004,101(1):372～377
Magalas Z.The serotonin/noradrenaline reuptake inhibitor venlafaxine attenuates acquisition,but not maintenance,of intravenous self-administration of heroin in rats.European Journal of Pharmacology.2005,528(1-3):103～109
Makino M,Kitano Y,Komiyama C,et al.Involvement of central opioid systems in human interfe ron-alpha induced immobility in the mouse forced swimming testl Br J Pharmacol,2000,130:1269～1274
Magalas Z.The serotonin/noradrenaline reuptake inhibitor venlafaxine attenuates acquisition,but not maintenance,of intravenous self-administration of heroin in rats.European Journal of Pharmacology.2005,528(1-3):103～109
Mhatre M.5-HT3 antagonist ICS 205-930 enhances naltrexone's effects on ethanol intake.European Journal of Pharmacology.2004,491 (2-3):149～156
Nestby P,Schotte A,Janssen P F,et al.Striatal dopamine receptors in rats displaying long-term behavioural sensitization to morphine.Synapse,1997,27(3):262～265
Naranjoa CA,Tremblaye E.The role of the brain reward system in depression.Progress in Neuro-Psycho pharmacology and Biological Psychiatry.2001,25(4):781～823
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