吗啡成瘾大鼠伏核毁损术后行为学，影像学改变与脑内单胺类神经递质变化的相关性
|
摘要
目的:
探讨吗啡成瘾大鼠伏核毁损术后行为学改变与脑内单胺类神经递质变化的相关性以及毁损前后的脑影像学变化。
方法:
通过给大鼠每日两次腹腔注射吗啡,逐日递增吗啡用量,制作急性吗啡成瘾模型。使用立体定向技术毁损伏核,对比毁损前后吗啡成瘾大鼠的行为学变化;高效液相色谱—荧光检测法测定脑内不同结构的单胺类神经递质含量,比较毁损前后递质含量的变化。综合分析吗啡成瘾大鼠伏核毁损术后行为学改变与脑内单胺类神经递质变化的相关性。条件性位置偏爱(CPP)试验观察毁损术前后吗啡成瘾大鼠的行为学变化。毁损术前后行磁共振(MRI)影像学检查,观察影像学的变化。综合分析吗啡成瘾大鼠伏核毁损术后行为学改变与影像学变化,从而判断手术戒毒的疗效。
结果:
1.急性吗啡成瘾模型制模成功率较高,大鼠成瘾前后以及毁损术后行为学变化明显,毁损伏核后可缓解成瘾大鼠的戒断症状。
2.毁损伏核后大鼠相关脑区多巴胺(DA)、去甲肾上腺素(NE)含量下降,5-羟色胺(5-HT)含量升高,毁损组较对照组的变化明显(P﹤0.01),差异有显著性。
3.成瘾后大鼠对CPP箱的白盒有明显的位置性偏爱,大鼠成瘾前后以及毁损术后行为学变化明显,真毁损伏核与假毁损伏核对大鼠的行为改变不同,毁损伏核后可改善成瘾大鼠的戒断症状。
4.毁损术前后影像学有明显变化:大鼠伏核毁损区脑组织水肿明显。
结论:
1.吗啡成瘾大鼠立体定向毁损伏核后相关脑区单胺递质含量的变化与毁损术前后行为学的改变有一定的相关性。
2.吗啡成瘾大鼠立体定向毁损伏核后,戒断症状明显改善,影像学显示毁损术后大鼠伏核区脑组织水肿明显。立体定向毁损伏核手术准确有效。
Objective
To investigate the relationship between the level of monoamine neurotransmitters and the change of ethology after nucleus accumbence lesioned in morphine-addicted rats,and observe the imageological changes in brain regin of morphine-addicted rats before and after stereotaxic lesion.
Methods
An acute morphine-addicted rat mode was made with morphine by abdominal cavity injection. The interval of the injection is 12 hours. The dose of injection was added by daily from 5 mg/kg to 90 mg/kg within 10 days. Before and after stereotaxic lesion, the level of monoamine neurotransmitters in different brain regions was detected by a fluorescence detector (high performance liuid chromatography). The relationship between the monoamine neurotransmitters and ethological changes was analyzed after nucleus accumbence lesioned in the experiment rats.
Results
(1) There was a high successful rate in making acute morphine-addicted rats, and remarkable ethological changes in morphine-addicted rats before and after stereotaxic lesion.
(2)There were significant difference in ethological changes between nucleus accumbens-lesioned group and nucleus accumbens pseudo-lesioned group.
(3)After nucleus accumbence lesioned, the abstinence syndrome could lessen. The levels of DA, NE, 5-HT in the regions of prefrontal cortex, hippocampus and ventral tegmental area were obvious changed compared with the unlesioned group in morphine-addicted rats (P<0.01).
(4) Before and after lesion, the imageology of the morphine-addicted rats’brain are different too, the brain edma of the nucleus accumbence region were evidently.
Conclusions
(1)There may have some relationships between changes of ethology and the levels of monoamine neurotransmitters in the morphine-addicted rat.
(2)Before and after lesion, the imageology of the morphine-addicted rats’brain are different too,the brain edma of the nucleus accumbence region were evidently.
探讨吗啡成瘾大鼠伏核毁损术后行为学改变与脑内单胺类神经递质变化的相关性以及毁损前后的脑影像学变化。
方法:
通过给大鼠每日两次腹腔注射吗啡,逐日递增吗啡用量,制作急性吗啡成瘾模型。使用立体定向技术毁损伏核,对比毁损前后吗啡成瘾大鼠的行为学变化;高效液相色谱—荧光检测法测定脑内不同结构的单胺类神经递质含量,比较毁损前后递质含量的变化。综合分析吗啡成瘾大鼠伏核毁损术后行为学改变与脑内单胺类神经递质变化的相关性。条件性位置偏爱(CPP)试验观察毁损术前后吗啡成瘾大鼠的行为学变化。毁损术前后行磁共振(MRI)影像学检查,观察影像学的变化。综合分析吗啡成瘾大鼠伏核毁损术后行为学改变与影像学变化,从而判断手术戒毒的疗效。
结果:
1.急性吗啡成瘾模型制模成功率较高,大鼠成瘾前后以及毁损术后行为学变化明显,毁损伏核后可缓解成瘾大鼠的戒断症状。
2.毁损伏核后大鼠相关脑区多巴胺(DA)、去甲肾上腺素(NE)含量下降,5-羟色胺(5-HT)含量升高,毁损组较对照组的变化明显(P﹤0.01),差异有显著性。
3.成瘾后大鼠对CPP箱的白盒有明显的位置性偏爱,大鼠成瘾前后以及毁损术后行为学变化明显,真毁损伏核与假毁损伏核对大鼠的行为改变不同,毁损伏核后可改善成瘾大鼠的戒断症状。
4.毁损术前后影像学有明显变化:大鼠伏核毁损区脑组织水肿明显。
结论:
1.吗啡成瘾大鼠立体定向毁损伏核后相关脑区单胺递质含量的变化与毁损术前后行为学的改变有一定的相关性。
2.吗啡成瘾大鼠立体定向毁损伏核后,戒断症状明显改善,影像学显示毁损术后大鼠伏核区脑组织水肿明显。立体定向毁损伏核手术准确有效。
Objective
To investigate the relationship between the level of monoamine neurotransmitters and the change of ethology after nucleus accumbence lesioned in morphine-addicted rats,and observe the imageological changes in brain regin of morphine-addicted rats before and after stereotaxic lesion.
Methods
An acute morphine-addicted rat mode was made with morphine by abdominal cavity injection. The interval of the injection is 12 hours. The dose of injection was added by daily from 5 mg/kg to 90 mg/kg within 10 days. Before and after stereotaxic lesion, the level of monoamine neurotransmitters in different brain regions was detected by a fluorescence detector (high performance liuid chromatography). The relationship between the monoamine neurotransmitters and ethological changes was analyzed after nucleus accumbence lesioned in the experiment rats.
Results
(1) There was a high successful rate in making acute morphine-addicted rats, and remarkable ethological changes in morphine-addicted rats before and after stereotaxic lesion.
(2)There were significant difference in ethological changes between nucleus accumbens-lesioned group and nucleus accumbens pseudo-lesioned group.
(3)After nucleus accumbence lesioned, the abstinence syndrome could lessen. The levels of DA, NE, 5-HT in the regions of prefrontal cortex, hippocampus and ventral tegmental area were obvious changed compared with the unlesioned group in morphine-addicted rats (P<0.01).
(4) Before and after lesion, the imageology of the morphine-addicted rats’brain are different too, the brain edma of the nucleus accumbence region were evidently.
Conclusions
(1)There may have some relationships between changes of ethology and the levels of monoamine neurotransmitters in the morphine-addicted rat.
(2)Before and after lesion, the imageology of the morphine-addicted rats’brain are different too,the brain edma of the nucleus accumbence region were evidently.
引文
1 Adinoff B. Neurobiologic processes in drug reward and addiction[J] .Harv Rev Psychiatry,2004,12(6): 305–320.
2魏孝琴,袁奇,邵云,等.伏隔核毁损对大鼠吗啡成瘾与戒断的影响及行为变化的研究[J].中国医科大学学报, 1998,27(3): 263-266.
3包新民,舒斯云.大鼠脑立体定位图谱[M].北京:人民卫生出版社,1991:9-20,97-105.
4侯海龙,陈晓蓉,胡祥友,等.痴呆模型大鼠中脑腹侧被盖区多巴胺能神经元的形态学改变[J ].安徽医科大学学报,2002,37(6):432-435.
5 Wu Q, Reith M E, Kuhar M J, et al. Preferential increases in nucleus accumbens dopamine aftersystemic cocaine administration are caused by unique characteristics of dopamine neurotransmission[J ]. J Neurosci,2001,21(16):6338-6347.
6 Baler R D , Volkow N D. Drug addiction: the neurobiology of disrupted self-control[J ].Trends Mol Med, 2006, 12(12):559-566.
7 Cami J, Farre M . Drug addiction[J ]. N Engl J Med ,2003, 349(10):975-986.
8 Bassareo V, De Luca M A, Di Chiara G. Differential expression of motivational stimulus properties by dopamine in nucleus accumbens shell versus core and prefrontal cortex[J ]. J Neurosci ,2002,22(11):4709-4719.
9 Espejo E F ,Serrano M I ,Caille S , et al . Behavioral expression of opiate withdrawal is altered after prefrontocortical dopamine depletion in rats : monoaminergic correlates[J ] . Neuropsychopharmacology ,2001 ,25 (2) :204-212.
10 Medvedev S V, Anichkov A D, Poliakov IuI. Physiological mechanisms of the effectiveness of bilateral stereotactic cingulotomy in treatment of strong psychological dependence in drug addiction [J]. Fiziol Cheloveka, 2003,29(4): 117-123.
11 Gao G, Wang X, He S, et al. Clinical study for alleviating opiate drug psychological dependence by a method of ablating the nucleus accumbens with stereotactic surgery [J]. Stereotact Funct Neurosurg,2003,81(1-4): 96-104.
12王林,傅先明,钱若兵,等.吗啡成瘾大鼠脑内核团毁损后的行为学研究及形态学变化[J].中国微侵袭神经外科杂志,2006,11(11):507-511.
1 Bryon Adinoff, MD .Neurobiologic processes in drug reward and addiction[J] .Harv Rev Psychiatry. 2004; 12(6): 305–320.
2包新民,舒斯云著。大鼠脑立体定位图谱。人民卫生出版社,1991年12月第一版。9-20,97-105.
3 Robbins TW , Everitt BJ . Drug addiction : bad habits add up[J].Nature,1999;398(6728):567-570.
4 Stolerman I. Drugs of abuse: behavioural principles, methods and terms. Trends Pharmacol Sci 1992;13:170-176.
5 Spanagel R, Weiss F. The dopamine hypothesis of reward: past and current status. Trends Neurosci 1999;22:521-527.
6 Koob GF , Le Moal M . Drug abuse : hedonic homeostatic dysregulation. Science 1997;278:52-58.
7 Koob GF,Le Moal M.Drug addiction, dysregulation of reward, and allostasis. Neuropsychopharmacology 2001;24:97-129.
8 Cami J, Farre M . Drug addiction. N Engl J Med 2003; 349:975-986.
9 Kalivas PW. Neurocircuitry of addiction. Neuropsychopharmacology.2002:1357-66
10 Goldstein RZ, Volkow ND. Drug addiction and its underlying neurobiological basis: neuroimaging evidence for the involvement of the frontal cortex. Am J Psychiatry 2002;159:1642-1652.
11 Hyman SE, Malenka RC. Addiction and the brain: the neurobiology of compulsion and its persistence. Nat Rev Neurosci 2001;2:695-703.
12 Kalivas PW. Neurocircuitry of addiction. In: Davis KL, Charney D, Coyle JT, Nemeroff C, eds. Neuropsychopharmacology: the fifth generation of progress. Philadelphia: Lippincott Williams & Wilkins, 2002:1357-66.
13 Di Chiara G. Drug addiction as dopamine-dependent associative learning disorder. Eur J Pharmacol 1999;375:13-30.
14 Nestler EJ. Molecular basis of long-term plasticity underlying addiction. Nat Rev Neurosci 2001;2:119-128. [Erratum, Nat Rev Neurosci 2001;2:215.]
15 McLellan AT, Lewis DC, O'Brien CP, Kleber HD. Drug dependence, a chronic medical illness: implications for treatment, insurance, and outcomes evaluation. JAMA 2000;284:1689-1695.
16 Kreek MJ, LaForge KS, Butelman E. Pharmacotherapy of addictions. Nat Rev Drug Discov 2002;1:710-726. [Erratum, Nat Rev Drug Discov 2002;1:920.]
17 Johnson RE, Chutuape MA, Strain EC, Walsh SL, Stitzer ML, Bigelow GE. A comparison of levomethadyl acetate, buprenorphine, and methadone for opioid dependence. N Engl J Med 2000;343:1290-1297.
18 Fudala PJ, Bridge TP, Herbert S, et al. Office-based treatment of opiate addiction with a sublingual-tablet formulation of buprenorphine and naloxone. N Engl J Med 2003;349:949-958.
19 Gaetano Di Chiara . Nucleus accumbens shell and core dopamine: differential role in behavior and addiction .Behavioural Brain Research 137 (2002) 75-114.
20 Wu Q, Reith ME, Kuhar MJ, Carroll FI, Garris PA.Preferential increases in nucleus accumbens dopamine aftersystemic cocaine administration are caused by unique characteristics of dopamine neurotransmission. J Neurosci.2001;21:6338-47.
21 Schultz W. Predictive reward signal of dopamine neurons. J Neurophysiol 1998;80:1-27.
1 Huda A, Meng F, Devine DP, et al. Molecular and neuroanatomical properties of the endogenous opiate system: implications for treatment of opiate addiction. Seminars in neuroscience, 1997,9∶70~83.
2 Koob GF , Le Moal . Drug addiction , dysregulation of reward and allostasis . Neuropsychopharmacology . 2001 , 24 (2) : 97-129.
3 Kosten TA, ZhangXY, Kehoe P. Infant ratswith chronic neonatal isolation experience show decreased extracellular serotonin levels in ventral striatum at baseline and in response to cocaine. Brain Res Dev Brain Res. 2004, 152(1): 19-24.
4 McBride WJ, Murphy JM, kemoto SI. Localization of brain rein-forcementmechanisms: intracranial self-administration and intracra-nial place-conditioning studies. Behav Brain Res, 1999, 101(4):129-152.
5 Gorelick DA, Gardner EL, Xi ZX. Agents in development for themanagement of cocaine abuse. Drugs, 2004, 64(14): 1547-1573.
6 Georges F, Stinus L, Bloch B,et al. Chronic morphine exposure and spontaneouswithdrawal are associated with modifications of do-pamine receptor and neuropeptide gene expression in the rat stria-tum. Eur JNeurosc.i 1999, 11(10): 481-490.
7 Muller CP, Carey RJ, Huston JP. Serotonin as an importantmediator of cocaine’s behavioral effects. DrugsToday (Barc). 2003, 39(7): 497-511.
8 Mylecharane EJ. Ventral tegmental area 5-HT receptors: mesolimbic dopamine release and behavioural studies. Behavioural Brain Research, 1996, 73∶1~5.
9 Jacobsen LK, Staley JK, Malison RT,etal. Elevated central serotonin transporterbinding availability in acutely abstinent cocaine-dependentpatients. Am J Psychiatry, 2000, 157(7): 1134-1140.
10 Kalivas PW, Volkow N, Seamans J. Unmanageable motivation in addiction: a pathology in prefrontal-accumbens glutamate transmis-sion. Neuron. 2005, 45(5): 647-650.
11 Cornish JL, KalivasPW. Glutamate transmission in the nucleus accumbensmediates relapse in cocaine addiction. J Neurosc,i 2000,20(15): 89.
12 Park WK, JangCG, Kim HS,etal. Cocaine administered into the medial prefrontal cortex reinstates cocaine-seeking behavior by in-creasingAMPA receptor-mediated glutamate transmission in the nucleus accumbens. JNeurosc,i 2002, 22(9): 2916-2925.
13 Childress AR, Mozley PD, McElgin W,et al. Limbic activation during cueinduced cocaine craving. Am J Psychiatry, 1999, 156(1): 11-18.
14 Williams JM, Steketee JD. Cocaine increasesmedialprefrontal cortical glutamate overflow in cocaine-sensitized rats: a time course study. Eur JNeurosc.i 2004, 20(6): 1639-1646.
15 Smith JE, Co C, Yin X. Involvement of cholinergic neuronal systems in intravenous cocaine self-administration. Neuroscience and BiobehavioralReviews, 2004, 27(8) : 841-850.
16 Hikida T, Kitabatake Y, Pastan I,et al. Acetylcholine enhancement in the nucleus accumbens prevents addictive behaviors of cocaine and morphine. Proc Natl Acad Sci USA, 2003, 100 (10):6169-6173.
17 Ikemoto S, GoedersNE. Intra-medial prefrontal cortex injections of scopolamine increase instrumental responses for cocaine: an intravenous self-administration study in rats. Brain Res Bul,l 2000, 51(3): 151-158.
18 Zhang W, YamadaM, Gomez J. muscarinic acetylcholine receptor subtypesmodulate striatal dopamine release, as studied with M1-M5 muscarinic receptor knock-out mice. J Neurosci 2002, 22 (10):6347-6352.
19 Zhou FM, LiangY, Dani JA. Endogenous nicotinic cholinergic activity regulates dopamine release in the striatum. Nature Neurosci, 2001, 4(9): 1224-1229.
20 Fu Y, Matta SG, GaoW,etal. Locala-bungarotoxin-sensitive nicotinic receptors in the nucleus accumbensmodulate nicotinestimulated dopamine secretion in vivo. Neuroscience 2000, 101(6): 369-375.
21 Panagis G, KastellakisA, Spyraki C,et al. Effects of methylcaconitine (MLA) an a7 nicotinic receptor antagonist, on nicotine and cocaine-induced potentiation of brain stimulation reward. Psychopharmacology, 2000, 149(4): 388-396.
22 Crosby MJ,Hanson JE,Fleckenstein AE,et al.Phencyclidine increase vesicular dopamine uptake.European Journal of Pharmacology, 2002,438(1-2):75-78·
23 Manzanedo C,Aguilar MA,Minarro J. The effects of dopamine D2 and D3 antagonisists on spontaneousmotor activity andmorphine-induced hyperactivity in male mice[J].Psychophacology(Berl),1999,143(1):82-88.
24 KelleyAE,Berridge KC.The neuroscience of natural rewards:relevance to addictive drugs[J].J Neurosci,2002,22(9):3306-3311.
25 Laviolette SR,Nader K,van der Kooy D.Motivational state determines the functional role of the mesolimbic dopamine system in the mediation of opiate reward processes[J].Behav Brain Res,2002,129(1-2):17-29.
26 Williams JT,Christie MJ,Manzoni O.Cellular and synaptic adaptation mediating opioid dependence[J].Physiol Rev,2001,81(1):299-343.
27 Nestler EJ. Molecular mechanisms underlying opiate addiction: Implications for medications development. Seminars in Neuroscience, 1997,9∶84-93.
28 Maldonado R, Saiardi A, Valverde O, et, al.Absence of opiate rewarding effects in mice lacking dopamine D2 receptors. Nature, 1997,388∶586-589.
2魏孝琴,袁奇,邵云,等.伏隔核毁损对大鼠吗啡成瘾与戒断的影响及行为变化的研究[J].中国医科大学学报, 1998,27(3): 263-266.
3包新民,舒斯云.大鼠脑立体定位图谱[M].北京:人民卫生出版社,1991:9-20,97-105.
4侯海龙,陈晓蓉,胡祥友,等.痴呆模型大鼠中脑腹侧被盖区多巴胺能神经元的形态学改变[J ].安徽医科大学学报,2002,37(6):432-435.
5 Wu Q, Reith M E, Kuhar M J, et al. Preferential increases in nucleus accumbens dopamine aftersystemic cocaine administration are caused by unique characteristics of dopamine neurotransmission[J ]. J Neurosci,2001,21(16):6338-6347.
6 Baler R D , Volkow N D. Drug addiction: the neurobiology of disrupted self-control[J ].Trends Mol Med, 2006, 12(12):559-566.
7 Cami J, Farre M . Drug addiction[J ]. N Engl J Med ,2003, 349(10):975-986.
8 Bassareo V, De Luca M A, Di Chiara G. Differential expression of motivational stimulus properties by dopamine in nucleus accumbens shell versus core and prefrontal cortex[J ]. J Neurosci ,2002,22(11):4709-4719.
9 Espejo E F ,Serrano M I ,Caille S , et al . Behavioral expression of opiate withdrawal is altered after prefrontocortical dopamine depletion in rats : monoaminergic correlates[J ] . Neuropsychopharmacology ,2001 ,25 (2) :204-212.
10 Medvedev S V, Anichkov A D, Poliakov IuI. Physiological mechanisms of the effectiveness of bilateral stereotactic cingulotomy in treatment of strong psychological dependence in drug addiction [J]. Fiziol Cheloveka, 2003,29(4): 117-123.
11 Gao G, Wang X, He S, et al. Clinical study for alleviating opiate drug psychological dependence by a method of ablating the nucleus accumbens with stereotactic surgery [J]. Stereotact Funct Neurosurg,2003,81(1-4): 96-104.
12王林,傅先明,钱若兵,等.吗啡成瘾大鼠脑内核团毁损后的行为学研究及形态学变化[J].中国微侵袭神经外科杂志,2006,11(11):507-511.
1 Bryon Adinoff, MD .Neurobiologic processes in drug reward and addiction[J] .Harv Rev Psychiatry. 2004; 12(6): 305–320.
2包新民,舒斯云著。大鼠脑立体定位图谱。人民卫生出版社,1991年12月第一版。9-20,97-105.
3 Robbins TW , Everitt BJ . Drug addiction : bad habits add up[J].Nature,1999;398(6728):567-570.
4 Stolerman I. Drugs of abuse: behavioural principles, methods and terms. Trends Pharmacol Sci 1992;13:170-176.
5 Spanagel R, Weiss F. The dopamine hypothesis of reward: past and current status. Trends Neurosci 1999;22:521-527.
6 Koob GF , Le Moal M . Drug abuse : hedonic homeostatic dysregulation. Science 1997;278:52-58.
7 Koob GF,Le Moal M.Drug addiction, dysregulation of reward, and allostasis. Neuropsychopharmacology 2001;24:97-129.
8 Cami J, Farre M . Drug addiction. N Engl J Med 2003; 349:975-986.
9 Kalivas PW. Neurocircuitry of addiction. Neuropsychopharmacology.2002:1357-66
10 Goldstein RZ, Volkow ND. Drug addiction and its underlying neurobiological basis: neuroimaging evidence for the involvement of the frontal cortex. Am J Psychiatry 2002;159:1642-1652.
11 Hyman SE, Malenka RC. Addiction and the brain: the neurobiology of compulsion and its persistence. Nat Rev Neurosci 2001;2:695-703.
12 Kalivas PW. Neurocircuitry of addiction. In: Davis KL, Charney D, Coyle JT, Nemeroff C, eds. Neuropsychopharmacology: the fifth generation of progress. Philadelphia: Lippincott Williams & Wilkins, 2002:1357-66.
13 Di Chiara G. Drug addiction as dopamine-dependent associative learning disorder. Eur J Pharmacol 1999;375:13-30.
14 Nestler EJ. Molecular basis of long-term plasticity underlying addiction. Nat Rev Neurosci 2001;2:119-128. [Erratum, Nat Rev Neurosci 2001;2:215.]
15 McLellan AT, Lewis DC, O'Brien CP, Kleber HD. Drug dependence, a chronic medical illness: implications for treatment, insurance, and outcomes evaluation. JAMA 2000;284:1689-1695.
16 Kreek MJ, LaForge KS, Butelman E. Pharmacotherapy of addictions. Nat Rev Drug Discov 2002;1:710-726. [Erratum, Nat Rev Drug Discov 2002;1:920.]
17 Johnson RE, Chutuape MA, Strain EC, Walsh SL, Stitzer ML, Bigelow GE. A comparison of levomethadyl acetate, buprenorphine, and methadone for opioid dependence. N Engl J Med 2000;343:1290-1297.
18 Fudala PJ, Bridge TP, Herbert S, et al. Office-based treatment of opiate addiction with a sublingual-tablet formulation of buprenorphine and naloxone. N Engl J Med 2003;349:949-958.
19 Gaetano Di Chiara . Nucleus accumbens shell and core dopamine: differential role in behavior and addiction .Behavioural Brain Research 137 (2002) 75-114.
20 Wu Q, Reith ME, Kuhar MJ, Carroll FI, Garris PA.Preferential increases in nucleus accumbens dopamine aftersystemic cocaine administration are caused by unique characteristics of dopamine neurotransmission. J Neurosci.2001;21:6338-47.
21 Schultz W. Predictive reward signal of dopamine neurons. J Neurophysiol 1998;80:1-27.
1 Huda A, Meng F, Devine DP, et al. Molecular and neuroanatomical properties of the endogenous opiate system: implications for treatment of opiate addiction. Seminars in neuroscience, 1997,9∶70~83.
2 Koob GF , Le Moal . Drug addiction , dysregulation of reward and allostasis . Neuropsychopharmacology . 2001 , 24 (2) : 97-129.
3 Kosten TA, ZhangXY, Kehoe P. Infant ratswith chronic neonatal isolation experience show decreased extracellular serotonin levels in ventral striatum at baseline and in response to cocaine. Brain Res Dev Brain Res. 2004, 152(1): 19-24.
4 McBride WJ, Murphy JM, kemoto SI. Localization of brain rein-forcementmechanisms: intracranial self-administration and intracra-nial place-conditioning studies. Behav Brain Res, 1999, 101(4):129-152.
5 Gorelick DA, Gardner EL, Xi ZX. Agents in development for themanagement of cocaine abuse. Drugs, 2004, 64(14): 1547-1573.
6 Georges F, Stinus L, Bloch B,et al. Chronic morphine exposure and spontaneouswithdrawal are associated with modifications of do-pamine receptor and neuropeptide gene expression in the rat stria-tum. Eur JNeurosc.i 1999, 11(10): 481-490.
7 Muller CP, Carey RJ, Huston JP. Serotonin as an importantmediator of cocaine’s behavioral effects. DrugsToday (Barc). 2003, 39(7): 497-511.
8 Mylecharane EJ. Ventral tegmental area 5-HT receptors: mesolimbic dopamine release and behavioural studies. Behavioural Brain Research, 1996, 73∶1~5.
9 Jacobsen LK, Staley JK, Malison RT,etal. Elevated central serotonin transporterbinding availability in acutely abstinent cocaine-dependentpatients. Am J Psychiatry, 2000, 157(7): 1134-1140.
10 Kalivas PW, Volkow N, Seamans J. Unmanageable motivation in addiction: a pathology in prefrontal-accumbens glutamate transmis-sion. Neuron. 2005, 45(5): 647-650.
11 Cornish JL, KalivasPW. Glutamate transmission in the nucleus accumbensmediates relapse in cocaine addiction. J Neurosc,i 2000,20(15): 89.
12 Park WK, JangCG, Kim HS,etal. Cocaine administered into the medial prefrontal cortex reinstates cocaine-seeking behavior by in-creasingAMPA receptor-mediated glutamate transmission in the nucleus accumbens. JNeurosc,i 2002, 22(9): 2916-2925.
13 Childress AR, Mozley PD, McElgin W,et al. Limbic activation during cueinduced cocaine craving. Am J Psychiatry, 1999, 156(1): 11-18.
14 Williams JM, Steketee JD. Cocaine increasesmedialprefrontal cortical glutamate overflow in cocaine-sensitized rats: a time course study. Eur JNeurosc.i 2004, 20(6): 1639-1646.
15 Smith JE, Co C, Yin X. Involvement of cholinergic neuronal systems in intravenous cocaine self-administration. Neuroscience and BiobehavioralReviews, 2004, 27(8) : 841-850.
16 Hikida T, Kitabatake Y, Pastan I,et al. Acetylcholine enhancement in the nucleus accumbens prevents addictive behaviors of cocaine and morphine. Proc Natl Acad Sci USA, 2003, 100 (10):6169-6173.
17 Ikemoto S, GoedersNE. Intra-medial prefrontal cortex injections of scopolamine increase instrumental responses for cocaine: an intravenous self-administration study in rats. Brain Res Bul,l 2000, 51(3): 151-158.
18 Zhang W, YamadaM, Gomez J. muscarinic acetylcholine receptor subtypesmodulate striatal dopamine release, as studied with M1-M5 muscarinic receptor knock-out mice. J Neurosci 2002, 22 (10):6347-6352.
19 Zhou FM, LiangY, Dani JA. Endogenous nicotinic cholinergic activity regulates dopamine release in the striatum. Nature Neurosci, 2001, 4(9): 1224-1229.
20 Fu Y, Matta SG, GaoW,etal. Locala-bungarotoxin-sensitive nicotinic receptors in the nucleus accumbensmodulate nicotinestimulated dopamine secretion in vivo. Neuroscience 2000, 101(6): 369-375.
21 Panagis G, KastellakisA, Spyraki C,et al. Effects of methylcaconitine (MLA) an a7 nicotinic receptor antagonist, on nicotine and cocaine-induced potentiation of brain stimulation reward. Psychopharmacology, 2000, 149(4): 388-396.
22 Crosby MJ,Hanson JE,Fleckenstein AE,et al.Phencyclidine increase vesicular dopamine uptake.European Journal of Pharmacology, 2002,438(1-2):75-78·
23 Manzanedo C,Aguilar MA,Minarro J. The effects of dopamine D2 and D3 antagonisists on spontaneousmotor activity andmorphine-induced hyperactivity in male mice[J].Psychophacology(Berl),1999,143(1):82-88.
24 KelleyAE,Berridge KC.The neuroscience of natural rewards:relevance to addictive drugs[J].J Neurosci,2002,22(9):3306-3311.
25 Laviolette SR,Nader K,van der Kooy D.Motivational state determines the functional role of the mesolimbic dopamine system in the mediation of opiate reward processes[J].Behav Brain Res,2002,129(1-2):17-29.
26 Williams JT,Christie MJ,Manzoni O.Cellular and synaptic adaptation mediating opioid dependence[J].Physiol Rev,2001,81(1):299-343.
27 Nestler EJ. Molecular mechanisms underlying opiate addiction: Implications for medications development. Seminars in Neuroscience, 1997,9∶84-93.
28 Maldonado R, Saiardi A, Valverde O, et, al.Absence of opiate rewarding effects in mice lacking dopamine D2 receptors. Nature, 1997,388∶586-589.