系統識別號 U0026-1408201415515600
論文名稱(中文) 大麻素一號受體拮抗劑利莫那班對於古柯鹼相關記憶的穩固化、再穩固化以及消除歷程之影響
論文名稱(英文) Effects of the cannabinoid CB1 receptor antagonist rimonabant on consolidation, reconsolidation, and forced extinction of cocaine-associated memory
校院名稱 成功大學
系所名稱(中) 心理學系認知科學碩士班
系所名稱(英) MS in Cognitive Science
學年度 102
學期 2
出版年 103
研究生(中文) 劉亞薇
研究生(英文) Ya-Wei Liu
學號 U76014041
學位類別 碩士
語文別 英文
論文頁數 54頁
口試委員 口試委員-梁庚辰
中文關鍵字 古柯鹼  復發  大麻素一號受體  利莫那班  穩固化歷程  再穩固化歷程  消除歷程  制約場地偏好 
英文關鍵字 Cocaine  Relapse  Cannabinoid CB1 receptor  Rimonabant  Consolidation  Reconsolidation  Forced extinction  Conditioned place preference 
中文摘要 古柯鹼濫用在當今社會中是一個相當嚴重的問題,截至目前為止尚未找到有效防止古柯鹼復發的方式。另一方面我們體內的內生性大麻素系統目前已知可以調控包含古柯鹼在內的多種成癮藥物的酬賞效果,但是唯獨針對古柯鹼的濫用,大麻素一號受體並未參與在古柯鹼的主要酬賞效果中,而是參與了古柯鹼復發的歷程。因此本研究旨在利用古柯鹼誘發制約場地偏好的動物模型來探討大麻素一號受體拮抗劑利莫那班是否參與在古柯鹼相關記憶的穩固化、再穩固化以及消除歷程。我們的實驗結果發現,以系統性或是於內側前額葉皮質注射利莫那班阻斷大麻素一號受體,對於古柯鹼相關記憶的穩固化會有雙向的調節。當以低劑量古柯鹼來誘發場地制約偏好時,大麻素一號受體的阻斷會促進該記憶的穩固化;當以高劑量古柯鹼誘發場地制約偏好,則相同處置會損害該記憶的穩固化。此外,以利莫那班阻斷大麻素一號受體會損壞古柯鹼相關記憶的再穩固化歷程以及促進古柯鹼相關記憶的消除歷程。綜合上述結果,大麻素一號受體的阻斷可以在臨床上用以促進高劑量古柯鹼成癮者對該藥物記憶的消除歷程,進而避免古柯鹼的復發。
英文摘要 Relapse to cocaine has been an unsolved problem for decades. The endocannabinoid system modulates addiction of several abused drugs including cocaine. The cannabinoid CB1 receptors have previously been implicated in the reinstatement but not the primary rewarding effect of cocaine. The purpose of this study was to exam whether rimonabant, a cannabinoid CB1 receptor antagonist, affected consolidation, reconsolidation and forced extinction of cocaine-associated memory by using a conditioned place preference (CPP) paradigm. Our results revealed that the CB1 receptors bidirectionally modulate cocaine-associated memory. That is, inactivation of CB1 receptors, either peripherally or within the medial prefrontal cortex (mPFC), facilitates memory consolidation of cocaine-induced CPP at low doses, whereas disrupts that at high ones. Rimonabant was also found to impair reconsolidation but dose-dependently facilitate forced extinction of cocaine-associated memory. Taken together, pharmacological targeting CB1 receptors may be a therapeutic strategy to prevent from relapse to cocaine in cocaine heavy users.
論文目次 摘要.....2
Materials and Methods.....14
1. Animal Models and Administration.....14
2. Drugs.....14
3. Cocaine-induced conditioned place preference (CPP).....14
4. Stereotaxic surgery.....16
5. Intra-mPFC infusion.....17
6. Rimonabant CPA/CPP test.....17
7. Locomotor activity.....18
8. Histology.....18
9. Experimental design.....19
10. Statistical analysis.....22

參考文獻 Abel T, Lattal KM (2001) Molecular mechanisms of memory acquisition, consolidation and retrieval. Current opinion in neurobiology 11:180-187.
Caille S, Alvarez-Jaimes L, Polis I, Stouffer DG, Parsons LH (2007) Specific alterations of extracellular endocannabinoid levels in the nucleus accumbens by ethanol, heroin, and cocaine self-administration. The Journal of neuroscience : the official journal of the Society for Neuroscience 27:3695-3702.
Capriles N, Rodaros D, Sorge RE, Stewart J (2003) A role for the prefrontal cortex in stress- and cocaine-induced reinstatement of cocaine seeking in rats. Psychopharmacology 168:66-74.
Carboni E, Spielewoy C, Vacca C, Nosten-Bertrand M, Giros B, Di Chiara G (2001) Cocaine and amphetamine increase extracellular dopamine in the nucleus accumbens of mice lacking the dopamine transporter gene. The Journal of neuroscience : the official journal of the Society for Neuroscience 21:Rc141: 141-144.
Chaperon F, Soubrie P, Puech AJ, Thiebot MH (1998) Involvement of central cannabinoid (CB1) receptors in the establishment of place conditioning in rats. Psychopharmacology 135:324-332.
Cherng CG, Tsai CW, Tsai YP, Ho MC, Kao SF, Yu L (2007) Methamphetamine-disrupted sensory processing mediates conditioned place preference performance. Behavioural brain research 182:103-108.
Choi DC, Maguschak KA, Ye K, Jang SW, Myers KM, Ressler KJ (2010) Prelimbic cortical BDNF is required for memory of learned fear but not extinction or innate fear. Proceedings of the National Academy of Sciences of the United States of America 107:2675-2680.
Cossu G, Ledent C, Fattore L, Imperato A, Bohme GA, Parmentier M, Fratta W (2001) Cannabinoid CB1 receptor knockout mice fail to self-administer morphine but not other drugs of abuse. Behavioural brain research 118:61-65.
De Vries TJ, Shaham Y, Homberg JR, Crombag H, Schuurman K, Dieben J, Vanderschuren LJ, Schoffelmeer AN (2001) A cannabinoid mechanism in relapse to cocaine seeking. Nature medicine 7:1151-1154.
Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, Gibson D, Mandelbaum A, Etinger A, Mechoulam R (1992) Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science (New York, NY) 258:1946-1949.
Di Marzo V, Melck D, Bisogno T, De Petrocellis L (1998) Endocannabinoids: endogenous cannabinoid receptor ligands with neuromodulatory action. Trends in neurosciences 21:521-528.
Felder CC, Joyce KE, Briley EM, Mansouri J, Mackie K, Blond O, Lai Y, Ma AL, Mitchell RL (1995) Comparison of the pharmacology and signal transduction of the human cannabinoid CB1 and CB2 receptors. Molecular pharmacology 48:443-450.
Foldy C, Neu A, Jones MV, Soltesz I (2006) Presynaptic, activity-dependent modulation of cannabinoid type 1 receptor-mediated inhibition of GABA release. The Journal of neuroscience : the official journal of the Society for Neuroscience 26:1465-1469.
Gaoni Y, Mechoulam R (1964) Isolation, Structure, and Partial Synthesis of an Active Constituent of Hashish. Journal of the American Chemical Society 86:1646-1647.
Greydanus DE, Hawver EK, Greydanus MM, Merrick J (2013) Marijuana: current concepts(dagger). Frontiers in public health 1:42.
Jaffe J, Cascella N, Kumor K, Sherer M (1989) Cocaine-induced cocaine craving. Psychopharmacology 97:59-64.
Justinova Z, Panlilio LV, Goldberg SR (2009) Drug addiction. Current topics in behavioral neurosciences 1:309-346.
Kalivas PW, Volkow N, Seamans J (2005) Unmanageable motivation in addiction: a pathology in prefrontal-accumbens glutamate transmission. Neuron 45:647-650.
Kodas E, Cohen C, Louis C, Griebel G (2007) Cortico-limbic circuitry for conditioned nicotine-seeking behavior in rats involves endocannabinoid signaling. Psychopharmacology 194:161-171.
LaLumiere RT, Niehoff KE, Kalivas PW (2010) The infralimbic cortex regulates the consolidation of extinction after cocaine self-administration. Learning & memory (Cold Spring Harbor, NY) 17:168-175.
Lambert DG (2004) Drugs and receptors. Continuing Education in Anaesthesia, Critical Care & Pain 4:181-184.
Lesscher HM, Hoogveld E, Burbach JP, van Ree JM, Gerrits MA (2005) Endogenous cannabinoids are not involved in cocaine reinforcement and development of cocaine-induced behavioural sensitization. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology 15:31-37.
Lichtman AH, Varvel SA, Martin BR (2002) Endocannabinoids in cognition and dependence. Prostaglandins, leukotrienes, and essential fatty acids 66:269-285.
Losonczy A, Biro AA, Nusser Z (2004) Persistently active cannabinoid receptors mute a subpopulation of hippocampal interneurons. Proceedings of the National Academy of Sciences of the United States of America 101:1362-1367.
Maldonado R, Valverde O, Berrendero F (2006) Involvement of the endocannabinoid system in drug addiction. Trends in neurosciences 29:225-232.
Martin M, Ledent C, Parmentier M, Maldonado R, Valverde O (2000) Cocaine, but not morphine, induces conditioned place preference and sensitization to locomotor responses in CB1 knockout mice. The European journal of neuroscience 12:4038-4046.
Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI (1990) Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346:561-564.
McFarland K, Kalivas PW (2001) The circuitry mediating cocaine-induced reinstatement of drug-seeking behavior. The Journal of neuroscience : the official journal of the Society for Neuroscience 21:8655-8663.
McFarland K, Lapish CC, Kalivas PW (2003) Prefrontal glutamate release into the core of the nucleus accumbens mediates cocaine-induced reinstatement of drug-seeking behavior. The Journal of neuroscience : the official journal of the Society for Neuroscience 23:3531-3537.
McFarland K, Davidge SB, Lapish CC, Kalivas PW (2004) Limbic and motor circuitry underlying footshock-induced reinstatement of cocaine-seeking behavior. The Journal of neuroscience : the official journal of the Society for Neuroscience 24:1551-1560.
Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminski NE, Schatz AR, Gopher A, Almog S, Martin BR, Compton DR, et al. (1995) Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochemical pharmacology 50:83-90.
Milad MR, Quirk GJ (2002) Neurons in medial prefrontal cortex signal memory for fear extinction. Nature 420:70-74.
Morgan MA, Romanski LM, LeDoux JE (1993) Extinction of emotional learning: contribution of medial prefrontal cortex. Neuroscience letters 163:109-113.
Munro S, Thomas KL, Abu-Shaar M (1993) Molecular characterization of a peripheral receptor for cannabinoids. Nature 365:61-65.
Nader K (2003) Memory traces unbound. Trends in neurosciences 26:65-72.
Pacher P, Batkai S, Kunos G (2006) The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacological reviews 58:389-462.
Panlilio LV, Goldberg SR (2007) Self-administration of drugs in animals and humans as a model and an investigative tool. Addiction 102:1863-1870.
Park WK, Bari AA, Jey AR, Anderson SM, Spealman RD, Rowlett JK, Pierce RC (2002) Cocaine administered into the medial prefrontal cortex reinstates cocaine-seeking behavior by increasing AMPA receptor-mediated glutamate transmission in the nucleus accumbens. The Journal of neuroscience : the official journal of the Society for Neuroscience 22:2916-2925.
Piet R, Garenne A, Farrugia F, Le Masson G, Marsicano G, Chavis P, Manzoni OJ (2011) State-dependent, bidirectional modulation of neural network activity by endocannabinoids. The Journal of neuroscience : the official journal of the Society for Neuroscience 31:16591-16596.
Piomelli D (2003) The molecular logic of endocannabinoid signalling. Nature reviews Neuroscience 4:873-884.
Shaham Y, Shalev U, Lu L, De Wit H, Stewart J (2003) The reinstatement model of drug relapse: history, methodology and major findings. Psychopharmacology 168:3-20.
Sugiura T, Kondo S, Sukagawa A, Nakane S, Shinoda A, Itoh K, Yamashita A, Waku K (1995) 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochemical and biophysical research communications 215:89-97.
Vlachou S, Nomikos GG, Panagis G (2003) WIN 55,212-2 decreases the reinforcing actions of cocaine through CB1 cannabinoid receptor stimulation. Behavioural brain research 141:215-222.
Xi ZX, Gilbert JG, Peng XQ, Pak AC, Li X, Gardner EL (2006) Cannabinoid CB1 receptor antagonist AM251 inhibits cocaine-primed relapse in rats: role of glutamate in the nucleus accumbens. The Journal of neuroscience : the official journal of the Society for Neuroscience 26:8531-8536.
Yu LL, Zhou SJ, Wang XY, Liu JF, Xue YX, Jiang W, Lu L (2011) Effects of cannabinoid CB(1) receptor antagonist rimonabant on acquisition and reinstatement of psychostimulant reward memory in mice. Behavioural brain research 217:111-116.
Zavala AR, Weber SM, Rice HJ, Alleweireldt AT, Neisewander JL (2003) Role of the prelimbic subregion of the medial prefrontal cortex in acquisition, extinction, and reinstatement of cocaine-conditioned place preference. Brain research 990:157-164.
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