海洛因诱导大鼠条件性位置偏爱的建立及对氯苯丙氨酸对其影响
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摘要
目的
本研究的目的是，设计并构建条件性位置偏爱实验计算机视频跟踪系统，并用不同剂量的海洛因诱导建立大鼠条件性位置偏爱(conditioned place preference，CPP)模型，用色氨酸羟化酶抑制剂对氯苯丙氨酸(PCPA)耗竭中枢神经系统5-羟色胺(5-HT)递质，观察大鼠海洛因诱导CPP的变化。在此基础上探讨中枢5-HT功能低下对海洛因精神依赖的形成以及对海洛因成瘾行为复燃的影响。
材料与方法
1 系统构建：视频跟踪大鼠CPP实验系统由大鼠穿梭盒、隔音箱、摄像系统和一台计算机组成。视频图像采用Mice Track软件分析。
2 实验动物：雄性Sprague-Dawley大鼠72只，其中24只被随机分为3组，每组8只，进行海洛因诱导CPP模型建立的实验，另48只分为6组，每组8只，进行PCPA对海洛因诱导大鼠CPP影响的实验研究。
3 方法
3．1 海洛因诱导大鼠CPP试验包括三个步骤：
(1)给药条件化处理：用封闭式隔板将灰区和黑区完全隔离。选择灰区为伴药盒。采取每日两次腹腔注射药物的训练程序，上午海洛因组大鼠分别注射海洛因0.5mg／3ml／kg、1mg／3ml／kg后立即放置灰区训练30分钟，下午注射生理盐水3ml／kg，立即置入黑区训练30分钟。如此轮回6次。对照组训练每次给予生理盐水外，余与海洛因组相同。
(2)位置偏爱测试：最后一次训练24小时后，采用通道型隔板，将大鼠放入穿梭盒20分钟，摄录视频图像，观察大鼠在灰区和黑区分别停留的时间和活
，好辽大，笋砰士学世忿戈.
动距离:自然消退10天后再次摄录20分钟的视频图像，测定位置偏爱效应。
(3)戒断症状评分:第一次测定C即后，三组大鼠给予纳络酮4mg/kg腹腔
注射，进行催促戒断评分。
3.2 pCPA对海洛因诱导大鼠C即影响的实验。把PC队按一定剂量(0mg/kg、
IO0mg/kg、300mg/kg)连续3天腹腔注射大鼠后，进行海洛因诱导的CPP试验，
CPP试验方法如前所述。自然消退第7、8、9天再次腹腔注射pCPA，观察C即
消退情况。C即观察完成后，大鼠心脏取血，严格按照Serotonin RIA试剂盒要
求的步骤测定血小板5一HT含量。
4观察指标和分析方法
研究分析的指标有大鼠在灰区停留时间、总运动距离、穿梭次数、戒断症状
评分及血小板5一HT含量。统计分析方法包括Kruskal一Wallis检验及Bonferroni
法多重比较、Wilcoxon符号秩和检验、单因素方差分析及LSD法多重比较、
Kendall’8 tua一b秩相关检验等。
结果
l系统性能
在本实验系统中，大鼠在稳定的低噪音、低照度、通风良好、较少外界干扰
的穿梭盒中自由活动。通过视频跟踪，实现计算机上实时观察并记录大鼠活动，
成像清晰稳定，可重复观看，实验资料直观、客观。
Mioe Track软件操作灵活、简便，可同时分析多个指标。
2海洛因诱导大鼠CPP的建立、消退和运动活性的变化
2.1海洛因诱导大鼠C即的建立、消退
训练结束24小时后，海洛因条件化训练组大鼠伴药盒内停留时间显著高于
对照组(P<0 .05)。经过10天消退期，大鼠仍维持对伴药盒的偏爱。消退期后大
鼠伴药盒内停留的时间高于消退前(P<0.05)。
2.2海洛因诱导大鼠CPP建立与消退后运动活性的变化
训练结束24小时后与消退期后，海洛因条件化训练组大鼠穿梭盒内运动的
距离和穿梭次数与对照组相比均无统计学差异。
2.3大鼠灰区内停留时间、运动距离和穿梭次数两两相关性分析
葫艺几才学硬全学夕蔚戈门
总活动距离与穿梭次数间呈强正相关关系(r二0.787，P<0 .001):灰区内停
留时间与总活动距离、穿梭次数间呈弱正泪关关系(分别r二0.287，P<0 .01;
r== 0 .205，P(0.01)。
3尸CPA对海洛因诱导大鼠CPP建立和消退及运动活性的影响
3.1 CPP的建立和消退
训练结束24小时后及消退期后6组大鼠伴药盒内停留时间均具有统计学差
异(分别广=25.797，p=0.0001;广=25.065，p=0.0001)。接触PCPA或海洛因
均可增加大鼠灰区内停留时间，而PCPA处理对海洛因诱导大鼠CPP形成影响不
大。消退前后自身比较具有统计学差异(Z二一8.507，p<0 .001)，接触海洛因的
PCPA低、中剂量组消退后伴药盒内停留的时间高于消退前(分别增加
121.64士32一95和182士43.265)，差异具有显著性(分别Z=一1.976，P=0.043;
Z=一1.998，P=0.042)，而且，随着PCPA剂量由0 mg/kg加大为100mg/kg，伴药
盒内停留时间增加更显著(F=8.47，p<0 .05)，说明与海洛因相联系的环境线索
(伴药盒)使大鼠觅药行为敏感化，PCPA具有增加消退期海洛因依赖大鼠对环
境线索的敏感作用。
3.2运动活性
PCPA及海洛因均增加消退期大鼠的穿梭次数，但PC队对海洛因诱导大鼠总
活动距离和穿梭次数影响不大。
3.3血小板5一HT含量
单独海洛因处理组大鼠血小板5一HT含量显著高于NS组(P<0 .01)，PCPA
处理组大鼠血小板5一HT含量显著低于NS组(P<0 .01)。
3.4血小板5一HT与大鼠灰区内停留时间、活动距离、穿梭次数两两比较相关分
析
5一HT含量与灰区内停留时间呈中等程度的负相关(r二一0.441，P=0.000)，
与总活动距离无相关性(r=o.015，P=0 .88)，与穿梭次数呈
Objective
The objective of the present study was to construct video track conditioned place preference(CPP) experimental system in rats and set up heroin-induced CPP. Tryptophan hydroxylase inhibitor PCPA was used to exhaust the center nerve system(CNS) 5-HT and heroin-induced CPP in rats were performed, on this basis we search for the variation of heroin dependence formation and relapse in the condition CNS 5-HT transmission dysfunction.
Materials and methods
1 System construction
The video track CPP experimental system in rats was composed of shuttle box, a sound-proof container, vedio apparatus and a computer. The video was analyzed using Mice Track software.
2 Animals
72 male Sprague-Dawley rats were used, in which 24 rats divided in three groups participated in heroin-induced CPP while the rest divided in six groups undertook the research of PCPA treatment.
3 Methods
3.1 Heroin induced place-preference conditioning schedule consisted of three phases.
(1) Conditioning phase, blocking partition were used to segregate the gray and black box, during which two groups of rats were treated for 2 consecutive with alternate injection of heroin (0. 5mg and Img per kg body weight in a volume of 3ml per kg body weight, i.p.) or saline one day for 6 days. Conditioning sessions were carried out over a 30min period immediately after injection. Rats were confined to the gray compartment after heroin injection and to the black compartment after saline injection. The control were offered saline(3ml per kg body weight, i.p.) before confinement to either compartment.
(2) Testing phase, during which video was captured and tests of conditioning were performed as follows: the passage partitions were used for rats to freely access each compartment 20min, 24h after the final conditioning session and 10 days extinction phase.
(3) Giving a mark of abstinent symptom, three groups of rats were administrated naloxone and undertook precipitated abstinent scores.
3. 2 To investigate the effects of PCPA on heroin-induced CPP, PCPA with fixed dosage (0mg/kg> 100mg/kg> 300mg/kg) were administered to rats by i.p. for 3 days before conditioning and on the extinction day 7,8,9. Tests of rats' movement were conducted 24h after the final conditioning session and 10 days extinction phase to observe CPP formation and extinction respectively. The content of 5-HT in the platelet was determined according to the procedure of the Serotonin RIA Kit after CPP observation.
4 Data analysis
The sojourn time in the gray compartment, the total distance rats moved, crossing times between the two compartments, the score of withdrawal symptom and the content of the 5-HT in platelet were obtained. Statistical analysis methods included Kruskal-Wallis test, Bonferroni
multicomparison, Wilcoxcn signed rank test, one-way ANOVA , LSD multicomparison and Kendall' s tua-b bibariate correlations test.
Results
1 The potency of the system
Rats moved freely in the shuttle box in a quiet, dim environment. Data were objectively obtained by analyzing the video using Mice Track software, which is flexible and can analyze several parameters simultaneously.
2 Heroin-induced CPP foundation, extinction and locomotion changes in rats
2.1 Heroin-induced CPP foundation and extinction
24h after conditioning, the sojourn time of the two groups of rats conditioning with heroin in the gray compartment was significantly longer than control. 10 days passby, two heroin treated groups rats remained the preference. The sojourn time in gray compartment after extinction was significantly longer than before.
2. 2 The movement changes after heroin-induce CPP creation and extinction in rats
24h after the final conditioning session and over the 10-day extinction phase, the distance and crossing times had no difference in three groups of tats.
2. 3 Correlation between sojourn time and distance in the gray compartment and crossing times
There was strong correlation between the total moved distance and crossing times (r=0. 787, P<0. 001); while the
本研究的目的是，设计并构建条件性位置偏爱实验计算机视频跟踪系统，并用不同剂量的海洛因诱导建立大鼠条件性位置偏爱(conditioned place preference，CPP)模型，用色氨酸羟化酶抑制剂对氯苯丙氨酸(PCPA)耗竭中枢神经系统5-羟色胺(5-HT)递质，观察大鼠海洛因诱导CPP的变化。在此基础上探讨中枢5-HT功能低下对海洛因精神依赖的形成以及对海洛因成瘾行为复燃的影响。
材料与方法
1 系统构建：视频跟踪大鼠CPP实验系统由大鼠穿梭盒、隔音箱、摄像系统和一台计算机组成。视频图像采用Mice Track软件分析。
2 实验动物：雄性Sprague-Dawley大鼠72只，其中24只被随机分为3组，每组8只，进行海洛因诱导CPP模型建立的实验，另48只分为6组，每组8只，进行PCPA对海洛因诱导大鼠CPP影响的实验研究。
3 方法
3．1 海洛因诱导大鼠CPP试验包括三个步骤：
(1)给药条件化处理：用封闭式隔板将灰区和黑区完全隔离。选择灰区为伴药盒。采取每日两次腹腔注射药物的训练程序，上午海洛因组大鼠分别注射海洛因0.5mg／3ml／kg、1mg／3ml／kg后立即放置灰区训练30分钟，下午注射生理盐水3ml／kg，立即置入黑区训练30分钟。如此轮回6次。对照组训练每次给予生理盐水外，余与海洛因组相同。
(2)位置偏爱测试：最后一次训练24小时后，采用通道型隔板，将大鼠放入穿梭盒20分钟，摄录视频图像，观察大鼠在灰区和黑区分别停留的时间和活
，好辽大，笋砰士学世忿戈.
动距离:自然消退10天后再次摄录20分钟的视频图像，测定位置偏爱效应。
(3)戒断症状评分:第一次测定C即后，三组大鼠给予纳络酮4mg/kg腹腔
注射，进行催促戒断评分。
3.2 pCPA对海洛因诱导大鼠C即影响的实验。把PC队按一定剂量(0mg/kg、
IO0mg/kg、300mg/kg)连续3天腹腔注射大鼠后，进行海洛因诱导的CPP试验，
CPP试验方法如前所述。自然消退第7、8、9天再次腹腔注射pCPA，观察C即
消退情况。C即观察完成后，大鼠心脏取血，严格按照Serotonin RIA试剂盒要
求的步骤测定血小板5一HT含量。
4观察指标和分析方法
研究分析的指标有大鼠在灰区停留时间、总运动距离、穿梭次数、戒断症状
评分及血小板5一HT含量。统计分析方法包括Kruskal一Wallis检验及Bonferroni
法多重比较、Wilcoxon符号秩和检验、单因素方差分析及LSD法多重比较、
Kendall’8 tua一b秩相关检验等。
结果
l系统性能
在本实验系统中，大鼠在稳定的低噪音、低照度、通风良好、较少外界干扰
的穿梭盒中自由活动。通过视频跟踪，实现计算机上实时观察并记录大鼠活动，
成像清晰稳定，可重复观看，实验资料直观、客观。
Mioe Track软件操作灵活、简便，可同时分析多个指标。
2海洛因诱导大鼠CPP的建立、消退和运动活性的变化
2.1海洛因诱导大鼠C即的建立、消退
训练结束24小时后，海洛因条件化训练组大鼠伴药盒内停留时间显著高于
对照组(P<0 .05)。经过10天消退期，大鼠仍维持对伴药盒的偏爱。消退期后大
鼠伴药盒内停留的时间高于消退前(P<0.05)。
2.2海洛因诱导大鼠CPP建立与消退后运动活性的变化
训练结束24小时后与消退期后，海洛因条件化训练组大鼠穿梭盒内运动的
距离和穿梭次数与对照组相比均无统计学差异。
2.3大鼠灰区内停留时间、运动距离和穿梭次数两两相关性分析
葫艺几才学硬全学夕蔚戈门
总活动距离与穿梭次数间呈强正相关关系(r二0.787，P<0 .001):灰区内停
留时间与总活动距离、穿梭次数间呈弱正泪关关系(分别r二0.287，P<0 .01;
r== 0 .205，P(0.01)。
3尸CPA对海洛因诱导大鼠CPP建立和消退及运动活性的影响
3.1 CPP的建立和消退
训练结束24小时后及消退期后6组大鼠伴药盒内停留时间均具有统计学差
异(分别广=25.797，p=0.0001;广=25.065，p=0.0001)。接触PCPA或海洛因
均可增加大鼠灰区内停留时间，而PCPA处理对海洛因诱导大鼠CPP形成影响不
大。消退前后自身比较具有统计学差异(Z二一8.507，p<0 .001)，接触海洛因的
PCPA低、中剂量组消退后伴药盒内停留的时间高于消退前(分别增加
121.64士32一95和182士43.265)，差异具有显著性(分别Z=一1.976，P=0.043;
Z=一1.998，P=0.042)，而且，随着PCPA剂量由0 mg/kg加大为100mg/kg，伴药
盒内停留时间增加更显著(F=8.47，p<0 .05)，说明与海洛因相联系的环境线索
(伴药盒)使大鼠觅药行为敏感化，PCPA具有增加消退期海洛因依赖大鼠对环
境线索的敏感作用。
3.2运动活性
PCPA及海洛因均增加消退期大鼠的穿梭次数，但PC队对海洛因诱导大鼠总
活动距离和穿梭次数影响不大。
3.3血小板5一HT含量
单独海洛因处理组大鼠血小板5一HT含量显著高于NS组(P<0 .01)，PCPA
处理组大鼠血小板5一HT含量显著低于NS组(P<0 .01)。
3.4血小板5一HT与大鼠灰区内停留时间、活动距离、穿梭次数两两比较相关分
析
5一HT含量与灰区内停留时间呈中等程度的负相关(r二一0.441，P=0.000)，
与总活动距离无相关性(r=o.015，P=0 .88)，与穿梭次数呈
Objective
The objective of the present study was to construct video track conditioned place preference(CPP) experimental system in rats and set up heroin-induced CPP. Tryptophan hydroxylase inhibitor PCPA was used to exhaust the center nerve system(CNS) 5-HT and heroin-induced CPP in rats were performed, on this basis we search for the variation of heroin dependence formation and relapse in the condition CNS 5-HT transmission dysfunction.
Materials and methods
1 System construction
The video track CPP experimental system in rats was composed of shuttle box, a sound-proof container, vedio apparatus and a computer. The video was analyzed using Mice Track software.
2 Animals
72 male Sprague-Dawley rats were used, in which 24 rats divided in three groups participated in heroin-induced CPP while the rest divided in six groups undertook the research of PCPA treatment.
3 Methods
3.1 Heroin induced place-preference conditioning schedule consisted of three phases.
(1) Conditioning phase, blocking partition were used to segregate the gray and black box, during which two groups of rats were treated for 2 consecutive with alternate injection of heroin (0. 5mg and Img per kg body weight in a volume of 3ml per kg body weight, i.p.) or saline one day for 6 days. Conditioning sessions were carried out over a 30min period immediately after injection. Rats were confined to the gray compartment after heroin injection and to the black compartment after saline injection. The control were offered saline(3ml per kg body weight, i.p.) before confinement to either compartment.
(2) Testing phase, during which video was captured and tests of conditioning were performed as follows: the passage partitions were used for rats to freely access each compartment 20min, 24h after the final conditioning session and 10 days extinction phase.
(3) Giving a mark of abstinent symptom, three groups of rats were administrated naloxone and undertook precipitated abstinent scores.
3. 2 To investigate the effects of PCPA on heroin-induced CPP, PCPA with fixed dosage (0mg/kg> 100mg/kg> 300mg/kg) were administered to rats by i.p. for 3 days before conditioning and on the extinction day 7,8,9. Tests of rats' movement were conducted 24h after the final conditioning session and 10 days extinction phase to observe CPP formation and extinction respectively. The content of 5-HT in the platelet was determined according to the procedure of the Serotonin RIA Kit after CPP observation.
4 Data analysis
The sojourn time in the gray compartment, the total distance rats moved, crossing times between the two compartments, the score of withdrawal symptom and the content of the 5-HT in platelet were obtained. Statistical analysis methods included Kruskal-Wallis test, Bonferroni
multicomparison, Wilcoxcn signed rank test, one-way ANOVA , LSD multicomparison and Kendall' s tua-b bibariate correlations test.
Results
1 The potency of the system
Rats moved freely in the shuttle box in a quiet, dim environment. Data were objectively obtained by analyzing the video using Mice Track software, which is flexible and can analyze several parameters simultaneously.
2 Heroin-induced CPP foundation, extinction and locomotion changes in rats
2.1 Heroin-induced CPP foundation and extinction
24h after conditioning, the sojourn time of the two groups of rats conditioning with heroin in the gray compartment was significantly longer than control. 10 days passby, two heroin treated groups rats remained the preference. The sojourn time in gray compartment after extinction was significantly longer than before.
2. 2 The movement changes after heroin-induce CPP creation and extinction in rats
24h after the final conditioning session and over the 10-day extinction phase, the distance and crossing times had no difference in three groups of tats.
2. 3 Correlation between sojourn time and distance in the gray compartment and crossing times
There was strong correlation between the total moved distance and crossing times (r=0. 787, P<0. 001); while the
引文
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5 秦伯益．戒毒药物的现状及研究进展．医药导报，2002，21(8)：467～468．
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7 Gilberto gerra, Amir Zaimovic, Mariaemanuela Timpano. Neuroendocrine correlates of temperament traits in abstinent opiate addictions. Journal of substance abuse, 2000, 11(4): 337-354.
8 Rose JS, Branchey M, Wallach L. Effects of buspirone in withdrawal from opiates. Am J Addict. 2003, 12(3): 253-259.
9 Taco J, De Vries, Toni S. Neural systems underlying opiate addiction. The journal of neuroscience, 2002, 22(9): 3321-3325.
10 M.T. Bardo, J.K. Rowlett. Conditioned Place Preference Using Opiate and Stimulant Drugs: A Meta-Analysis. Neuroscience and Biobehavioral Reviews, 1995, 19(1): 39～51.
11 Tzschentke TM. Measuring reward with the conditioned place preference paradigm: a comprehensive rewiew of drug effects, recent progress and new issues. Prog Neurobiol. 1998, 56: 613-672.
12 Andrew J, Megeehan M, Foster Olive. The anti-relapse compound acamprosate inhibits the development of a conditioned place preference to ethanol and cocaine but not morphine. Brain journal of pharmacology, 2003, 138: 9-12.
13 叶晓明等．海洛因依赖大鼠模型的建立．第二军医大学学报，2000，21(1)：95．
14 Ann E, Kelley and Kent c. Berrdge. The Neuroscience of Natural Rewards: Relevance to Addictive Drugs. The Neuroscience of Natural Rewards,
2002, 22(9): 3306～3311.
15 Nora D. Volkow, Joanna S. Fowter, and Gene-Jack Wang. The addicted human brain: Insights from Imaging Studies. The Journal of Clinical Investigation, 2003, 111(10): 1444～1451.
16 Uri Shalev, Jeffrey W. Grimm, and Yavin Shaham. Neurobiology of Relapse to Heroin and Cocaine Seeking: A Review. Psychopharmacology Reviews, 2002, 54(1): 1～42.
17 L.A. Sell, J.S. Morris. Neural Ressponses Associated with Cue Evoked Emotional States and Heroin in Opiate Addicts. Drug and Alcohol Dependence, 2000, 60: 207～216.
18 Lu L, Xu NJ, Ge X, Yue W, Su WJ, Pei G, Ma L. Reactivation of morphine conditioned place preference by drug priming: role of environmental cues and sensitization. Psychopharmacology, 2002, 159(2): 125～32.
19 Bardo MT, Miller JS, Neisewander JL. Conditioned Place preference with morphine: the effect of extinction training on the reinforcing CR. Phamacol Biochem Behav. 1984, 21(4): 545-549.
20 Jan M. Van Ree, Miriam. A. F. M, Louk. J.M.J. Vanderschren. Opioids, rewarding and addiction: an encounter of biology, psychology, and medicine. Pharmocolgical Reviews, 1999, 51(2): 341-384.
21 Becker A, Grecksch G, Brodemann R. Morphine self-administration in mu-opioid receptor-deficient mice. Naunyn Schmiedebergs Arch Pharmacol. 2000, 361(6): 584-589.
22 Michael H. Ebert, Peter T. Loosen, Barry Nurcombe. Current diagnosis & treatment in psychiatry. McGraw-Hill, 2000: 246-247.
23 Tomas R. Rosten, Tony P. George. The nerobiolog y of opioid dependence: implications for treatment. Science & practice perspectives, 2002,7: 13-20.
24 Yan Z. Regulation of GABAergic inhibition by serotonin signaling in prefrontal cortex: molecular mechanisms and functional implications.
Mol Neurobiol. 2002, 26(2-3): 203-216.
25 Filip M, Cunningham KA. Hyperlocomotive and discriminative stimulus effects of cocaine are under the control of serotonin(2C) (5-HT(2C)) receptors in rat prefrontal cortex. J Pharmacol Exp Ther. 2003, 306(2): 734-743.
26 Bishop C, Tessmer JL, Ullrich T. Serotonin 5-HT2A receptors underlie increased motor behaviors induced in dopamine -depleted rats by intrastriatal 5-HT2A/2C agonism. J Pharmacol Exp Ther. 2004, 25: 452-467.
27 John T. Williams, Macdonald J. Christie, Olivier Manzoni. Cellular and synaptic adaptations mediating opioid dependence. Physiological Reviews, 2001; 81(1): 299-330.
28 Pu L, Bao GB, Xu NJ. Hippocampal long-term potentiationes reduced by chronic opiate treatment and can be restored by re-exposure to opiates. Neuroscience, 2002, 22(5): 1914-1921.
29 Amallia J. Eisch, Michel Barrot, Christina A. Schad. Opiates inhibit neurogenesis in the adult rat hippocampus. PANS, 2000, 97(13): 7579-7584.
30 Ronald S. Duman, Jessica Malberg, Shin Nakagawa. Regulation of adult neurogenesis by psychotropic drugs and stress. Perspective in pharmacology, 2001, 299(2): 401-407.
31 Schluger JH, Bart G, Green M. Corticotropin-releasing factor testing reveals a dose-dependent difference in methadone maintained vs control subjects. Neuropsychopharmacology, 2003 May; 28(5): 985-94.
32 高志勤，余海鹰，刘贵永等．海洛因依赖者血小板5-羟色胺水平的观察．临床精神医学杂志，2001，11(3)：161-162．
2 蔡志基．国际和国内禁毒和戒毒工作回顾．中国药物滥用防治杂志，2001，33(4)：2～5．
3 张开镐．评价药物精神依赖性的试验方法(一)．中国药物依赖性杂志，2000，9(2)：91～93．
4 赵成正等．分析《中国药物依赖性杂志》十年载文看我国药物依赖性研究现状．中国药物依赖性杂志，2002：11(1)，44～46．
5 秦伯益．戒毒药物的现状及研究进展．医药导报，2002，21(8)：467～468．
6 Gilberto gerra, Amir Zaimovic, Ursula Zambelli. Neuroendocrine correlates of depression in abstinent heroin-dependent subjects. Psychiatry Research, 2000, 96: 221-234.
7 Gilberto gerra, Amir Zaimovic, Mariaemanuela Timpano. Neuroendocrine correlates of temperament traits in abstinent opiate addictions. Journal of substance abuse, 2000, 11(4): 337-354.
8 Rose JS, Branchey M, Wallach L. Effects of buspirone in withdrawal from opiates. Am J Addict. 2003, 12(3): 253-259.
9 Taco J, De Vries, Toni S. Neural systems underlying opiate addiction. The journal of neuroscience, 2002, 22(9): 3321-3325.
10 M.T. Bardo, J.K. Rowlett. Conditioned Place Preference Using Opiate and Stimulant Drugs: A Meta-Analysis. Neuroscience and Biobehavioral Reviews, 1995, 19(1): 39～51.
11 Tzschentke TM. Measuring reward with the conditioned place preference paradigm: a comprehensive rewiew of drug effects, recent progress and new issues. Prog Neurobiol. 1998, 56: 613-672.
12 Andrew J, Megeehan M, Foster Olive. The anti-relapse compound acamprosate inhibits the development of a conditioned place preference to ethanol and cocaine but not morphine. Brain journal of pharmacology, 2003, 138: 9-12.
13 叶晓明等．海洛因依赖大鼠模型的建立．第二军医大学学报，2000，21(1)：95．
14 Ann E, Kelley and Kent c. Berrdge. The Neuroscience of Natural Rewards: Relevance to Addictive Drugs. The Neuroscience of Natural Rewards,
2002, 22(9): 3306～3311.
15 Nora D. Volkow, Joanna S. Fowter, and Gene-Jack Wang. The addicted human brain: Insights from Imaging Studies. The Journal of Clinical Investigation, 2003, 111(10): 1444～1451.
16 Uri Shalev, Jeffrey W. Grimm, and Yavin Shaham. Neurobiology of Relapse to Heroin and Cocaine Seeking: A Review. Psychopharmacology Reviews, 2002, 54(1): 1～42.
17 L.A. Sell, J.S. Morris. Neural Ressponses Associated with Cue Evoked Emotional States and Heroin in Opiate Addicts. Drug and Alcohol Dependence, 2000, 60: 207～216.
18 Lu L, Xu NJ, Ge X, Yue W, Su WJ, Pei G, Ma L. Reactivation of morphine conditioned place preference by drug priming: role of environmental cues and sensitization. Psychopharmacology, 2002, 159(2): 125～32.
19 Bardo MT, Miller JS, Neisewander JL. Conditioned Place preference with morphine: the effect of extinction training on the reinforcing CR. Phamacol Biochem Behav. 1984, 21(4): 545-549.
20 Jan M. Van Ree, Miriam. A. F. M, Louk. J.M.J. Vanderschren. Opioids, rewarding and addiction: an encounter of biology, psychology, and medicine. Pharmocolgical Reviews, 1999, 51(2): 341-384.
21 Becker A, Grecksch G, Brodemann R. Morphine self-administration in mu-opioid receptor-deficient mice. Naunyn Schmiedebergs Arch Pharmacol. 2000, 361(6): 584-589.
22 Michael H. Ebert, Peter T. Loosen, Barry Nurcombe. Current diagnosis & treatment in psychiatry. McGraw-Hill, 2000: 246-247.
23 Tomas R. Rosten, Tony P. George. The nerobiolog y of opioid dependence: implications for treatment. Science & practice perspectives, 2002,7: 13-20.
24 Yan Z. Regulation of GABAergic inhibition by serotonin signaling in prefrontal cortex: molecular mechanisms and functional implications.
Mol Neurobiol. 2002, 26(2-3): 203-216.
25 Filip M, Cunningham KA. Hyperlocomotive and discriminative stimulus effects of cocaine are under the control of serotonin(2C) (5-HT(2C)) receptors in rat prefrontal cortex. J Pharmacol Exp Ther. 2003, 306(2): 734-743.
26 Bishop C, Tessmer JL, Ullrich T. Serotonin 5-HT2A receptors underlie increased motor behaviors induced in dopamine -depleted rats by intrastriatal 5-HT2A/2C agonism. J Pharmacol Exp Ther. 2004, 25: 452-467.
27 John T. Williams, Macdonald J. Christie, Olivier Manzoni. Cellular and synaptic adaptations mediating opioid dependence. Physiological Reviews, 2001; 81(1): 299-330.
28 Pu L, Bao GB, Xu NJ. Hippocampal long-term potentiationes reduced by chronic opiate treatment and can be restored by re-exposure to opiates. Neuroscience, 2002, 22(5): 1914-1921.
29 Amallia J. Eisch, Michel Barrot, Christina A. Schad. Opiates inhibit neurogenesis in the adult rat hippocampus. PANS, 2000, 97(13): 7579-7584.
30 Ronald S. Duman, Jessica Malberg, Shin Nakagawa. Regulation of adult neurogenesis by psychotropic drugs and stress. Perspective in pharmacology, 2001, 299(2): 401-407.
31 Schluger JH, Bart G, Green M. Corticotropin-releasing factor testing reveals a dose-dependent difference in methadone maintained vs control subjects. Neuropsychopharmacology, 2003 May; 28(5): 985-94.
32 高志勤，余海鹰，刘贵永等．海洛因依赖者血小板5-羟色胺水平的观察．临床精神医学杂志，2001，11(3)：161-162．