大麻素CB1受体拮抗剂利莫那班对小鼠甲基苯丙胺条件性位置偏爱的影响
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摘要
目的:甲基苯丙胺(methamphetamine, METH)是一种常用的成瘾药物,具有强烈的中枢兴奋作用。近年来,我国滥用METH人数持续上升。随着这类药物的长期滥用,其精神依赖性和严重的毒副作用也日益突出。这不仅给滥用者自身带来危害,也造成了严重的社会问题。新的理论表明,药物成瘾是一种慢性复发性脑病,反复使用成瘾药物可以形成异常持久的药物奖赏性记忆,作为一种异常的学习记忆,它与正常记忆的相似之处在于,也需要经过一个信息获得和巩固的过程才能形成较为稳定的记忆。而且当该记忆被再次唤起后,会处于一种不稳定而易被破坏的状态,其再次稳定仍需要一个类似于巩固的过程,因此,通过干预药物奖赏记忆的巩固过程可以破坏记忆的形成,而对记忆再巩固过程的干预,则可以改变或消除原有记忆。大麻素CB1受体是用于治疗药物成瘾的一个新的靶点,内源性大麻素(endocannabinoids)和CB1受体广泛分布于记忆相关脑区,参与记忆的调节。已有很多研究将CB1受体作为新的靶点用于研究空间记忆和恐怖记忆,不同的记忆类型其研究结果也存在差异。在成瘾记忆中,尚缺乏与CB1受体有关的系统研究。条件性位置偏爱(conditioned place preference, CPP)是广泛应用于评价药物奖赏效应的实验方法,近年来也被用于药物成瘾记忆的研究,药物与环境之间的反复关联使动物产生长期的行为改变,反映了奖赏控制的学习过程。METH-CPP使动物对与METH相关的特定环境产生偏爱,这一行为模型模拟了METH应用-联想记忆,特定环境线索(条件性刺激)与METH所产生的欣快感(非条件性刺激)反复关联,激发了动物在无药状态选择药物相关环境的动机行为。本实验的目的是用CB1受体拮抗剂利莫那班(rimonabant)对CPP模型奖赏记忆形成的不同阶段进行干预,观察其在METH奖赏记忆中的作用。
方法:1、小鼠6组(n=6),分别用生理盐水(NS)和METH(0.5mg/kg或2mg/kg,i.p)训练CPP,训练时间分别为20min或60min,训练8天后进行CPP测试,观察在不同条件下METH-CPP的形成是否有显著性差异,确定METH-CPP形成的最佳条件。2、小鼠3组(n=10)训练METH-CPP(2mg/kg, 20min,i.p),并在每次训练后立即分别给予不同剂量的利莫那班(0mg/kg,1.0mg/kg和3.0mg/kg,i.p)观察利莫那班对METH-CPP形成的影响。3、小鼠3组(n=8),训练METH-CPP(2mg/kg,20min,i.p),在CPP测试前30min分别给予不同剂量的利莫那班(0mg/kg,1.0mg/kg和3.0mg/kg),观察利莫那班对METH-CPP的影响。并在测试后24小时,7天和14天时重复测定CPP值,并于第15天给予METH(0.5mg/kg,i.p),观察METH-CPP能否重现;4、小鼠3组(n=9),训练METH-CPP(2mg/kg, 20min,i.p),在CPP测试结束后立即分别给予不同剂量的利莫那班(0mg/kg,1.0mg/kg和3.0mg/kg)并在测试后24小时,7天和14天时重复测定CPP值,并于第15天给予METH(0.5mg/kg,i.p),观察METH-CPP能否重现;5、小鼠3组(n=10),训练METH-CPP(2mg/kg,20min,i.p),CPP形成后使其消退,测试消退后第二天给予METH(0.5mg/kg,i.p),观察METH-CPP能否复现;并在点燃前30min给予不同剂量的利莫那班( 0mg/kg , 1.0mg/kg和3.0mg/kg),观察其对点燃的影响。
结果:1、与生理盐水对照组相比,4种不同训练条件下的小鼠均形成CPP;2、与空白对照组相比,利莫那班1.0mg/kg组和3.0mg/kg组均未形成CPP,提示利莫那班破坏了METH奖赏记忆的巩固过程;3、与空白对照组相比,利莫那班3mg/kg组小鼠未能表达显著的CPP,提示利莫那班阻断了奖赏记忆的唤起,抑制了小鼠METH-CPP的表达;4、与空白对照组相比,CPP测试后立即给予3mg/kg的利莫那班,可以破坏已经形成的CPP,而未经唤起的小鼠其CPP持续存在,提示利莫那班破坏了奖赏记忆的再巩固过程,且这一作用是唤起依赖的;5、与空白对照组相比,3mg/kg的利莫那班可以抑制METH(0.5mg/kg)诱导的CPP消退后复现。
结论:昆明小鼠可以形成显著的METH-CPP,大麻素CB1受体拮抗剂利莫那班可以破坏METH奖赏记忆的巩固、唤起和再巩固过程;小剂量的METH可以使小鼠已经消退的CPP行为重现,利莫那班可以抑制METH的这一点燃作用。
Objectives: Methamphetamine (METH) is a commonly used, addictive drug, and a powerful stimulant that dramatically affects the central nervous system. METH users continually increased in our country in recent years. And its psychological dependence and serious adverse effects have been outstanding day by day. METH abuse not only brings about health problems to drug users, but also results in serious social problems. Drug addiction is a chronic, relapsing brain disorder. Repeated drug use associated with contexts lead to form an abnormally persistent rewarding memory. Similar to normal learning and memory, drug memory achieve a stable and relatively permanent state via an acquisition and consolidation process to form long term memory. However, they become labile when they are reactivated and must be reconsolidated to achieve a stable state again. Thus, some treatments could be used to block acquisition of memory via interfere with memory consolidation and impair original memory through disrupting memory reconsolidation. Cannabinoid CB1 receptor is a new target for drug addiction therapy. Endocannabinoids and CB1 receptor are widely distributed in memory-related brain regions, participated in memory modulation. There have been many studies to investigate the role of CB1 receptor in spatial or fear memory. Conclusions were not consistent since the types of memory were different. Drug-related memory studies using CB1 receptor were concentrated on extinction learning, which indicated that cannabinoid CB1 receptor blocked extinction process and inhibitory extinction behaviors. Conditioned place preference (CPP) paradigm has been widely used to evaluate the rewarding effect. Repeated association of drugs use with contexts predicting drug availability leads to long-lasting behavioral responses that reflect reward-controlled learning. METH-induced conditioned place preference (CPP), the preference for the specific place containing the METH conditioned cues over a natural control place, has been used as a behavioral paradigm for mimicking the METH use-associated memory. In this conditioning paradigm, repeated association of the specific environmental cues (conditioned stimulus) with METH-induced subjective euphoria (unconditioned stimulus) has been suggested to motivate animals’later approaching behavior toward the euphoria-linked environment at a drug-free status. In the present study, we used the conditioned place preference (CPP) paradigm in order to investigate the role of cannabinoid CB1 receptor antagonist in the drug-related memory.
Methods: 1, Mice were divided into 6 groups which were saline-20min, saline-60min, 0.5mg/kg-20min, 0.5mg/kg-60min, 2mg/kg-20min and 2mg/kg-60min by different training paradigms. The acquisition of CPP was observed after training. The dose of METH and confining time were then identified and applied to subsequent experiments. 2, Mice were divided into 3 groups to be trained for METH CPP(2mg/kg, 20min, i.p)and were given intra-peritoneal injections of different doses of rimonabant(0, 1.0mg/kg and 3.0mg/kg) immediately after each conditioning session. After 8 consecutive sessions, mice were tested for CPP. 3, Mice were divided into 3 groups to be trained for METH CPP(2mg/kg, 20min, i.p). Administrations of different doses of rimonabant (0mg/kg, 1.0mg/kg and 3.0 mg/kg) were given 30min before place preference testing. Retesting of METH CPP was done 24 hours, 7 days or 14 days after rimonabant administration. On the 15th day, mice were injected with a priming dose of METH (0.5mg/kg) and were tested to see whether place preference was reinstated. 4, Mice were divided into 3 groups to be trained for METH CPP(2mg/kg, 20min, i.p). Administrations of different doses of rimonabant (0mg/kg, 1.0mg/kg and 3.0 mg/kg) were given immediately after place preference testing. Retesting of METH CPP was done 24 hours, 7 days or 14 days after rimonabant administration. On the 15th day, mice were injected with a priming dose of METH (0.5mg/kg) and were tested to see whether place preference was reinstated. 5, Mice were divided into 3 groups to be trained for METH CPP(2mg/kg, 20min, i.p). After 8 consecutive sessions and tested for METH CPP, mice were not given any treatment and were retest every 3 days. One day after the determination of place preference extinction, mice were injected with a priming dose of METH (0.5mg/kg) and were tested to see whether place preference was reinstated. Different doses of rimonabant (0mg/kg, 1.0mg/kg and 3.0 mg/kg) were administered 30 minutes prior to the priming injection of METH.
Results: 1, Compared with saline groups, 4 METH groups with different training paradigms all expressed a METH CPP and no significant difference was found between any two groups. 2, Compared with vehicle group, post-training administration of 1mg/kg and 3mg/kg rimonabant blocked the acquisition of METH CPP, suggesting rimonabant disrupted consolidation of METH rewarding memory. 3, Compared with vehicle group, pre-test administration of 3mg/kg rimonabant inhibited CPP expression while other two groups expressed significant CPP, suggesting rimonabant blocked retrieval of METH rewarding memory. The effect lasted for at least 1 week. 4, Compared with vehicle group, 24h after post-testing administration of different doses of rimonabant, mice in 3mg/kg group which expressed significant CPP in the first place preference testing failed to express CPP the next day and in subsequent tests. However, mice in groups without retrieval expressed CPP persistently, suggesting the effect of rimonabant on memory reconsolidation was retrieval-dependent. 5, Compared with vehicle group, a dose of 0.5mgkg METH failed to induce the reinstatement of CPP in the group of 3mg/kg rimonabant, suggesting rimonabant could inhibit reinstatement of METH CPP.
Conclusion: The present study indicated that mice expressed significant CPP produced by METH. Cannabinoid CB1 receptor antagonist disrupted consolidation, retrieval and reconsolidation of METH rewarding memory. A priming dose of METH induced reinstatement of CPP which could be attenuated by rimonabant.
方法:1、小鼠6组(n=6),分别用生理盐水(NS)和METH(0.5mg/kg或2mg/kg,i.p)训练CPP,训练时间分别为20min或60min,训练8天后进行CPP测试,观察在不同条件下METH-CPP的形成是否有显著性差异,确定METH-CPP形成的最佳条件。2、小鼠3组(n=10)训练METH-CPP(2mg/kg, 20min,i.p),并在每次训练后立即分别给予不同剂量的利莫那班(0mg/kg,1.0mg/kg和3.0mg/kg,i.p)观察利莫那班对METH-CPP形成的影响。3、小鼠3组(n=8),训练METH-CPP(2mg/kg,20min,i.p),在CPP测试前30min分别给予不同剂量的利莫那班(0mg/kg,1.0mg/kg和3.0mg/kg),观察利莫那班对METH-CPP的影响。并在测试后24小时,7天和14天时重复测定CPP值,并于第15天给予METH(0.5mg/kg,i.p),观察METH-CPP能否重现;4、小鼠3组(n=9),训练METH-CPP(2mg/kg, 20min,i.p),在CPP测试结束后立即分别给予不同剂量的利莫那班(0mg/kg,1.0mg/kg和3.0mg/kg)并在测试后24小时,7天和14天时重复测定CPP值,并于第15天给予METH(0.5mg/kg,i.p),观察METH-CPP能否重现;5、小鼠3组(n=10),训练METH-CPP(2mg/kg,20min,i.p),CPP形成后使其消退,测试消退后第二天给予METH(0.5mg/kg,i.p),观察METH-CPP能否复现;并在点燃前30min给予不同剂量的利莫那班( 0mg/kg , 1.0mg/kg和3.0mg/kg),观察其对点燃的影响。
结果:1、与生理盐水对照组相比,4种不同训练条件下的小鼠均形成CPP;2、与空白对照组相比,利莫那班1.0mg/kg组和3.0mg/kg组均未形成CPP,提示利莫那班破坏了METH奖赏记忆的巩固过程;3、与空白对照组相比,利莫那班3mg/kg组小鼠未能表达显著的CPP,提示利莫那班阻断了奖赏记忆的唤起,抑制了小鼠METH-CPP的表达;4、与空白对照组相比,CPP测试后立即给予3mg/kg的利莫那班,可以破坏已经形成的CPP,而未经唤起的小鼠其CPP持续存在,提示利莫那班破坏了奖赏记忆的再巩固过程,且这一作用是唤起依赖的;5、与空白对照组相比,3mg/kg的利莫那班可以抑制METH(0.5mg/kg)诱导的CPP消退后复现。
结论:昆明小鼠可以形成显著的METH-CPP,大麻素CB1受体拮抗剂利莫那班可以破坏METH奖赏记忆的巩固、唤起和再巩固过程;小剂量的METH可以使小鼠已经消退的CPP行为重现,利莫那班可以抑制METH的这一点燃作用。
Objectives: Methamphetamine (METH) is a commonly used, addictive drug, and a powerful stimulant that dramatically affects the central nervous system. METH users continually increased in our country in recent years. And its psychological dependence and serious adverse effects have been outstanding day by day. METH abuse not only brings about health problems to drug users, but also results in serious social problems. Drug addiction is a chronic, relapsing brain disorder. Repeated drug use associated with contexts lead to form an abnormally persistent rewarding memory. Similar to normal learning and memory, drug memory achieve a stable and relatively permanent state via an acquisition and consolidation process to form long term memory. However, they become labile when they are reactivated and must be reconsolidated to achieve a stable state again. Thus, some treatments could be used to block acquisition of memory via interfere with memory consolidation and impair original memory through disrupting memory reconsolidation. Cannabinoid CB1 receptor is a new target for drug addiction therapy. Endocannabinoids and CB1 receptor are widely distributed in memory-related brain regions, participated in memory modulation. There have been many studies to investigate the role of CB1 receptor in spatial or fear memory. Conclusions were not consistent since the types of memory were different. Drug-related memory studies using CB1 receptor were concentrated on extinction learning, which indicated that cannabinoid CB1 receptor blocked extinction process and inhibitory extinction behaviors. Conditioned place preference (CPP) paradigm has been widely used to evaluate the rewarding effect. Repeated association of drugs use with contexts predicting drug availability leads to long-lasting behavioral responses that reflect reward-controlled learning. METH-induced conditioned place preference (CPP), the preference for the specific place containing the METH conditioned cues over a natural control place, has been used as a behavioral paradigm for mimicking the METH use-associated memory. In this conditioning paradigm, repeated association of the specific environmental cues (conditioned stimulus) with METH-induced subjective euphoria (unconditioned stimulus) has been suggested to motivate animals’later approaching behavior toward the euphoria-linked environment at a drug-free status. In the present study, we used the conditioned place preference (CPP) paradigm in order to investigate the role of cannabinoid CB1 receptor antagonist in the drug-related memory.
Methods: 1, Mice were divided into 6 groups which were saline-20min, saline-60min, 0.5mg/kg-20min, 0.5mg/kg-60min, 2mg/kg-20min and 2mg/kg-60min by different training paradigms. The acquisition of CPP was observed after training. The dose of METH and confining time were then identified and applied to subsequent experiments. 2, Mice were divided into 3 groups to be trained for METH CPP(2mg/kg, 20min, i.p)and were given intra-peritoneal injections of different doses of rimonabant(0, 1.0mg/kg and 3.0mg/kg) immediately after each conditioning session. After 8 consecutive sessions, mice were tested for CPP. 3, Mice were divided into 3 groups to be trained for METH CPP(2mg/kg, 20min, i.p). Administrations of different doses of rimonabant (0mg/kg, 1.0mg/kg and 3.0 mg/kg) were given 30min before place preference testing. Retesting of METH CPP was done 24 hours, 7 days or 14 days after rimonabant administration. On the 15th day, mice were injected with a priming dose of METH (0.5mg/kg) and were tested to see whether place preference was reinstated. 4, Mice were divided into 3 groups to be trained for METH CPP(2mg/kg, 20min, i.p). Administrations of different doses of rimonabant (0mg/kg, 1.0mg/kg and 3.0 mg/kg) were given immediately after place preference testing. Retesting of METH CPP was done 24 hours, 7 days or 14 days after rimonabant administration. On the 15th day, mice were injected with a priming dose of METH (0.5mg/kg) and were tested to see whether place preference was reinstated. 5, Mice were divided into 3 groups to be trained for METH CPP(2mg/kg, 20min, i.p). After 8 consecutive sessions and tested for METH CPP, mice were not given any treatment and were retest every 3 days. One day after the determination of place preference extinction, mice were injected with a priming dose of METH (0.5mg/kg) and were tested to see whether place preference was reinstated. Different doses of rimonabant (0mg/kg, 1.0mg/kg and 3.0 mg/kg) were administered 30 minutes prior to the priming injection of METH.
Results: 1, Compared with saline groups, 4 METH groups with different training paradigms all expressed a METH CPP and no significant difference was found between any two groups. 2, Compared with vehicle group, post-training administration of 1mg/kg and 3mg/kg rimonabant blocked the acquisition of METH CPP, suggesting rimonabant disrupted consolidation of METH rewarding memory. 3, Compared with vehicle group, pre-test administration of 3mg/kg rimonabant inhibited CPP expression while other two groups expressed significant CPP, suggesting rimonabant blocked retrieval of METH rewarding memory. The effect lasted for at least 1 week. 4, Compared with vehicle group, 24h after post-testing administration of different doses of rimonabant, mice in 3mg/kg group which expressed significant CPP in the first place preference testing failed to express CPP the next day and in subsequent tests. However, mice in groups without retrieval expressed CPP persistently, suggesting the effect of rimonabant on memory reconsolidation was retrieval-dependent. 5, Compared with vehicle group, a dose of 0.5mgkg METH failed to induce the reinstatement of CPP in the group of 3mg/kg rimonabant, suggesting rimonabant could inhibit reinstatement of METH CPP.
Conclusion: The present study indicated that mice expressed significant CPP produced by METH. Cannabinoid CB1 receptor antagonist disrupted consolidation, retrieval and reconsolidation of METH rewarding memory. A priming dose of METH induced reinstatement of CPP which could be attenuated by rimonabant.
引文
1 O'Brien CP, McLellan AT. Myths about the treatment of addiction. Lancet 1996, 347:237-240
2 Leshner AI. Addiction is a brain disease, and it matters. Science 1997, 278:45-47
3 Nestler EJ. Neurobiology. Total recall-the memory of addiction. Science 2001, 292:2266-2267
4 McGaugh JL. Memory-a century of consolidation. Science 2000, 287(5451):248-51
5 Nader K, Schafe GE, Le Doux Je. Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval. Nature 2000, 406(6797):722-6
6 Wilson, R.I., & Nicoll, R.A. Endocannabinoid signaling in the brain. Science, 2002, 296:678-682
7 Katona, I., Rancz, E.A., Acsady, L., Distribution of CB1 cannabinoid receptors in the amygdala and their role in the control of GABAergic transmission. J. Neurosci. 2001, 21, 9506–9518
8 Tsou, K., Brown, S., Sanudo-Pena, M.C. Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system. Neuroscience 1998,83, 393–411
9 Tzschentke TM: Measuring reward with the conditioned place preference paradigm: a comprehensive review of drug effects, recent progress and new issues. Prog Neurobiol1998,56: 613- 672
10 Miller CA, Marshall JF. Molecular substrates for retrieval and reconsolidation of cocaine-associated contextual memory. Neuron. 2005,47(6):873-84
11 Valjent E, Corbillé AG, Bertran-Gonzalez J. Inhibition of ERK pathway or protein synthesis during reexposure to drugs of abuse erases previously learned place preference. Proc Natl Acad Sci U S A.2006, 103(8):2932-7
12 Shaham Y, Shalev U, Lu L, The reinstatement model of drug relapse: history, methodology and major findings. Psychopharmacology (Berl). 2003,168(1-2):3-20
13 Kuo Y-M, Liang KC. Chen CG, Cocaine- but not methamphetamine-associated memory require de novo protein synthesis. Neurobiol Learn Mem. 2006, 87:93-100
14 Harris GC, Wimmer M, Aston-Jones G. A role for lateral hypothalamic orexin neurons in reward seeking. Nature,2005,437:556-559
15 Bernardi RE, Lattal KM, Berger SP. Postretrieval propranolol disrupts a cocaine conditioned place preference. Neuroreport. 2006, 17(13):1443-7
16 Hyman SE (2005) Addiction: a disease of learning and memory. Am J Psychiatry 162:1414-1422
17 Hyman SE, Malenka RC, Nestler EJ (2006) Neural mechanisms of addiction: the role of reward-related learning and memory. Annu Rev Neurosci 29:565-598
18 Nestler EJ. Common molecular and cellular substrates ofaddiction and memory. Neurobiol Learn Mem. 2002,78(3):637-47
19 Arenos JD, Musty RE, Bucci DJ. Blockade of cannabinoid CB1 receptors alters contextual learning and memory. Eur J Pharmacol. 2006 ,539(3):177-83
20 de Oliveira Alvares L, de Oliveira LF, Camboim C. Amnestic effect of intrahippocampal AM251, a CB1-selective blocker, in the inhibitory avoidance, but not in the open field habituation task, in rats. Neurobiol Learn Mem. 2005,83(2):119-24
21 de Oliveira Alvares L, Genro BP, Vaz Breda R. AM251, a selective antagonist of the CB1 receptor, inhibits the induction of long-term potentiation and induces retrograde amnesia in rats. Brain Res. 2006,23;1075(1):60-7
22 Takahashi RN, Pamplona FA, Fernandes MS. The cannabinoid antagonist SR141716A facilitates memory acquisition and consolidation in the mouse elevated T-maze. Neurosci Lett. 2005,380(3):270-5
23 Niyuhire F, Varvel SA, Thorpe AJ. The disruptive effects of the CB1 receptor antagonist rimonabant on extinction learning in mice are task-specific. Psychopharmacology (Berl). 2007,191(2):223-31
24 Davies, S. N., Pertwee, R. G., & Riedel, G. Functions of cannabinoid receptors in the hippocampus. Neuropharmacology, 2002, 42, 993–1007
25 Hernandez-Tristan, R., Arevalo, C., Canals, S. The effect ofacute treatment with delta9-THC on exploratory behaviour and memory in the rat. Journal of Physiology and Biochemistry.2000, 56, 17–24
26 Lichtman, A. H. SR141716A enhances spatial memory as assessed in a radial-arm maze task in rats. European Journal of Pharmacology, 2000,404, 175–179
27 Varvel, S. A., Wise, L. E., Niyuhire, F. Inhibition of fatty-acid amide hydrolase accelerates acquisition and extinction rates in a spatial memory task. Neuropsychopharmacology, 2006,32(5), 1032–1041
28 Cossu G, Ledent C, Fattore L, et al.: Cannabinoid CB1 receptor knockout mice fail to self-administer morphine but not other drugs of abuse. Behav Brain Res 2001,118:61-65
29 De Vries TJ, Shaham Y, Homberg JR, et al.: A cannabinoid mechanism in relapse to cocaine seeking. Nat Med 2001,7:1151-1154
30 Miquel M, Catherine L, Marc Parmentier, Cocaine, but not morphine, induces conditioned place preference and sensitization to locomotor responses in CB1 knockout mice. European Journal of Neuroscience; 2000, 12(11):4038-4046
31 Vinklerova J, Novakova J, Sulcova A: Inhibition of methamphetamine self-administration in rats by cannabinoid receptor antagonist AM 251. J Psychopharmacol 2002,16:139-143
32 Chaperon F, Soubrie P, Puech AJ, Thiebot MH: Involvement of central cannabinoid (CB1) receptors in the establishmentof place conditioning in rats. Psychopharmacology (Berl) 1998,135:324-332
33 McGaugh JL. Time-dependent processes in memory storage. Science. 1966,16;153(742):1351-8
34 De Vries TJ, Homberg JR, Binnekade R, et al.: Cannabinoid modulation of the reinforcing and motivational properties of heroin and heroin-associated cues in rats. Psychopharmacology (Berl) 2003,168:164-169
35 Soria G, Mendizábal V, Touri?o C. Lack of CB1 cannabinoid receptor impairs cocaine self-administration. Neuropsychopharmacology. 2005,Sep;30(9):1670-80
36 Lopez-Moreno JA, Gonzalez-Cuevas G, Rodriguez de Fonseca F, Navarro M: Long-lasting increase of alcohol relapse by the cannabinoid receptor agonist WIN 55,212-2 during alcohol deprivation. J Neurosci 2004,24:8245-8252
37 McGregor IS, Dam KD, Mallet PE, Gallate JE: Delta9-THC reinstates beer- and sucrose-seeking behaviour in abstinent rats: comparison with midazolam, food deprivation and predator odour. Alcohol Alcohol 2005,40:35-45
38 Cohen C, Perrault G, Griebel G, Soubrie P: Nicotine-associated cues maintain nicotine-seeking behavior in rats several weeks after nicotine withdrawal: reversal by the cannabinoid (CB1) receptor antagonist, rimonabant (SR141716). Neuropsychopharmacology 2005,30:145-155
39 Anggadiredja K, Nakamichi M, Hiranita T. Endocannabinoid system modulates relapse to methamphetamine seeking: possible mediation by the arachidonic acid cascade. Neuropsychopharmacology. 2004,29(8):1470-8
1. Cami J, Farre M: Drug addiction. N Engl J Med 2003;349:975-986
2. Koob GF, Ahmed SH, Boutrel B, et al.: Neurobiological mechanisms in the transition from drug use to drug dependence. Neurosci Biobehav Rev 2004;27:739-749
3. Nestler EJ: Molecular mechanisms of drug addiction. Neuropharmacology 2004;47 Suppl 1:24-32
4. Wise R: Dopamine, learning and motivation. Nat rev neurosci 2004;5:483-494
5. Maldonado R, Valverde O, Berrendero F: Involvement of the endocannabinoid system in drug addiction. Trends Neurosci 2006;29:225-232
6. Koob G, Kreek MJ: Stress, dysregulation of drug reward pathways, and the transition to drug dependence. Am J Psychiatry 2007;164:1149-1159
7. Munro S, Thomas KL, Abu-Shaar M: Molecular characterization of a peripheral receptor for cannabinoids. Nature 1993;365:61-65
8. Matsuda LA, Lolait SJ, Brownstein MJ, et al.: Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 1990;346:561-564
9. Begg M, Pacher P, Batkai S, et al.: Evidence for novel cannabinoid receptors. Pharmacol Ther 2005;106:133-145
10. Hajos N, Freund TF: Distinct cannabinoid sensitivereceptors regulate hippocampal excitation and inhibition. Chem Phys Lipids 2002;121:73-82
11. Wiley JL, Martin BR: Cannabinoid pharmacology: implications for additional cannabinoid receptor subtypes. Chem Phys Lipids 2002;121:57-63
12. Howlett AC, Barth F, Bonner TI, et al.: International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev 2002;54:161-202
13. Wilson RI, Nicoll RA: Endocannabinoid signaling in the brain. Science 2002;296:678-682
14. Solinas M, Yasar S, Goldberg SR: Endocannabinoid system involvement in brain reward processes related to drug abuse. Pharmacol Res 2007;56:393-405
15. Fattore L, Deiana S, Spano SM, et al.: Endocannabinoid system and opioid addiction: behavioural aspects. Pharmacol Biochem Behav 2005;81:343-359
16. Herkenham M, Lynn AB, Little MD, et al.: Cannabinoid receptor localization in brain. Proc Natl Acad Sci U S A 1990;87:1932-1936
17. Mansour A, Khachaturian H, Lewis ME, et al.: Autoradiographic differentiation of mu, delta, and kappa opioid receptors in the rat forebrain and midbrain. J Neurosci 1987;7:2445-2464
18. Pickel VM, Chan J, Kash TL, et al.: Compartment-specific localization of cannabinoid 1 (CB1) and mu-opioid receptors in rat nucleus accumbens.Neuroscience 2004;127:101-112
19. Rodriguez JJ, Mackie K, Pickel VM: Ultrastructural localization of the CB1 cannabinoid receptor in mu-opioid receptor patches of the rat Caudate putamen nucleus. J Neurosci 2001;21:823-833
20. Corchero J, Manzanares J, Fuentes JA: Cannabinoid/opioid crosstalk in the central nervous system. Crit Rev Neurobiol 2004;16:159-172
21. Maldonado R, Valverde O: Participation of the opioid system in cannabinoid-induced antinociception and emotional-like responses. Eur Neuropsychopharmacol 2003;13:401-410
22. Manzanares J, Corchero J, Romero J, et al.: Pharmacological and biochemical interactions between opioids and cannabinoids. Trends Pharmacol Sci 1999;20:287-294
23. Vigano D, Rubino T, Parolaro D: Molecular and cellular basis of cannabinoid and opioid interactions. Pharmacol Biochem Behav 2005;81:360-368
24. Ghozland S, Matthes HW, Simonin F, et al.: Motivational effects of cannabinoids are mediated by mu-opioid and kappa-opioid receptors. J Neurosci 2002;22:1146-1154
25. Justinova Z, Tanda G, Munzar P, Goldberg SR: The opioid antagonist naltrexone reduces the reinforcing effects of Delta 9 tetrahydrocannabinol (THC) in squirrel monkeys. Psychopharmacology (Berl) 2004;173:186-194
26. Martin M, Ledent C, Parmentier M, et al.: Cocaine, but not morphine, induces conditioned place preference and sensitization to locomotor responses in CB1 knockout mice. Eur J Neurosci 2000;12:4038-4046
27. Ledent C, Valverde O, Cossu G, et al.: Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice. Science 1999;283:401-404
28. De Vries TJ, Homberg JR, Binnekade R, et al.: Cannabinoid modulation of the reinforcing and motivational properties of heroin and heroin-associated cues in rats. Psychopharmacology (Berl) 2003;168:164-169
29. Navarro M, Carrera MR, Fratta W, et al.: Functional interaction between opioid and cannabinoid receptors in drug self-administration. J Neurosci 2001;21:5344-5350
30. Chaperon F, Soubrie P, Puech AJ, Thiebot MH: Involvement of central cannabinoid (CB1) receptors in the establishment of place conditioning in rats. Psychopharmacology (Berl) 1998;135:324-332
31. Cossu G, Ledent C, Fattore L, et al.: Cannabinoid CB1 receptor knockout mice fail to self-administer morphine but not other drugs of abuse. Behav Brain Res 2001;118:61-65
32. De Vries TJ, Shaham Y, Homberg JR, et al.: A cannabinoid mechanism in relapse to cocaine seeking. Nat Med 2001;7:1151-1154
33. Tanda G, Munzar P, Goldberg SR: Self-administration behavior is maintained by the psychoactive ingredient of marijuana in squirrel monkeys. Nat Neurosci 2000;3:1073-1074
34. Vinklerova J, Novakova J, Sulcova A: Inhibition of methamphetamine self-administration in rats by cannabinoid receptor antagonist AM 251. J Psychopharmacol 2002;16:139-143
35. Soria G, Mendizabal V, Tourino C, et al.: Lack of CB1 cannabinoid receptor impairs cocaine self-administration. Neuropsychopharmacology 2005;30:1670-1680
36. Colombo G, Serra S, Vacca G, et al.: Endocannabinoid system and alcohol addiction: pharmacological studies. Pharmacol Biochem Behav 2005;81:369-380
37. Hungund BL, Basavarajappa BS, Vadasz C, et al.: Ethanol, endocannabinoids, and the cannabinoidergic signaling system. Alcohol Clin Exp Res 2002;26:565-574
38. Cippitelli A, Bilbao A, Hansson AC, et al.: Cannabinoid CB1 receptor antagonism reduces conditioned reinstatement of ethanol-seeking behavior in rats. Eur J Neurosci 2005;21:2243-2251
39. Economidou D, Mattioli L, Cifani C, et al.: Effect of the cannabinoid CB1 receptor antagonist SR-141716A on ethanol self-administration and ethanol-seeking behaviour in rats. Psychopharmacology (Berl) 2006;183:394-403
40. Gessa GL, Serra S, Vacca G, et al.: Suppressing effect of the cannabinoid CB1 receptor antagonist, SR147778, on alcohol intake and motivational properties of alcohol in alcohol-preferring sP rats. Alcohol Alcohol 2005;40:46-53
41. Lallemand F, De Witte P: SR147778, a CB1 cannabinoid receptor antagonist, suppresses ethanol preference in chronically alcoholized Wistar rats. Alcohol 2006;39:125-134
42. Hungund BL, Szakall I, Adam A, et al.: Cannabinoid CB1 receptor knockout mice exhibit markedly reduced voluntary alcohol consumption and lack alcohol-induced dopamine release in the nucleus accumbens. J Neurochem 2003;84:698-704
43. Naassila M, Pierrefiche O, Ledent C, Daoust M: Decreased alcohol self-administration and increased alcohol sensitivity and withdrawal in CB1 receptor knockout mice. Neuropharmacology 2004;46:243-253
44. Thanos PK, Dimitrakakis ES, Rice O, et al.: Ethanol self-administration and ethanol conditioned place preference are reduced in mice lacking cannabinoid CB1 receptors. Behav Brain Res 2005;164:206-213
45. Wang L, Liu J, Harvey-White J, et al.: Endocannabinoid signaling via cannabinoid receptor 1 is involved in ethanol preference and its age-dependent decline in mice. Proc Natl Acad Sci U S A 2003;100:1393-1398
46. Colombo G, Serra S, Brunetti G, et al.: Stimulation of voluntary ethanol intake by cannabinoid receptor agonists in ethanol-preferring sP rats. Psychopharmacology (Berl) 2002;159:181-187
47. Gallate JE, Saharov T, Mallet PE, McGregor IS: Increased motivation for beer in rats following administration of a cannabinoid CB1 receptor agonist. Eur J Pharmacol 1999;370:233-240
48. Cota D, Tschop MH, Horvath TL, Levine AS: Cannabinoids, opioids and eating behavior: the molecular face of hedonism? Brain Res Rev 2006;51:85-107
49. Horvath TL: The unfolding cannabinoid story on energy homeostasis: central or peripheral site of action? Int J Obes (Lond) 2006;30 Suppl 1:S30-32
50. Matias I, Bisogno T, Di Marzo V: Endogenous cannabinoids in the brain and peripheral tissues: regulation of their levels and control of food intake. Int J Obes (Lond) 2006;30 Suppl 1:S7-S12
51. Solinas M, Goldberg SR: Motivational effects of cannabinoids and opioids on food reinforcement depend on simultaneous activation of cannabinoid and opioid systems. Neuropsychopharmacology 2005;30:2035-2045
52. Lopez-Moreno JA, Gonzalez-Cuevas G, Rodriguez de Fonseca F, Navarro M: Long-lasting increase of alcohol relapse by the cannabinoid receptor agonist WIN 55,212-2 during alcohol deprivation. J Neurosci2004;24:8245-8252
53. McGregor IS, Dam KD, Mallet PE, Gallate JE: Delta9-THC reinstates beer- and sucrose-seeking behaviour in abstinent rats: comparison with midazolam, food deprivation and predator odour. Alcohol Alcohol 2005;40:35-45
54. Valjent E, Mitchell JM, Besson MJ, et al.: Behavioural and biochemical evidence for interactions between Delta 9-tetrahydrocannabinol and nicotine. Br J Pharmacol 2002;135:564-578
55. Castane A, Valjent E, Ledent C, et al.: Lack of CB1 cannabinoid receptors modifies nicotine behavioural responses, but not nicotine abstinence. Neuropharmacology 2002;43:857-867
56. Cohen C, Perrault G, Voltz C, et al.: SR141716, a central cannabinoid (CB(1)) receptor antagonist, blocks the motivational and dopamine-releasing effects of nicotine in rats. Behav Pharmacol 2002;13:451-463
57. Le Foll B, Goldberg SR: Rimonabant, a CB1 antagonist, blocks nicotine-conditioned place preferences. Neuroreport 2004;15:2139-2143
58. Cohen C, Perrault G, Griebel G, Soubrie P: Nicotine-associated cues maintain nicotine-seeking behavior in rats several weeks after nicotine withdrawal: reversal by the cannabinoid (CB1) receptor antagonist, rimonabant (SR141716). Neuropsychopharmacology2005;30:145-155
59. Gardner EL: Endocannabinoid signaling system and brain reward: emphasis on dopamine. Pharmacol Biochem Behav 2005;81:263-284
60. Lupica CR, Riegel AC: Endocannabinoid release from midbrain dopamine neurons: a potential substrate for cannabinoid receptor antagonist treatment of addiction. Neuropharmacology 2005;48:1105-1116
61. Riegel AC, Lupica CR: Independent presynaptic and postsynaptic mechanisms regulate endocannabinoid signaling at multiple synapses in the ventral tegmental area. J Neurosci 2004;24:11070-11078
62. Melis M, Pistis M, Perra S, et al.: Endocannabinoids mediate presynaptic inhibition of glutamatergic transmission in rat ventral tegmental area dopamine neurons through activation of CB1 receptors. J Neurosci 2004;24:53-62
63. Robbe D, Alonso G, Duchamp F, et al.: Localization and mechanisms of action of cannabinoid receptors at the glutamatergic synapses of the mouse nucleus accumbens. J Neurosci 2001;21:109-116
64. Le Foll B, Goldberg SR: Cannabinoid CB1 receptor antagonists as promising new medications for drug dependence. J Pharmacol Exp Ther 2005;312:875-883
65. Giuffrida A, Parsons LH, Kerr TM, et al.: Dopamine activation of endogenous cannabinoid signaling in dorsalstriatum. Nat Neurosci 1999;2:358-363
66. Vigano D, Valenti M, Cascio MG, et al.: Changes in endocannabinoid levels in a rat model of behavioural sensitization to morphine. Eur J Neurosci 2004;20:1849-1857
67. Gonzalez S, Cascio MG, Fernandez-Ruiz J, et al.: Changes in endocannabinoid contents in the brain of rats chronically exposed to nicotine, ethanol or cocaine. Brain Res 2002;954:73-81
68. Nestler EJ: Molecular basis of long-term plasticity underlying addiction. Nat Rev Neurosci 2001;2:119-128
69. Azad SC, Monory K, Marsicano G, et al.: Circuitry for associative plasticity in the amygdala involves endocannabinoid signaling. J Neurosci 2004;24:9953-9961
70. Robbe D, Kopf M, Remaury A, et al.: Endogenous cannabinoids mediate long-term synaptic depression in the nucleus accumbens. Proc Natl Acad Sci U S A 2002;99:8384-8388
71. Gerdeman GL, Ronesi J, Lovinger DM: Postsynaptic endocannabinoid release is critical to long-term depression in the striatum. Nat Neurosci 2002;5:446-451
72. Mato S, Chevaleyre V, Robbe D, et al.: A single in-vivo exposure to delta 9THC blocks endocannabinoid-mediated synaptic plasticity. Nat Neurosci 2004;7:585-586
2 Leshner AI. Addiction is a brain disease, and it matters. Science 1997, 278:45-47
3 Nestler EJ. Neurobiology. Total recall-the memory of addiction. Science 2001, 292:2266-2267
4 McGaugh JL. Memory-a century of consolidation. Science 2000, 287(5451):248-51
5 Nader K, Schafe GE, Le Doux Je. Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval. Nature 2000, 406(6797):722-6
6 Wilson, R.I., & Nicoll, R.A. Endocannabinoid signaling in the brain. Science, 2002, 296:678-682
7 Katona, I., Rancz, E.A., Acsady, L., Distribution of CB1 cannabinoid receptors in the amygdala and their role in the control of GABAergic transmission. J. Neurosci. 2001, 21, 9506–9518
8 Tsou, K., Brown, S., Sanudo-Pena, M.C. Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system. Neuroscience 1998,83, 393–411
9 Tzschentke TM: Measuring reward with the conditioned place preference paradigm: a comprehensive review of drug effects, recent progress and new issues. Prog Neurobiol1998,56: 613- 672
10 Miller CA, Marshall JF. Molecular substrates for retrieval and reconsolidation of cocaine-associated contextual memory. Neuron. 2005,47(6):873-84
11 Valjent E, Corbillé AG, Bertran-Gonzalez J. Inhibition of ERK pathway or protein synthesis during reexposure to drugs of abuse erases previously learned place preference. Proc Natl Acad Sci U S A.2006, 103(8):2932-7
12 Shaham Y, Shalev U, Lu L, The reinstatement model of drug relapse: history, methodology and major findings. Psychopharmacology (Berl). 2003,168(1-2):3-20
13 Kuo Y-M, Liang KC. Chen CG, Cocaine- but not methamphetamine-associated memory require de novo protein synthesis. Neurobiol Learn Mem. 2006, 87:93-100
14 Harris GC, Wimmer M, Aston-Jones G. A role for lateral hypothalamic orexin neurons in reward seeking. Nature,2005,437:556-559
15 Bernardi RE, Lattal KM, Berger SP. Postretrieval propranolol disrupts a cocaine conditioned place preference. Neuroreport. 2006, 17(13):1443-7
16 Hyman SE (2005) Addiction: a disease of learning and memory. Am J Psychiatry 162:1414-1422
17 Hyman SE, Malenka RC, Nestler EJ (2006) Neural mechanisms of addiction: the role of reward-related learning and memory. Annu Rev Neurosci 29:565-598
18 Nestler EJ. Common molecular and cellular substrates ofaddiction and memory. Neurobiol Learn Mem. 2002,78(3):637-47
19 Arenos JD, Musty RE, Bucci DJ. Blockade of cannabinoid CB1 receptors alters contextual learning and memory. Eur J Pharmacol. 2006 ,539(3):177-83
20 de Oliveira Alvares L, de Oliveira LF, Camboim C. Amnestic effect of intrahippocampal AM251, a CB1-selective blocker, in the inhibitory avoidance, but not in the open field habituation task, in rats. Neurobiol Learn Mem. 2005,83(2):119-24
21 de Oliveira Alvares L, Genro BP, Vaz Breda R. AM251, a selective antagonist of the CB1 receptor, inhibits the induction of long-term potentiation and induces retrograde amnesia in rats. Brain Res. 2006,23;1075(1):60-7
22 Takahashi RN, Pamplona FA, Fernandes MS. The cannabinoid antagonist SR141716A facilitates memory acquisition and consolidation in the mouse elevated T-maze. Neurosci Lett. 2005,380(3):270-5
23 Niyuhire F, Varvel SA, Thorpe AJ. The disruptive effects of the CB1 receptor antagonist rimonabant on extinction learning in mice are task-specific. Psychopharmacology (Berl). 2007,191(2):223-31
24 Davies, S. N., Pertwee, R. G., & Riedel, G. Functions of cannabinoid receptors in the hippocampus. Neuropharmacology, 2002, 42, 993–1007
25 Hernandez-Tristan, R., Arevalo, C., Canals, S. The effect ofacute treatment with delta9-THC on exploratory behaviour and memory in the rat. Journal of Physiology and Biochemistry.2000, 56, 17–24
26 Lichtman, A. H. SR141716A enhances spatial memory as assessed in a radial-arm maze task in rats. European Journal of Pharmacology, 2000,404, 175–179
27 Varvel, S. A., Wise, L. E., Niyuhire, F. Inhibition of fatty-acid amide hydrolase accelerates acquisition and extinction rates in a spatial memory task. Neuropsychopharmacology, 2006,32(5), 1032–1041
28 Cossu G, Ledent C, Fattore L, et al.: Cannabinoid CB1 receptor knockout mice fail to self-administer morphine but not other drugs of abuse. Behav Brain Res 2001,118:61-65
29 De Vries TJ, Shaham Y, Homberg JR, et al.: A cannabinoid mechanism in relapse to cocaine seeking. Nat Med 2001,7:1151-1154
30 Miquel M, Catherine L, Marc Parmentier, Cocaine, but not morphine, induces conditioned place preference and sensitization to locomotor responses in CB1 knockout mice. European Journal of Neuroscience; 2000, 12(11):4038-4046
31 Vinklerova J, Novakova J, Sulcova A: Inhibition of methamphetamine self-administration in rats by cannabinoid receptor antagonist AM 251. J Psychopharmacol 2002,16:139-143
32 Chaperon F, Soubrie P, Puech AJ, Thiebot MH: Involvement of central cannabinoid (CB1) receptors in the establishmentof place conditioning in rats. Psychopharmacology (Berl) 1998,135:324-332
33 McGaugh JL. Time-dependent processes in memory storage. Science. 1966,16;153(742):1351-8
34 De Vries TJ, Homberg JR, Binnekade R, et al.: Cannabinoid modulation of the reinforcing and motivational properties of heroin and heroin-associated cues in rats. Psychopharmacology (Berl) 2003,168:164-169
35 Soria G, Mendizábal V, Touri?o C. Lack of CB1 cannabinoid receptor impairs cocaine self-administration. Neuropsychopharmacology. 2005,Sep;30(9):1670-80
36 Lopez-Moreno JA, Gonzalez-Cuevas G, Rodriguez de Fonseca F, Navarro M: Long-lasting increase of alcohol relapse by the cannabinoid receptor agonist WIN 55,212-2 during alcohol deprivation. J Neurosci 2004,24:8245-8252
37 McGregor IS, Dam KD, Mallet PE, Gallate JE: Delta9-THC reinstates beer- and sucrose-seeking behaviour in abstinent rats: comparison with midazolam, food deprivation and predator odour. Alcohol Alcohol 2005,40:35-45
38 Cohen C, Perrault G, Griebel G, Soubrie P: Nicotine-associated cues maintain nicotine-seeking behavior in rats several weeks after nicotine withdrawal: reversal by the cannabinoid (CB1) receptor antagonist, rimonabant (SR141716). Neuropsychopharmacology 2005,30:145-155
39 Anggadiredja K, Nakamichi M, Hiranita T. Endocannabinoid system modulates relapse to methamphetamine seeking: possible mediation by the arachidonic acid cascade. Neuropsychopharmacology. 2004,29(8):1470-8
1. Cami J, Farre M: Drug addiction. N Engl J Med 2003;349:975-986
2. Koob GF, Ahmed SH, Boutrel B, et al.: Neurobiological mechanisms in the transition from drug use to drug dependence. Neurosci Biobehav Rev 2004;27:739-749
3. Nestler EJ: Molecular mechanisms of drug addiction. Neuropharmacology 2004;47 Suppl 1:24-32
4. Wise R: Dopamine, learning and motivation. Nat rev neurosci 2004;5:483-494
5. Maldonado R, Valverde O, Berrendero F: Involvement of the endocannabinoid system in drug addiction. Trends Neurosci 2006;29:225-232
6. Koob G, Kreek MJ: Stress, dysregulation of drug reward pathways, and the transition to drug dependence. Am J Psychiatry 2007;164:1149-1159
7. Munro S, Thomas KL, Abu-Shaar M: Molecular characterization of a peripheral receptor for cannabinoids. Nature 1993;365:61-65
8. Matsuda LA, Lolait SJ, Brownstein MJ, et al.: Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 1990;346:561-564
9. Begg M, Pacher P, Batkai S, et al.: Evidence for novel cannabinoid receptors. Pharmacol Ther 2005;106:133-145
10. Hajos N, Freund TF: Distinct cannabinoid sensitivereceptors regulate hippocampal excitation and inhibition. Chem Phys Lipids 2002;121:73-82
11. Wiley JL, Martin BR: Cannabinoid pharmacology: implications for additional cannabinoid receptor subtypes. Chem Phys Lipids 2002;121:57-63
12. Howlett AC, Barth F, Bonner TI, et al.: International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev 2002;54:161-202
13. Wilson RI, Nicoll RA: Endocannabinoid signaling in the brain. Science 2002;296:678-682
14. Solinas M, Yasar S, Goldberg SR: Endocannabinoid system involvement in brain reward processes related to drug abuse. Pharmacol Res 2007;56:393-405
15. Fattore L, Deiana S, Spano SM, et al.: Endocannabinoid system and opioid addiction: behavioural aspects. Pharmacol Biochem Behav 2005;81:343-359
16. Herkenham M, Lynn AB, Little MD, et al.: Cannabinoid receptor localization in brain. Proc Natl Acad Sci U S A 1990;87:1932-1936
17. Mansour A, Khachaturian H, Lewis ME, et al.: Autoradiographic differentiation of mu, delta, and kappa opioid receptors in the rat forebrain and midbrain. J Neurosci 1987;7:2445-2464
18. Pickel VM, Chan J, Kash TL, et al.: Compartment-specific localization of cannabinoid 1 (CB1) and mu-opioid receptors in rat nucleus accumbens.Neuroscience 2004;127:101-112
19. Rodriguez JJ, Mackie K, Pickel VM: Ultrastructural localization of the CB1 cannabinoid receptor in mu-opioid receptor patches of the rat Caudate putamen nucleus. J Neurosci 2001;21:823-833
20. Corchero J, Manzanares J, Fuentes JA: Cannabinoid/opioid crosstalk in the central nervous system. Crit Rev Neurobiol 2004;16:159-172
21. Maldonado R, Valverde O: Participation of the opioid system in cannabinoid-induced antinociception and emotional-like responses. Eur Neuropsychopharmacol 2003;13:401-410
22. Manzanares J, Corchero J, Romero J, et al.: Pharmacological and biochemical interactions between opioids and cannabinoids. Trends Pharmacol Sci 1999;20:287-294
23. Vigano D, Rubino T, Parolaro D: Molecular and cellular basis of cannabinoid and opioid interactions. Pharmacol Biochem Behav 2005;81:360-368
24. Ghozland S, Matthes HW, Simonin F, et al.: Motivational effects of cannabinoids are mediated by mu-opioid and kappa-opioid receptors. J Neurosci 2002;22:1146-1154
25. Justinova Z, Tanda G, Munzar P, Goldberg SR: The opioid antagonist naltrexone reduces the reinforcing effects of Delta 9 tetrahydrocannabinol (THC) in squirrel monkeys. Psychopharmacology (Berl) 2004;173:186-194
26. Martin M, Ledent C, Parmentier M, et al.: Cocaine, but not morphine, induces conditioned place preference and sensitization to locomotor responses in CB1 knockout mice. Eur J Neurosci 2000;12:4038-4046
27. Ledent C, Valverde O, Cossu G, et al.: Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice. Science 1999;283:401-404
28. De Vries TJ, Homberg JR, Binnekade R, et al.: Cannabinoid modulation of the reinforcing and motivational properties of heroin and heroin-associated cues in rats. Psychopharmacology (Berl) 2003;168:164-169
29. Navarro M, Carrera MR, Fratta W, et al.: Functional interaction between opioid and cannabinoid receptors in drug self-administration. J Neurosci 2001;21:5344-5350
30. Chaperon F, Soubrie P, Puech AJ, Thiebot MH: Involvement of central cannabinoid (CB1) receptors in the establishment of place conditioning in rats. Psychopharmacology (Berl) 1998;135:324-332
31. Cossu G, Ledent C, Fattore L, et al.: Cannabinoid CB1 receptor knockout mice fail to self-administer morphine but not other drugs of abuse. Behav Brain Res 2001;118:61-65
32. De Vries TJ, Shaham Y, Homberg JR, et al.: A cannabinoid mechanism in relapse to cocaine seeking. Nat Med 2001;7:1151-1154
33. Tanda G, Munzar P, Goldberg SR: Self-administration behavior is maintained by the psychoactive ingredient of marijuana in squirrel monkeys. Nat Neurosci 2000;3:1073-1074
34. Vinklerova J, Novakova J, Sulcova A: Inhibition of methamphetamine self-administration in rats by cannabinoid receptor antagonist AM 251. J Psychopharmacol 2002;16:139-143
35. Soria G, Mendizabal V, Tourino C, et al.: Lack of CB1 cannabinoid receptor impairs cocaine self-administration. Neuropsychopharmacology 2005;30:1670-1680
36. Colombo G, Serra S, Vacca G, et al.: Endocannabinoid system and alcohol addiction: pharmacological studies. Pharmacol Biochem Behav 2005;81:369-380
37. Hungund BL, Basavarajappa BS, Vadasz C, et al.: Ethanol, endocannabinoids, and the cannabinoidergic signaling system. Alcohol Clin Exp Res 2002;26:565-574
38. Cippitelli A, Bilbao A, Hansson AC, et al.: Cannabinoid CB1 receptor antagonism reduces conditioned reinstatement of ethanol-seeking behavior in rats. Eur J Neurosci 2005;21:2243-2251
39. Economidou D, Mattioli L, Cifani C, et al.: Effect of the cannabinoid CB1 receptor antagonist SR-141716A on ethanol self-administration and ethanol-seeking behaviour in rats. Psychopharmacology (Berl) 2006;183:394-403
40. Gessa GL, Serra S, Vacca G, et al.: Suppressing effect of the cannabinoid CB1 receptor antagonist, SR147778, on alcohol intake and motivational properties of alcohol in alcohol-preferring sP rats. Alcohol Alcohol 2005;40:46-53
41. Lallemand F, De Witte P: SR147778, a CB1 cannabinoid receptor antagonist, suppresses ethanol preference in chronically alcoholized Wistar rats. Alcohol 2006;39:125-134
42. Hungund BL, Szakall I, Adam A, et al.: Cannabinoid CB1 receptor knockout mice exhibit markedly reduced voluntary alcohol consumption and lack alcohol-induced dopamine release in the nucleus accumbens. J Neurochem 2003;84:698-704
43. Naassila M, Pierrefiche O, Ledent C, Daoust M: Decreased alcohol self-administration and increased alcohol sensitivity and withdrawal in CB1 receptor knockout mice. Neuropharmacology 2004;46:243-253
44. Thanos PK, Dimitrakakis ES, Rice O, et al.: Ethanol self-administration and ethanol conditioned place preference are reduced in mice lacking cannabinoid CB1 receptors. Behav Brain Res 2005;164:206-213
45. Wang L, Liu J, Harvey-White J, et al.: Endocannabinoid signaling via cannabinoid receptor 1 is involved in ethanol preference and its age-dependent decline in mice. Proc Natl Acad Sci U S A 2003;100:1393-1398
46. Colombo G, Serra S, Brunetti G, et al.: Stimulation of voluntary ethanol intake by cannabinoid receptor agonists in ethanol-preferring sP rats. Psychopharmacology (Berl) 2002;159:181-187
47. Gallate JE, Saharov T, Mallet PE, McGregor IS: Increased motivation for beer in rats following administration of a cannabinoid CB1 receptor agonist. Eur J Pharmacol 1999;370:233-240
48. Cota D, Tschop MH, Horvath TL, Levine AS: Cannabinoids, opioids and eating behavior: the molecular face of hedonism? Brain Res Rev 2006;51:85-107
49. Horvath TL: The unfolding cannabinoid story on energy homeostasis: central or peripheral site of action? Int J Obes (Lond) 2006;30 Suppl 1:S30-32
50. Matias I, Bisogno T, Di Marzo V: Endogenous cannabinoids in the brain and peripheral tissues: regulation of their levels and control of food intake. Int J Obes (Lond) 2006;30 Suppl 1:S7-S12
51. Solinas M, Goldberg SR: Motivational effects of cannabinoids and opioids on food reinforcement depend on simultaneous activation of cannabinoid and opioid systems. Neuropsychopharmacology 2005;30:2035-2045
52. Lopez-Moreno JA, Gonzalez-Cuevas G, Rodriguez de Fonseca F, Navarro M: Long-lasting increase of alcohol relapse by the cannabinoid receptor agonist WIN 55,212-2 during alcohol deprivation. J Neurosci2004;24:8245-8252
53. McGregor IS, Dam KD, Mallet PE, Gallate JE: Delta9-THC reinstates beer- and sucrose-seeking behaviour in abstinent rats: comparison with midazolam, food deprivation and predator odour. Alcohol Alcohol 2005;40:35-45
54. Valjent E, Mitchell JM, Besson MJ, et al.: Behavioural and biochemical evidence for interactions between Delta 9-tetrahydrocannabinol and nicotine. Br J Pharmacol 2002;135:564-578
55. Castane A, Valjent E, Ledent C, et al.: Lack of CB1 cannabinoid receptors modifies nicotine behavioural responses, but not nicotine abstinence. Neuropharmacology 2002;43:857-867
56. Cohen C, Perrault G, Voltz C, et al.: SR141716, a central cannabinoid (CB(1)) receptor antagonist, blocks the motivational and dopamine-releasing effects of nicotine in rats. Behav Pharmacol 2002;13:451-463
57. Le Foll B, Goldberg SR: Rimonabant, a CB1 antagonist, blocks nicotine-conditioned place preferences. Neuroreport 2004;15:2139-2143
58. Cohen C, Perrault G, Griebel G, Soubrie P: Nicotine-associated cues maintain nicotine-seeking behavior in rats several weeks after nicotine withdrawal: reversal by the cannabinoid (CB1) receptor antagonist, rimonabant (SR141716). Neuropsychopharmacology2005;30:145-155
59. Gardner EL: Endocannabinoid signaling system and brain reward: emphasis on dopamine. Pharmacol Biochem Behav 2005;81:263-284
60. Lupica CR, Riegel AC: Endocannabinoid release from midbrain dopamine neurons: a potential substrate for cannabinoid receptor antagonist treatment of addiction. Neuropharmacology 2005;48:1105-1116
61. Riegel AC, Lupica CR: Independent presynaptic and postsynaptic mechanisms regulate endocannabinoid signaling at multiple synapses in the ventral tegmental area. J Neurosci 2004;24:11070-11078
62. Melis M, Pistis M, Perra S, et al.: Endocannabinoids mediate presynaptic inhibition of glutamatergic transmission in rat ventral tegmental area dopamine neurons through activation of CB1 receptors. J Neurosci 2004;24:53-62
63. Robbe D, Alonso G, Duchamp F, et al.: Localization and mechanisms of action of cannabinoid receptors at the glutamatergic synapses of the mouse nucleus accumbens. J Neurosci 2001;21:109-116
64. Le Foll B, Goldberg SR: Cannabinoid CB1 receptor antagonists as promising new medications for drug dependence. J Pharmacol Exp Ther 2005;312:875-883
65. Giuffrida A, Parsons LH, Kerr TM, et al.: Dopamine activation of endogenous cannabinoid signaling in dorsalstriatum. Nat Neurosci 1999;2:358-363
66. Vigano D, Valenti M, Cascio MG, et al.: Changes in endocannabinoid levels in a rat model of behavioural sensitization to morphine. Eur J Neurosci 2004;20:1849-1857
67. Gonzalez S, Cascio MG, Fernandez-Ruiz J, et al.: Changes in endocannabinoid contents in the brain of rats chronically exposed to nicotine, ethanol or cocaine. Brain Res 2002;954:73-81
68. Nestler EJ: Molecular basis of long-term plasticity underlying addiction. Nat Rev Neurosci 2001;2:119-128
69. Azad SC, Monory K, Marsicano G, et al.: Circuitry for associative plasticity in the amygdala involves endocannabinoid signaling. J Neurosci 2004;24:9953-9961
70. Robbe D, Kopf M, Remaury A, et al.: Endogenous cannabinoids mediate long-term synaptic depression in the nucleus accumbens. Proc Natl Acad Sci U S A 2002;99:8384-8388
71. Gerdeman GL, Ronesi J, Lovinger DM: Postsynaptic endocannabinoid release is critical to long-term depression in the striatum. Nat Neurosci 2002;5:446-451
72. Mato S, Chevaleyre V, Robbe D, et al.: A single in-vivo exposure to delta 9THC blocks endocannabinoid-mediated synaptic plasticity. Nat Neurosci 2004;7:585-586