Drug Addiction

  • Zuzana Justinova
  • Leigh V. Panlilio
  • Steven R. GoldbergEmail author
Part of the Current Topics in Behavioral Neurosciences book series (CTBN, volume 1)


Many drugs of abuse, including cannabinoids, opioids, alcohol and nicotine, can alter the levels of endocannabinoids in the brain. Recent studies show that release of endocannabinoids in the ventral tegmental area can modulate the reward-related effects of dopamine and might therefore be an important neurobiological mechanism underlying drug addiction. There is strong evidence that the endocannabinoid system is involved in drug-seeking behavior (especially behavior that is reinforced by drug-related cues), as well as in the mechanisms that underlie relapse to drug use. The cannabinoid CB1 antagonist/inverse agonist rimonabant has been shown to reduce the behavioral effects of stimuli associated with drugs of abuse, including nicotine, alcohol, cocaine, and marijuana. Thus, the endocannabinoid system represents a promising target for development of new treatments for drug addiction.


Drug addiction Cannabinoids Endocannabinoids Self-administration Relapse Reward THC 







ventral tegmental area


dopamine transporter




fatty acid amide hydrolase



The preparation of this manuscript was supported in part by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services and Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland.


  1. Abood ME, Martin BR (1992) Neurobiology of marijuana abuse. Trends Pharmacol Sci 13:201–206PubMedGoogle Scholar
  2. Aceto MD, Scates SM, Lowe JA et al. (1995) Cannabinoid precipitated withdrawal by the selective cannabinoid receptor antagonist, SR 141716A. Eur J Pharmacol 282:R1–R2PubMedGoogle Scholar
  3. Aceto MD, Scates SM, Lowe JA et al. (1996) Dependence on delta 9-tetrahydrocannabinol: studies on precipitated and abrupt withdrawal. J Pharmacol Exp Ther 278:1290–1295PubMedGoogle Scholar
  4. Aceto MD, Scates SM, Razdan RK et al. (1998) Anandamide, an endogenous cannabinoid, has a very low physical dependence potential. J Pharmacol Exp Ther 287:598–605PubMedGoogle Scholar
  5. Acquas E, Carboni E, Di Chiara G (1991) Profound depression of mesolimbic dopamine release after morphine withdrawal in dependent rats. Eur J Pharmacol 193:133–134PubMedGoogle Scholar
  6. Agurell S, Halldin M, Lindgren JE et al. (1986) Pharmacokinetics and metabolism of delta 1-tetrahydrocannabinol and other cannabinoids with emphasis on man. Pharmacol Rev 38:21–43PubMedGoogle Scholar
  7. Alici T, Appel JB (2004) Increasing the selectivity of the discriminative stimulus effects of delta 9-tetrahydrocannabinol: complete substitution with methanandamide. Pharmacol Biochem Behav 79:431–437PubMedGoogle Scholar
  8. American Psychiatric Association (1994) DSM-IV: diagnostic and statistical manual of mental disorders, 4th edn. APA, Washington DCGoogle Scholar
  9. Anggadiredja K, Nakamichi M, Hiranita T et al. (2004) Endocannabinoid system modulates relapse to methamphetamine seeking: possible mediation by the arachidonic acid cascade. Neuropsychopharmacology 29:1470–1478PubMedGoogle Scholar
  10. Arnold JM, Roberts DC (1997) A critique of fixed and progressive ratio schedules used to examine the neural substrates of drug reinforcement. Pharmacol Biochem Behav 57:441–447PubMedGoogle Scholar
  11. Arnone M, Maruani J, Chaperon F et al. (1997) Selective inhibition of sucrose and ethanol intake by SR 141,716, an antagonist of central cannabinoid (CB1) receptors. Psychopharmacology (Berl) 132:104–106Google Scholar
  12. Arroyo M, Markou A, Robbins TW et al. (1998) Acquisition, maintenance and reinstatement of intravenous cocaine self-administration under a second-order schedule of reinforcement in rats: effects of conditioned cues and continuous access to cocaine. Psychopharmacology (Berl) 140:331–344Google Scholar
  13. Ballon N, Leroy S, Roy C et al. (2006) (AAT)n repeat in the cannabinoid receptor gene (CNR1): association with cocaine addiction in an African–Caribbean population. Pharmacogenomics J 6:126–130PubMedGoogle Scholar
  14. Barrett RL, Wiley JL, Balster RL et al. (1995) Pharmacological specificity of delta 9-tetrahydrocannabinol discrimination in rats. Psychopharmacology (Berl) 118:419–424Google Scholar
  15. Basavarajappa BS, Saito M, Cooper TB et al. (2003) Chronic ethanol inhibits the anandamide transport and increases extracellular anandamide levels in cerebellar granule neurons. Eur J Pharmacol 466:73–83PubMedGoogle Scholar
  16. Bazinet RP, Lee HJ, Felder CC et al. (2005) Rapid high-energy microwave fixation is required to determine the anandamide (N-arachidonoylethanolamine) concentration of rat brain. Neurochem Res 30:597–601PubMedGoogle Scholar
  17. Bequet F, Uzabiaga F, Desbazeille M et al. (2007) CB1 receptor-mediated control of the release of endocannabinoids (as assessed by microdialysis coupled with LC/MS) in the rat hypothalamus. Eur J Neurosci 26:3458–3464PubMedGoogle Scholar
  18. Bergman J, Johanson CE (1985) The reinforcing properties of diazepam under several conditions in the rhesus monkey. Psychopharmacology (Berl) 86:108–113Google Scholar
  19. Blednov YA, Cravatt BF, Boehm SL et al. (2007) Role of endocannabinoids in alcohol consumption and intoxication: studies of mice lacking fatty acid amide hydrolase. Neuropsychopharmacology 32:1570–1582PubMedGoogle Scholar
  20. Bortolato M, Campolongo P, Mangieri RA et al. (2006) Anxiolytic-like properties of the anandamide transport inhibitor AM404. Neuropsychopharmacology 31:2652–2659PubMedGoogle Scholar
  21. Braida D, Pozzi M, Cavallini R et al. (2001a) Conditioned place preference induced by the cannabinoid agonist CP 55,940: interaction with the opioid system. Neuroscience 104:923–926PubMedGoogle Scholar
  22. Braida D, Pozzi M, Parolaro D et al. (2001b) Intracerebral self-administration of the cannabinoid receptor agonist CP 55,940 in the rat: interaction with the opioid system. Eur J Pharmacol 413:227–234PubMedGoogle Scholar
  23. Braida D, Iosue S, Pegorini S et al. (2004) Delta9-tetrahydrocannabinol-induced conditioned place preference and intracerebroventricular self-administration in rats. Eur J Pharmacol 506:63–69PubMedGoogle Scholar
  24. Braida D, Iosue S, Pegorini S et al. (2005) 3, 4 Methylenedioxymethamphetamine-induced conditioned place preference (CPP) is mediated by endocannabinoid system. Pharmacol Res 51:177–182PubMedGoogle Scholar
  25. Branch MN, Dearing ME, Lee DM (1980) Acute and chronic effects of delta 9-tetrahydrocannabinol on complex behavior of squirrel monkeys. Psychopharmacology (Berl) 71:247–256Google Scholar
  26. Brodie MS, Pesold C, Appel SB (1999) Ethanol directly excites dopaminergic ventral tegmental area reward neurons. Alcohol Clin Exp Res 23:1848–1852PubMedGoogle Scholar
  27. Burkey RT, Nation JR (1997) (R)-methanandamide, but not anandamide, substitutes for delta 9-THC in a drug-discrimination procedure. Exp Clin Psychopharmacol 5:195–202PubMedGoogle Scholar
  28. Cadoni C, Pisanu A, Solinas M et al. (2001) Behavioural sensitization after repeated exposure to Delta 9-tetrahydrocannabinol and cross-sensitization with morphine. Psychopharmacology (Berl) 158:259–266Google Scholar
  29. Cadoni C, Valentini V, Di Chiara G (2008) Behavioral sensitization to Delta(9)-tetrahydrocannabinol and cross-sensitization with morphine: differential changes in accumbal shell and core dopamine transmission. J Neurochem 106:1586–1593PubMedGoogle Scholar
  30. Caille S, Parsons LH (2003) SR141716A reduces the reinforcing properties of heroin but not heroin-induced increases in nucleus accumbens dopamine in rats. Eur J Neurosci 18:3145–3149PubMedGoogle Scholar
  31. Caille S, Varez-Jaimes L, Polis I et al. (2007) Specific alterations of extracellular endocannabinoid levels in the ucleus accumbens by ethanol, heroin, and cocaine self-administration. J Neurosci 27:3695–3702PubMedGoogle Scholar
  32. Cami J, Farre M (2003) Drug addiction. N Engl J Med 349:975–986PubMedGoogle Scholar
  33. Carroll ME, Meisch RA (1984) Increased drug-reinforced behavior due to food deprivation. In: Thompson T, Dews PB, Barrett JE (eds) Advances in behavioral pharmacology. Academic Press, New York, pp 47–88Google Scholar
  34. Castane A, Valjent E, Ledent C et al. (2002) Lack of CB1 cannabinoid receptors modifies nicotine behavioural responses, but not nicotine abstinence. Neuropharmacology 43:857–867PubMedGoogle Scholar
  35. Castane A, Robledo P, Matifas A et al. (2003) Cannabinoid withdrawal syndrome is reduced in double mu and delta opioid receptor knockout mice. Eur J Neurosci 17:155–159PubMedGoogle Scholar
  36. Castane A, Maldonado R, Valverde O (2004) Role of different brain structures in the behavioural expression of WIN 55,212–2 withdrawal in mice. Br J Pharmacol 142:1309–1317PubMedGoogle Scholar
  37. CEWG (2007) Epidemiologic trends in drug abuse. Proceedings of the Community Epidemiology Work Group. Highlights and executive summary. National Institute on Drug Abuse, NIH Publication No. 07-6,200, Bethesda, MDGoogle Scholar
  38. Chaperon F, Thiebot MH (1999) Behavioral effects of cannabinoid agents in animals. Crit Rev Neurobiol 13:243–281PubMedGoogle Scholar
  39. Chaperon F, Soubrie P, Puech AJ et al. (1998) Involvement of central cannabinoid (CB1) receptors in the establishment of place conditioning in rats. Psychopharmacology (Berl) 135:324–332Google Scholar
  40. Cheer JF, Kendall DA, Marsden CA (2000) Cannabinoid receptors and reward in the rat: a conditioned place preference study. Psychopharmacology (Berl) 151:25–30Google Scholar
  41. Chen JP, Paredes W, Li J et al. (1990) Delta 9-tetrahydrocannabinol produces naloxone-blockable enhancement of presynaptic basal dopamine efflux in nucleus accumbens of conscious, freely-moving rats as measured by intracerebral microdialysis. Psychopharmacology (Berl) 102: 156–162Google Scholar
  42. Cheng HY, Laviolette SR, van der Kooy D et al. (2004) DREAM ablation selectively alters THC place aversion and analgesia but leaves intact the motivational and analgesic effects of morphine. Eur J Neurosci 19:3033–3041PubMedGoogle Scholar
  43. Cippitelli A, Bilbao A, Hansson AC et al. (2005) Cannabinoid CB1 receptor antagonism reduces conditioned reinstatement of ethanol-seeking behavior in rats. Eur J Neurosci 21:2243–2251PubMedGoogle Scholar
  44. Cippitelli A, Bilbao A, Gorriti MA et al. (2007) The anandamide transport inhibitor AM404 reduces ethanol self-administration. Eur J Neurosci 26:476–486PubMedGoogle Scholar
  45. Cippitelli A, Cannella N, Braconi S et al. (2008) Increase of brain endocannabinoid anandamide levels by FAAH inhibition and alcohol abuse behaviours in the rat. Psychopharmacology (Berl) 198:449–460Google Scholar
  46. Cohen C, Perrault G, Voltz C et al. (2002) SR141716, a central cannabinoid (CB(1)) receptor antagonist, blocks the motivational and dopamine-releasing effects of nicotine in rats. Behav Pharmacol 13:451–463PubMedGoogle Scholar
  47. Cohen C, Kodas E, Griebel G (2005) CB1 receptor antagonists for the treatment of nicotine addiction. Pharmacol Biochem Behav 81:387–395PubMedGoogle Scholar
  48. Collins RJ, Weeks JR, Cooper MM et al. (1984) Prediction of abuse liability of drugs using IV self-administration by rats. Psychopharmacology (Berl) 82:6–13Google Scholar
  49. Colombo G, Serra S, Brunetti G et al. (2002) Stimulation of voluntary ethanol intake by cannabinoid receptor agonists in ethanol-preferring sP rats. Psychopharmacology (Berl) 159:181–187Google Scholar
  50. Colpaert FC (1999) Drug discrimination in neurobiology. Pharmacol Biochem Behav 64:337–345PubMedGoogle Scholar
  51. Comings DE, Muhleman D, Gade R et al. (1997) Cannabinoid receptor gene (CNR1): association with i.v. drug use. Mol Psychiatry 2:161–168PubMedGoogle Scholar
  52. Cossu G, Ledent C, Fattore L et al. (2001) Cannabinoid CB1 receptor knockout mice fail to self-administer morphine but not other drugs of abuse. Behav Brain Res 118:61–65PubMedGoogle Scholar
  53. Costa B, Giagnoni G, Colleoni M (2000) Precipitated and spontaneous withdrawal in rats tolerant to anandamide. Psychopharmacology (Berl) 149:121–128Google Scholar
  54. Crabbe JC, Phillips TJ, Harris RA et al. (2006) Alcohol-related genes: contributions from studies with genetically engineered mice. Addict Biol 11:195–269PubMedGoogle Scholar
  55. Delatte MS, Winsauer PJ, Moerschbaecher JM (2002) Tolerance to the disruptive effects of Delta(9)-THC on learning in rats. Pharmacol Biochem Behav 74:129–140PubMedGoogle Scholar
  56. De Vries TJ, Schoffelmeer AN (2005) Cannabinoid CB1 receptors control conditioned drug seeking. Trends Pharmacol Sci 26:420–426PubMedGoogle Scholar
  57. De Vries TJ, Schoffelmeer AN, Binnekade R et al. (1998) Drug-induced reinstatement of heroin- and cocaine-seeking behaviour following long-term extinction is associated with expression of behavioural sensitization. Eur J Neurosci 10:3565–3571PubMedGoogle Scholar
  58. De Vries TJ, Shaham Y, Homberg JR et al. (2001) A cannabinoid mechanism in relapse to cocaine seeking. Nat Med 7:1151–1154PubMedGoogle Scholar
  59. De Vries TJ, Homberg JR, Binnekade R et al. (2003) Cannabinoid modulation of the reinforcing and motivational properties of heroin and heroin-associated cues in rats. Psychopharmacology (Berl) 168:164–169Google Scholar
  60. Dewey WL (1986) Cannabinoid pharmacology. Pharmacol Rev 38:151–178PubMedGoogle Scholar
  61. Di Chiara G, Tanda G, Bassareo V et al. (1999) Drug addiction as a disorder of associative learning. Role of nucleus accumbens shell/extended amygdala dopamine. Ann N Y Acad Sci 877:461–485PubMedGoogle Scholar
  62. Di Marzo V, Berrendero F, Bisogno T et al. (2000) Enhancement of anandamide formation in the limbic forebrain and reduction of endocannabinoid contents in the striatum of delta9-tetrahydrocannabinol-tolerant rats. J Neurochem 74:1627–1635PubMedGoogle Scholar
  63. Evenden J, Ko T (2007) The effects of anorexic drugs on free-fed rats responding under a second-order FI15-min (FR10:S) schedule for high incentive foods. Behav Pharmacol 18:61–69PubMedGoogle Scholar
  64. Everitt BJ, Robbins TW (2000) Second-order schedules of drug reinforcement in rats and monkeys: measurement of reinforcing efficacy and drug-seeking behaviour. Psychopharmacology (Berl) 153:17–30Google Scholar
  65. Fattore L, Cossu G, Martellotta CM et al. (2001) Intravenous self-administration of the cannabinoid CB1 receptor agonist WIN 55, 212-2 in rats. Psychopharmacology (Berl) 156:410–416Google Scholar
  66. Fattore L, Spano MS, Cossu G et al. (2003) Cannabinoid mechanism in reinstatement of heroin-seeking after a long period of abstinence in rats. Eur J Neurosci 17:1723–1726PubMedGoogle Scholar
  67. Fattore L, Deiana S, Spano SM et al. (2005) Endocannabinoid system and opioid addiction: behavioural aspects. Pharmacol Biochem Behav 81:343–359PubMedGoogle Scholar
  68. Fattore L, Fadda P, Fratta W (2007) Endocannabinoid regulation of relapse mechanisms. Pharmacol Res 56:418–427PubMedGoogle Scholar
  69. Fernandez JR, Allison DB (2004) Rimonabants sanofi-synthelabo. Curr Opin Invest Drugs 5:430–435Google Scholar
  70. Ferrer B, Bermudez-Silva FJ, Bilbao A et al. (2007) Regulation of brain anandamide by acute administration of ethanol. Biochem J 404:97–104PubMedGoogle Scholar
  71. Fourgeaud L, Mato S, Bouchet D et al. (2004) A single in vivo exposure to cocaine abolishes endocannabinoid-mediated long-term depression in the nucleus accumbens. J Neurosci 24:6939–6945PubMedGoogle Scholar
  72. Fusco FR, Martorana A, Giampa C et al. (2004) Immunolocalization of CB1 receptor in rat striatal neurons: a confocal microscopy study. Synapse 53:159–167PubMedGoogle Scholar
  73. Gessa GL, Serra S, Vacca G et al. (2005) Suppressing effect of the cannabinoid CB1 receptor antagonist, SR147778, on alcohol intake and motivational properties of alcohol in alcohol-preferring sP rats. Alcohol Alcohol 40:46–53PubMedGoogle Scholar
  74. Ghozland S, Matthes HW, Simonin F et al. (2002) Motivational effects of cannabinoids are mediated by mu-opioid and kappa-opioid receptors. J Neurosci 22:1146–1154Google Scholar
  75. Giuffrida A, Parsons LH, Kerr TM et al. (1999) Dopamine activation of endogenous cannabinoid signaling in dorsal striatum. Nat Neurosci 2:358–363PubMedGoogle Scholar
  76. Gobbi G, Bambico FR, Mangieri R et al. (2005) Antidepressant-like activity and modulation of brain monoaminergic transmission by blockade of anandamide hydrolysis. Proc Natl Acad Sci USA 102:18620–18625PubMedGoogle Scholar
  77. Goldberg SR, Hoffmeister F, Schlichting UU et al. (1971) A comparison of pentobarbital and cocaine self-administration in rhesus monkeys: effects of dose and fixed-ratio parameter. J Pharmacol Exp Ther 179:277–283PubMedGoogle Scholar
  78. Goldberg SR, Kelleher RT, Morse WH (1975) Second-order schedules of drug injection. Fed Proc 34:1771–1776PubMedGoogle Scholar
  79. Goldberg SR, Spealman RD, Goldberg DM (1981) Persistent behavior at high rates maintained by intravenous self-administration of nicotine. Science 214:573–575PubMedGoogle Scholar
  80. Gonzalez S, Cascio MG, Fernandez-Ruiz J et al. (2002) Changes in endocannabinoid contents in the brain of rats chronically exposed to nicotine, ethanol or cocaine. Brain Res 954:73–81PubMedGoogle Scholar
  81. Gonzalez S, Schmid PC, Fernandez-Ruiz J et al. (2003) Region-dependent changes in endocannabinoid transmission in the brain of morphine-dependent rats. Addict Biol 8:159–166PubMedGoogle Scholar
  82. Gonzalez S, Fernandez-Ruiz J, Di Marzo V et al. (2004) Behavioral and molecular changes elicited by acute administration of SR141716 to Delta9-tetrahydrocannabinol-tolerant rats: an experimental model of cannabinoid abstinence. Drug Alcohol Depend 74:159–170PubMedGoogle Scholar
  83. Gorriti MA, de Rodriguez FF, Navarro M et al. (1999) Chronic (-)-delta9-tetrahydrocannabinol treatment induces sensitization to the psychomotor effects of amphetamine in rats. Eur J Pharmacol 365:133–142PubMedGoogle Scholar
  84. Haller J, Matyas F, Soproni K et al. (2007) Correlated species differences in the effects of cannabinoid ligands on anxiety and on GABAergic and glutamatergic synaptic transmission. Eur J Neurosci 25:2445–2456PubMedGoogle Scholar
  85. Haney M, Comer SD, Ward AS et al. (1997) Factors influencing marijuana self-administration by humans. Behav Pharmacol 8:101–112PubMedGoogle Scholar
  86. Haney M, Ward AS, Comer SD et al. (1999a) Abstinence symptoms following oral THC administration to humans. Psychopharmacology (Berl) 141:385–394Google Scholar
  87. Haney M, Ward AS, Comer SD et al. (1999b) Abstinence symptoms following smoked marijuana in humans. Psychopharmacology (Berl) 141:395–404Google Scholar
  88. Harris RT, Waters W, McLendon D (1974) Evaluation of reinforcing capability of delta-9-tetrahydrocannabinol in rhesus monkeys. Psychopharmacologia 37:23–29PubMedGoogle Scholar
  89. Hine B, Torrelio M, Gershon S (1975) Attenuation of precipitated abstinence in methadone-dependent rats by delta 9-THC. Psychopharmacol Commun 1:275–283PubMedGoogle Scholar
  90. HODOS W (1961) Progressive ratio as a measure of reward strength. Science 134:943–944PubMedGoogle Scholar
  91. Hohmann AG, Herkenham M (2000) Localization of cannabinoid CB(1) receptor mRNA in neuronal subpopulations of rat striatum: a double-label in situ hybridization study. Synapse 37:71–80PubMedGoogle Scholar
  92. Hollister LE (1986) Health aspects of cannabis. Pharmacol Rev 38:1–20PubMedGoogle Scholar
  93. Huang YC, Wang SJ, Chiou LC et al. (2003) Mediation of amphetamine-induced long-term depression of synaptic transmission by CB1 cannabinoid receptors in the rat amygdala. J Neurosci 23:10311–10320PubMedGoogle Scholar
  94. Huestis MA, Gorelick DA, Heishman SJ et al. (2001) Blockade of effects of smoked marijuana by he CB1-selective cannabinoid receptor antagonist SR141716. Arch Gen Psychiatry 58:322–328PubMedGoogle Scholar
  95. Hungund BL, Basavarajappa BS (2004) Role of endocannabinoids and cannabinoid CB1 receptors in alcohol-related behaviors. Ann N Y Acad Sci 1025:515–527PubMedGoogle Scholar
  96. Hungund BL, Szakall I, Adam A et al. (2003) Cannabinoid CB1 receptor knockout mice exhibit markedly reduced voluntary alcohol consumption and lack alcohol-induced dopamine release in the nucleus accumbens. J Neurochem 84:698–704PubMedGoogle Scholar
  97. Hutcheson DM, Tzavara ET, Smadja C et al. (1998) Behavioural and biochemical evidence for signs of abstinence in mice chronically treated with delta-9-tetrahydrocannabinol. Br J Pharmacol 125:1567–1577PubMedGoogle Scholar
  98. Jacobs EH, Smit AB, De Vries TJ et al. (2003) Neuroadaptive effects of active versus passive drug administration in addiction research. Trends Pharmacol Sci 24:566–573PubMedGoogle Scholar
  99. Jarbe TU, Lamb RJ, Lin S et al. (2001) (R)-methanandamide and Delta 9-THC as discriminative stimuli in rats: tests with the cannabinoid antagonist SR-141,716 and the endogenous ligand anandamide. Psychopharmacology (Berl) 156:369–380Google Scholar
  100. Jarbe TU, Lamb RJ, Liu Q et al. (2006) Discriminative stimulus functions of AM-1,346, a CB1R selective anandamide analog in rats trained with Delta9-THC or (R)-methanandamide (AM-356). Psychopharmacology (Berl) 188:315–323Google Scholar
  101. Jayamanne A, Greenwood R, Mitchell VA et al. (2006) Actions of the FAAH inhibitor URB597 in neuropathic and inflammatory chronic pain models. Br J Pharmacol 147:281–288PubMedGoogle Scholar
  102. Jentsch JD, Taylor JR (1999) Impulsivity resulting from frontostriatal dysfunction in drug abuse: implications for the control of behavior by reward-related stimuli. Psychopharmacology (Berl) 146:373–390Google Scholar
  103. Johanson CE, Balster RL (1978) A summary of the results of a drug self-administration study using substitution procedures in rhesus monkeys. Bull Narc 30:43–54PubMedGoogle Scholar
  104. Justinova Z, Goldberg SR (2004) The abuse potential of the endocannabinoid transport inhibitor AM404: Self-administration by squirrel monkeys. 2005 Symposium on the Cannabinoids, Burlington, Vermont, International Cannabinoid Research Society, page 176Google Scholar
  105. Justinova Z, Tanda G, Redhi GH et al. (2003) Self-administration of Delta(9)-tetrahydrocannabinol (THC) by drug naive squirrel monkeys. Psychopharmacology (Berl) 169:135–140Google Scholar
  106. Justinova Z, Tanda G, Munzar P et al. (2004) The opioid antagonist naltrexone reduces the reinforcing effects of Delta 9 tetrahydrocannabinol (THC) in squirrel monkeys. Psychopharmacology (Berl) 173:186–194Google Scholar
  107. Justinova Z, Goldberg SR, Heishman SJ et al. (2005a) Self-administration of cannabinoids by experimental animals and human marijuana smokers. Pharmacol Biochem Behav 81:285–299PubMedGoogle Scholar
  108. Justinova Z, Solinas M, Tanda G et al. (2005b) The endogenous cannabinoid anandamide and its synthetic analog R(+)-methanandamide are intravenously self-administered by squirrel monkeys. J Neurosci 25:5645–5650PubMedGoogle Scholar
  109. Justinova Z, Bortolato M, Mangieri RA et al. (2007) Lack of abuse liability of the FAAH inhibitor URB597 in squirrel monkeys. FASEB J 21:A409Google Scholar
  110. Justinova Z, Mangieri RA, Bortolato M et al. (2008a) Fatty acid amide hydrolase inhibition heightens anandamide signaling without producing reinforcing effects in primates. Biol Psychiatry 64:930–937Google Scholar
  111. Justinova Z, Munzar P, Panlilio LV et al. (2008a) Blockade of THC-seeking behavior and relapse in monkeys by the cannabinoid CB(1)-receptor antagonist rimonabant. Neuropsychopharmacology 33:2870–2877PubMedGoogle Scholar
  112. Kalivas PW (2007) Cocaine and amphetamine-like psychostimulants: neurocircuitry and glutamate neuroplasticity. Dialogues Clin Neurosci 9:389–397PubMedGoogle Scholar
  113. Kathuria S, Gaetani S, Fegley D et al. (2003) Modulation of anxiety through blockade of anandamide hydrolysis. Nat Med 9:76–81PubMedGoogle Scholar
  114. Kauer JA (2004) Learning mechanisms in addiction: synaptic plasticity in the ventral tegmental area as a result of exposure to drugs of abuse. Annu Rev Physiol 66:447–475PubMedGoogle Scholar
  115. Kaymakcalan S (1973) Tolerance to and dependence on cannabis. Bull Narc 25:39–47Google Scholar
  116. Kofalvi A, Rodrigues RJ, Ledent C et al. (2005) Involvement of cannabinoid receptors in the regulation of neurotransmitter release in the rodent striatum: a combined immunochemical and pharmacological analysis. J Neurosci 25:2874–2884PubMedGoogle Scholar
  117. Koob GF (1992) Drugs of abuse: anatomy, pharmacology and function of reward pathways. Trends Pharmacol Sci 13:177–184PubMedGoogle Scholar
  118. Koob GF, Weiss F (1990) Pharmacology of drug self-administration. Alcohol 7:193–197PubMedGoogle Scholar
  119. Koob GF, Sanna PP, Bloom FE (1998) Neuroscience of addiction. Neuron 21:467–476PubMedGoogle Scholar
  120. Kreek MJ, LaForge KS, Butelman E (2002) Pharmacotherapy of addictions. Nat Rev Drug Discov 1:710–726PubMedGoogle Scholar
  121. Lallemand F, De Witte P (2006) SR147778, a CB1 cannabinoid receptor antagonist, suppresses ethanol preference in chronically alcoholized Wistar rats. Alcohol 39:125–134Google Scholar
  122. Lamarque S, Taghzouti K, Simon H (2001) Chronic treatment with Delta(9)-tetrahydrocannabinol enhances the locomotor response to amphetamine and heroin. Implications for vulnerability to drug addiction. Neuropharmacology 41:118–129PubMedGoogle Scholar
  123. Le Foll B, Goldberg SR (2004) Rimonabant, a CB1 antagonist, blocks nicotine-conditioned place preferences. Neuroreport 15:2139–2143PubMedGoogle Scholar
  124. Le Foll B, Goldberg SR (2005) Cannabinoid CB1 receptor antagonists as promising new medications for drug dependence. J Pharmacol Exp Ther 312:875–883PubMedGoogle Scholar
  125. Le Foll B, Wiggins M, Goldberg SR (2006) Nicotine pre-exposure does not potentiate the locomotor or rewarding effects of Delta-9-tetrahydrocannabinol in rats. Behav Pharmacol 17:195–199PubMedGoogle Scholar
  126. Ledent C, Valverde O, Cossu G et al. (1999) Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice. Science 283:401–404PubMedGoogle Scholar
  127. Lepore M, Vorel SR, Lowinson J et al. (1995) Conditioned place preference induced by delta 9-tetrahydrocannabinol: comparison with cocaine, morphine, and food reward. Life Sci 56: 2073–2080PubMedGoogle Scholar
  128. Lesscher HM, Hoogveld E, Burbach JP et al. (2005) Endogenous cannabinoids are not involved in cocaine reinforcement and development of cocaine-induced behavioural sensitization. Eur Neuropsychopharmacol 15:31–37PubMedGoogle Scholar
  129. Lichtman AH, Sheikh SM, Loh HH et al. (2001) Opioid and cannabinoid modulation of precipitated withdrawal in delta(9)-tetrahydrocannabinol and morphine-dependent mice. J Pharmacol Exp Ther 298:1007–1014PubMedGoogle Scholar
  130. Lopez-Moreno JA, Gonzalez-Cuevas G, Rodriguez de Fonseca F et al. (2004) Long-lasting increase of alcohol relapse by the cannabinoid receptor agonist WIN 55, 212–2 during alcohol deprivation. J Neurosci 24:8245–8252PubMedGoogle Scholar
  131. Lupica CR, Riegel AC (2005) Endocannabinoid release from midbrain dopamine neurons: a potential substrate for cannabinoid receptor antagonist treatment of addiction. Neuropharmacology 48:1105–1116PubMedGoogle Scholar
  132. Maldonado R (2002) Study of cannabinoid dependence in animals. Pharmacol Ther 95:153–164PubMedGoogle Scholar
  133. Maldonado R, Rodriguez de Fonseca F (2002) Cannabinoid addiction: behavioral models and neural correlates. J Neurosci 22:3326–3331PubMedGoogle Scholar
  134. Maldonado R, Valverde O, Berrendero F (2006) Involvement of the endocannabinoid system in drug addiction. Trends Neurosci 29:225–232PubMedGoogle Scholar
  135. Mallet PE, Beninger RJ (1998) Delta9-tetrahydrocannabinol, but not the endogenous cannabinoid receptor ligand anandamide, produces conditioned place avoidance. Life Sci 62:2431–2439PubMedGoogle Scholar
  136. Martellotta MC, Cossu G, Fattore L et al. (1998) Self-administration of the cannabinoid receptor agonist WIN 55, 212-2 in drug-naive mice. Neuroscience 85:327–330PubMedGoogle Scholar
  137. Martin BR (2005) Role of lipids and lipid signaling in the development of cannabinoid tolerance. Life Sci 77:1543–1558PubMedGoogle Scholar
  138. Martin BR, Compton DR, Thomas BF et al. (1991) Behavioral, biochemical, and molecular modeling evaluations of cannabinoid analogs. Pharmacol Biochem Behav 40:471–478PubMedGoogle Scholar
  139. Martin M, Ledent C, Parmentier M et al. (2000) Cocaine, but not morphine, induces conditioned place preference and sensitization to locomotor responses in CB1 knockout mice. Eur J Neurosci 12:4038–4046PubMedGoogle Scholar
  140. Mascia MS, Obinu MC, Ledent C et al. (1999) Lack of morphine-induced dopamine release in the nucleus accumbens of cannabinoid CB(1) receptor knockout mice. Eur J Pharmacol 383:R1–R2PubMedGoogle Scholar
  141. Masuzawa M, Nakao S, Miyamoto E et al. (2003) Pentobarbital inhibits ketamine-induced dopamine release in the rat nucleus accumbens: a microdialysis study. Anesth Analg 96:148–152PubMedGoogle Scholar
  142. McDonald J, Schleifer L, Richards JB et al. (2003) Effects of THC on behavioral measures of impulsivity in humans. Neuropsychopharmacology 28:1356–1365PubMedGoogle Scholar
  143. McGregor IS, Gallate JE (2004) Rats on the grog: novel pharmacotherapies for alcohol craving. Addict Behav 29:1341–1357PubMedGoogle Scholar
  144. McGregor IS, Issakidis CN, Prior G (1996) Aversive effects of the synthetic cannabinoid CP 55, 940 in rats. Pharmacol Biochem Behav 53:657–664PubMedGoogle Scholar
  145. McGregor IS, Dam KD, Mallet PE et al. (2005) Delta9-THC reinstates beer- and sucrose-seeking behaviour in abstinent rats: comparison with midazolam, food deprivation and predator odour. Alcohol Alcohol 40:35–45PubMedGoogle Scholar
  146. Melis M, Pistis M, Perra S et al. (2004) Endocannabinoids mediate presynaptic inhibition of glutamatergic transmission in rat ventral tegmental area dopamine neurons through activation of CB1 receptors. J Neurosci 24:53–62PubMedGoogle Scholar
  147. Merritt LL, Martin BR, Walters C et al. (2008) The endogenous cannabinoid system modulates nicotine reward and dependence. J Pharmacol Exp Ther 326:483–492PubMedGoogle Scholar
  148. Mokler DJ, Nelson BD, Harris LS et al. (1986) The role of benzodiazepine receptors in the discriminative stimulus properties of delta-9-tetrahydrocannabinol. Life Sci 38:1581–1589PubMedGoogle Scholar
  149. Nava F, Carta G, Colombo G et al. (2001) Effects of chronic Delta(9)-tetrahydrocannabinol treatment on hippocampal extracellular acetylcholine concentration and alternation performance in the T-maze. Neuropharmacology 41:392–399PubMedGoogle Scholar
  150. Navarro M, Chowen J, Carrera MR et al. (1998) CB1 cannabinoid receptor antagonist-induced opiate withdrawal in morphine-dependent rats. Neuroreport 9:3397–3402PubMedGoogle Scholar
  151. Navarro M, Carrera MR, Fratta W et al. (2001) Functional interaction between opioid and cannabinoid receptors in drug self-administration. J Neurosci 21:5344–5350PubMedGoogle Scholar
  152. O'Brien C (2001) Drug addiction and drug abuse. In: Hardman J, Limbird L, Gilman AG (eds) The pharmacological basis of therapeutics. McGraw-Hill, New York, pp 621–642Google Scholar
  153. Oliva JM, Ortiz S, Palomo T et al. (2003) Behavioural and gene transcription alterations induced by spontaneous cannabinoid withdrawal in mice. J Neurochem 85:94–104PubMedGoogle Scholar
  154. Parker LA, Gillies T (1995) THC-induced place and taste aversions in Lewis and Sprague–Dawley rats. Behav Neurosci 109:71–78PubMedGoogle Scholar
  155. Parker LA, Mcdonald RV (2000) Reinstatement of both a conditioned place preference and a conditioned place aversion with drug primes. Pharmacol Biochem Behav 66:559–561PubMedGoogle Scholar
  156. Patel S, Rademacher DJ, Hillard CJ (2003) Differential regulation of the endocannabinoids anandamide and 2-arachidonylglycerol within the limbic forebrain by dopamine receptor activity. J Pharmacol Exp Ther 306:880–888PubMedGoogle Scholar
  157. Patel S, Carrier EJ, Ho WS et al. (2005) The postmortal accumulation of brain N-arachidonylethanolamine (anandamide) is dependent upon fatty acid amide hydrolase activity. J Lipid Res 46:342–349PubMedGoogle Scholar
  158. Pattij T, Vanderschuren LJ (2008) The neuropharmacology of impulsive behaviour. Trends Pharmacol Sci 29:192–199PubMedGoogle Scholar
  159. Pattij T, Janssen MC, Schepers I et al. (2007) Effects of the cannabinoid CB1 receptor antagonist rimonabant on distinct measures of impulsive behavior in rats. Psychopharmacology (Berl) 193:85–96Google Scholar
  160. Pertwee RG, Stevenson LA, Griffin G (1993) Cross-tolerance between delta-9-tetrahydrocannabinol and the cannabimimetic agents, CP 55, 940, WIN 55, 212- 2 and anandamide. Br J Pharmacol 110:1483–1490PubMedGoogle Scholar
  161. Pickel VM, Chan J, Kash TL et al. (2004) Compartment-specific localization of cannabinoid 1 (CB1) and mu-opioid receptors in rat nucleus accumbens. Neuroscience 127:101–112PubMedGoogle Scholar
  162. Pickel VM, Chan J, Kearn CS et al. (2006) Targeting dopamine D2 and cannabinoid-1 (CB1) receptors in rat nucleus accumbens. J Comp Neurol 495:299–313PubMedGoogle Scholar
  163. Pierce RC, Bell K, Duffy P et al. (1996) Repeated cocaine augments excitatory amino acid transmission in the nucleus accumbens only in rats having developed behavioral sensitization. J Neurosci 16:1550–1560PubMedGoogle Scholar
  164. Pistis M, Pillolla G, Luchicchi A et al. (2008) Inhibition of FAAH blocks the excitatory effects of nicotine on mesolimbic dopamine neurons via CB1 and PPAR-alpha receptors. 18th Annual Symposium on the Cannabinoids Burlington, Vermont, International Cannabinoid Research Society, page 40Google Scholar
  165. Pontieri FE, Tanda G, Di Chiara G (1995) Intravenous cocaine, morphine, and amphetamine preferentially increase extracellular dopamine in the “shell” as compared with the “core” of the rat nucleus accumbens. Proc Natl Acad Sci USA 92:12304–12308PubMedGoogle Scholar
  166. Pontieri FE, Tanda G, Orzi F et al. (1996) Effects of nicotine on the nucleus accumbens and similarity to those of addictive drugs. Nature 382:255–257PubMedGoogle Scholar
  167. Pontieri FE, Monnazzi P, Scontrini A et al. (2001a) Behavioral sensitization to WIN 55,212-2 in rats pretreated with heroin. Brain Res 898:178–180PubMedGoogle Scholar
  168. Pontieri FE, Monnazzi P, Scontrini A et al. (2001b) Behavioral sensitization to heroin by cannabinoid pretreatment in the rat. Eur J Pharmacol 421:R1–R3PubMedGoogle Scholar
  169. Ramaekers JG, Kauert G, van Ruitenbeek P et al. (2006) High-potency marijuana impairs executive function and inhibitory motor control. Neuropsychopharmacology 31:2296–2303PubMedGoogle Scholar
  170. Rice OV, Gordon N, Gifford AN (2002) Conditioned place preference to morphine in cannabinoid CB1 receptor knockout mice. Brain Res 945:135–138PubMedGoogle Scholar
  171. Richter RM, Pich EM, Koob GF et al. (1995) Sensitization of cocaine-stimulated increase in extracellular levels of corticotropin-releasing factor from the rat amygdala after repeated administration as determined by intracranial microdialysis. Neurosci Lett 187:169–172PubMedGoogle Scholar
  172. Riddle EL, Fleckenstein AE, Hanson GR (2005) Role of monoamine transporters in mediating psychostimulant effects. AAPS J 7:E847–E851PubMedGoogle Scholar
  173. Riegel AC, Lupica CR (2004) Independent presynaptic and postsynaptic mechanisms regulate endocannabinoid signaling at multiple synapses in the ventral tegmental area. J Neurosci 24:11070–11078PubMedGoogle Scholar
  174. Robbe D, Alonso G, Duchamp F et al. (2001) Localization and mechanisms of action of cannabinoid receptors at the glutamatergic synapses of the mouse nucleus accumbens. J Neurosci 21:109–116PubMedGoogle Scholar
  175. Robinson TE, Berridge KC (1993) The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Brain Res Rev 18:247–291PubMedGoogle Scholar
  176. Robinson TE, Berridge KC (2001) Incentive-sensitization and addiction. Addiction 96:103–114PubMedGoogle Scholar
  177. Rodriguez de Fonseca F, Gorriti MA, Fernandez-Ruiz JJ et al. (1994) Downregulation of rat brain cannabinoid binding sites after chronic delta 9-tetrahydrocannabinol treatment. Pharmacol Biochem Behav 47:33–40PubMedGoogle Scholar
  178. Rodriguez de Fonseca F, Carrera MR, Navarro M et al. (1997) Activation of corticotropin-releasing factor in the limbic system during cannabinoid withdrawal. Science 276:2050–2054PubMedGoogle Scholar
  179. Rossetti ZL, Melis F, Carboni S et al. (1991) Marked decrease of extraneuronal dopamine after alcohol withdrawal in rats: reversal by MK-801. Eur J Pharmacol 200:371–372PubMedGoogle Scholar
  180. Rothman RB, Baumann MH (2003) Monoamine transporters and psychostimulant drugs. Eur J Pharmacol 479:23–40PubMedGoogle Scholar
  181. Rubino T, Massi P, Vigano D et al. (2000a) Long-term treatment with SR141716A, the CB1 receptor antagonist, influences morphine withdrawal syndrome. Life Sci 66:2213–2219PubMedGoogle Scholar
  182. Rubino T, Vigano' D, Massi P et al. (2000b) Chronic delta-9-tetrahydrocannabinol treatment increases cAMP levels and cAMP-dependent protein kinase activity in some rat brain regions. Neuropharmacology 39:1331–1336PubMedGoogle Scholar
  183. Rubino T, Vigano D, Massi P et al. (2000c) Changes in the cannabinoid receptor binding, G protein coupling, and cyclic AMP cascade in the CNS of rats tolerant to and dependent on the synthetic cannabinoid compound CP55,940. J Neurochem 75:2080–2086PubMedGoogle Scholar
  184. Rubino T, Vigano D, Massi P et al. (2003) Cellular mechanisms of Delta 9-tetrahydrocannabinol behavioural sensitization. Eur J Neurosci 17:325–330PubMedGoogle Scholar
  185. Rubino T, Forlani G, Vigano D et al. (2004) Modulation of extracellular signal-regulated kinases cascade by chronic delta 9-tetrahydrocannabinol treatment. Mol Cell Neurosci 25:355–362PubMedGoogle Scholar
  186. Rubino T, Forlani G, Vigano D et al. (2005) Ras/ERK signalling in cannabinoid tolerance: from behaviour to cellular aspects. J Neurochem 93:984–991PubMedGoogle Scholar
  187. Sala M, Braida D (2005) Endocannabinoids and 3, 4-methylenedioxymethamphetamine (MDMA) interaction. Pharmacol Biochem Behav 81:407–416PubMedGoogle Scholar
  188. Salamone JD, McLaughlin PJ, Sink K et al. (2007) Cannabinoid CB1 receptor inverse agonists and neutral antagonists: effects on food intake, food-reinforced behavior and food aversions. Physiol Behav 91:383–388PubMedGoogle Scholar
  189. Sanudo-Pena MC, Tsou K, Delay ER et al. (1997) Endogenous cannabinoids as an aversive or counter-rewarding system in the rat. Neurosci Lett 223:125–128PubMedGoogle Scholar
  190. Scherma M, Medalie J, Fratta W et al. (2008a) The endogenous cannabinoid anandamide has effects on motivation and anxiety that are revealed by fatty acid amide hydrolase (FAAH) inhibition. Neuropharmacology 54:129–140PubMedGoogle Scholar
  191. Scherma M, Panlilio LV, Fadda P et al. (2008b) Inhibition of anandamide hydrolysis by URB597 reverses abuse-related behavioral and neurochemical effects of nicotine in rats. J Pharmacol Exp Ther 327:482–490Google Scholar
  192. Schindler ACW, Panlilio LV, Goldberg SR (2002) Second-order schedules of drug self-administration in animals. Psychopharmacology (Berl) 163:327–344Google Scholar
  193. Sink KS, McLaughlin PJ, Wood JA et al. (2008) The novel cannabinoid CB1 receptor neutral antagonist AM4113 suppresses food intake and food-reinforced behavior but does not induce signs of nausea in rats. Neuropsychopharmacology 33:946–955PubMedGoogle Scholar
  194. Solinas M, Panlilio LV, Antoniou K et al. (2003) The cannabinoid CB1 antagonist N-piperidinyl-5-(4-chlorophenyl)-1-(2, 4-dichlorophenyl) -4-methylpyrazole-3-carboxamide (SR-141716A) differentially alters the reinforcing effects of heroin under continuous reinforcement, fixed ratio, and progressive ratio schedules of drug self-administration in rats. J Pharmacol Exp Ther 306:93–102PubMedGoogle Scholar
  195. Solinas M, Zangen A, Thiriet N et al. (2004) Beta-endorphin elevations in the ventral tegmental area regulate the discriminative effects of Delta-9-tetrahydrocannabinol. Eur J Neurosci 19:3183–3192PubMedGoogle Scholar
  196. Solinas M, Panlilio LV, Tanda G et al. (2005) Cannabinoid agonists but not inhibitors of endogenous cannabinoid transport or metabolism enhance the reinforcing efficacy of heroin in rats. Neuropsychopharmacology 30:2046–2057PubMedGoogle Scholar
  197. Solinas M, Justinova Z, Goldberg SR et al. (2006a) Anandamide administration alone and after inhibition of fatty acid amide hydrolase (FAAH) increases dopamine levels in the nucleus accumbens shell in rats. J Neurochem 98:408–419PubMedGoogle Scholar
  198. Solinas M, Panlilio LV, Justinova Z et al. (2006b) Using drug-discrimination techniques to study the abuse-related effects of psychoactive drugs in rats. Nat Protoc 1:1194–1206PubMedGoogle Scholar
  199. Solinas M, Scherma M, Fattore L et al. (2007a) Nicotinic alpha 7 receptors as a new target for treatment of cannabis abuse. J Neurosci 27:5615–5620PubMedGoogle Scholar
  200. Solinas M, Scherma M, Tanda G et al. (2007b) Nicotinic facilitation of delta9-tetrahydrocannabinol discrimination involves endogenous anandamide. J Pharmacol Exp Ther 321:1127–1134PubMedGoogle Scholar
  201. Solinas M, Tanda G, Justinova Z et al. (2007c) The endogenous cannabinoid anandamide produces delta-9-tetrahydrocannabinol-like discriminative and neurochemical effects that are enhanced by inhibition of fatty acid amide hydrolase but not by inhibition of anandamide transport. J Pharmacol Exp Ther 321:370–380PubMedGoogle Scholar
  202. Solinas M, Yasar S, Goldberg SR (2007d) Endocannabinoid system involvement in brain reward processes related to drug abuse. Pharmacol Res 56:393–405PubMedGoogle Scholar
  203. Solinas M, Goldberg SR, Piomelli D (2008) The endocannabinoid system in brain reward processes. Br J Pharmacol 154:369–382PubMedGoogle Scholar
  204. Soria G, Mendizabal V, Tourino C et al. (2005) Lack of CB1 cannabinoid receptor impairs cocaine self-administration. Neuropsychopharmacology 30:1670–1680PubMedGoogle Scholar
  205. Spano MS, Fattore L, Cossu G et al. (2004) CB1 receptor agonist and heroin, but not cocaine, reinstate cannabinoid-seeking behaviour in the rat. Br J Pharmacol 143:343–350PubMedGoogle Scholar
  206. Spyraki C, Fibiger HC (1988) A role for the mesolimbic dopamine system in the reinforcing properties of diazepam. Psychopharmacology (Berl) 94:133–137Google Scholar
  207. Substance Abuse and Mental Health Services Administration (2007) Results from the 2005 National Survey on Drug Use and Health: National Findings. Office of Applied Studies, NSDUH Series H-32, DHHS Publication No SMA 07-4,293, Rockville, MDGoogle Scholar
  208. Takahashi RN, Singer G (1979) Self-administration of delta 9-tetrahydrocannabinol by rats. Pharmacol Biochem Behav 11:737–740PubMedGoogle Scholar
  209. Takahashi RN, Singer G (1980) Effects of body weight levels on cannabis self-injection. Pharmacol Biochem Behav 13:877–881PubMedGoogle Scholar
  210. Tanda G, Goldberg SR (2003) Cannabinoids: reward, dependence, and underlying neurochemical mechanisms-a review of recent preclinical data. Psychopharmacology (Berl) 169:115–134Google Scholar
  211. Tanda G, Pontieri FE, Di Chiara G (1997) Cannabinoid and heroin activation of mesolimbic dopamine transmission by a common mu1 opioid receptor mechanism. Science 276:2048–2050PubMedGoogle Scholar
  212. Tanda G, Loddo P, Di Chiara G (1999) Dependence of mesolimbic dopamine transmission on delta9-tetrahydrocannabinol. Eur J Pharmacol 376:23–26PubMedGoogle Scholar
  213. Tanda G, Munzar P, Goldberg SR (2000) Self-administration behavior is maintained by the psychoactive ingredient of marijuana in squirrel monkeys. Nat Neurosci 3:1073–1074PubMedGoogle Scholar
  214. Taylor DA, Fennessy MR (1982) Time-course of the effects of chronic delta 9-tetrahydrocannabinol on behaviour, body temperature, brain amines and withdrawal-like behaviour in the rat. J Pharm Pharmacol 34:240–245PubMedGoogle Scholar
  215. Thanos PK, Dimitrakakis ES, Rice O et al. (2005) Ethanol self-administration and ethanol conditioned place preference are reduced in mice lacking cannabinoid CB1 receptors. Behav Brain Res 164:206–213PubMedGoogle Scholar
  216. Thiemann G, van der Stelt M, Petrosino S et al. (2008) The role of the CB1 cannabinoid receptor and its endogenous ligands, anandamide and 2-arachidonoylglycerol, in amphetamine-induced behavioural sensitization. Behav Brain Res 187:289–296PubMedGoogle Scholar
  217. Thomas MJ, Beurrier C, Bonci A et al. (2001) Long-term depression in the nucleus accumbens: a neural correlate of behavioral sensitization to cocaine. Nat Neurosci 4:1217–1223PubMedGoogle Scholar
  218. Thorat SN, Bhargava HN (1994) Evidence for a bidirectional cross-tolerance between morphine and delta 9-tetrahydrocannabinol in mice. Eur J Pharmacol 260:5–13PubMedGoogle Scholar
  219. Thornton-Jones ZD, Vickers SP, Clifton PG (2005) The cannabinoid CB1 receptor antagonist SR141716A reduces appetitive and consummatory responses for food. Psychopharmacology (Berl) 179:452–460Google Scholar
  220. Valjent E, Maldonado R (2000) A behavioural model to reveal place preference to delta 9-tetrahydrocannabinol in mice. Psychopharmacology (Berl) 147:436–438Google Scholar
  221. Valjent E, Mitchell JM, Besson MJ et al. (2002) Behavioural and biochemical evidence for interactions between Delta 9-tetrahydrocannabinol and nicotine. Br J Pharmacol 135:564–578PubMedGoogle Scholar
  222. Valverde O, Maldonado R, Valjent E et al. (2000) Cannabinoid withdrawal syndrome is reduced in pre-proenkephalin knock-out mice. J Neurosci 20:9284–9289PubMedGoogle Scholar
  223. van der Laan JW, Eigeman L, Jansen van’t Land C (1992) Benzodiazepines preferentially affect mesolimbic dopamine turnover in rats. Eur Neuropsychopharmacol 2:425–431PubMedGoogle Scholar
  224. van der Stelt M, Di Marzo V (2003) The endocannabinoid system in the basal ganglia and in the mesolimbic reward system: implications for neurological and psychiatric disorders. Eur J Pharmacol 480:133–150PubMedGoogle Scholar
  225. Varvel SA, Martin BR, Lichtman AH (2007) Lack of behavioral sensitization after repeated exposure to THC in mice and comparison to methamphetamine. Psychopharmacology (Berl) 193:511–519Google Scholar
  226. Vela G, Ruiz-Gayo M, Fuentes JA (1995) Anandamide decreases naloxone-precipitated withdrawal signs in mice chronically treated with morphine. Neuropharmacology 34:665–668PubMedGoogle Scholar
  227. Vengeliene V, Bilbao A, Molander A et al. (2008) Neuropharmacology of alcohol addiction. Br J Pharmacol 154:299–315PubMedGoogle Scholar
  228. Verberne AJ, Taylor DA, Fennessy MR (1981) Attenuation of delta 9-tetrahydrocannabinol-induced withdrawal-like behaviour by delta 9-tetrahydrocannabinol. Psychopharmacology (Berl) 73:97–98Google Scholar
  229. Vigano D, Grazia CM, Rubino T et al. (2003) Chronic morphine modulates the contents of the endocannabinoid, 2-arachidonoyl glycerol, in rat brain. Neuropsychopharmacology 28:1160–1167PubMedGoogle Scholar
  230. Vigano D, Valenti M, Cascio MG et al. (2004) Changes in endocannabinoid levels in a rat model of behavioural sensitization to morphine. Eur J Neurosci 20:1849–1857PubMedGoogle Scholar
  231. Vinklerova J, Novakova J, Sulcova A (2002) Inhibition of methamphetamine self-administration in rats by cannabinoid receptor antagonist AM 251. J Psychopharmacol 16:139–143PubMedGoogle Scholar
  232. Welch SP (1997) Characterization of anandamide-induced tolerance: comparison to delta 9-THC-induced interactions with dynorphinergic systems. Drug Alcohol Depend 45:39–45PubMedGoogle Scholar
  233. Wiley JL, Martin BR (1999) Effects of SR141716A on diazepam substitution for delta9-tetrahydrocannabinol in rat drug discrimination. Pharmacol Biochem Behav 64:519–522PubMedGoogle Scholar
  234. Wiley JL, Huffman JW, Balster RL et al. (1995a) Pharmacological specificity of the discriminative stimulus effects of delta 9-tetrahydrocannabinol in rhesus monkeys. Drug Alcohol Depend 40:81–86PubMedGoogle Scholar
  235. Wiley JL, Lowe JA, Balster RL et al. (1995b) Antagonism of the discriminative stimulus effects of delta 9-tetrahydrocannabinol in rats and rhesus monkeys. J Pharmacol Exp Ther 275:1–6PubMedGoogle Scholar
  236. Wiley JL, Golden KM, Ryan WJ et al. (1997) Evaluation of cannabimimetic discriminative stimulus effects of anandamide and methylated fluoroanandamide in rhesus monkeys. Pharmacol Biochem Behav 58:1139–1143PubMedGoogle Scholar
  237. Wiley JL, Ryan WJ, Razdan RK et al. (1998) Evaluation of cannabimimetic effects of structural analogs of anandamide in rats. Eur J Pharmacol 355:113–118PubMedGoogle Scholar
  238. Wiley JL, LaVecchia KL, Karp NE et al. (2004) A comparison of the discriminative stimulus effects of Delta(9)-tetrahydrocannabinol and O-1,812, a potent and metabolically stable anandamide analog, in rats. Exp Clin Psychopharmacol 12:173–179PubMedGoogle Scholar
  239. Wise RA (2004) Dopamine, learning and motivation. Nat Rev Neurosci 5:483–494PubMedGoogle Scholar
  240. Wise RA, Bozarth MA (1987) A psychomotor stimulant theory of addiction. Psychol Rev 94: 469–492PubMedGoogle Scholar
  241. Wolf ME, Sun X, Mangiavacchi S et al. (2004) Psychomotor stimulants and neuronal plasticity. Neuropharmacology 47:61–79PubMedGoogle Scholar
  242. Xi ZX, Gilbert JG, Peng XQ et al. (2006) Cannabinoid CB1 receptor antagonist AM251 inhibits cocaine-primed relapse in rats: role of glutamate in the nucleus accumbens. J Neurosci 26:8531–8536PubMedGoogle Scholar
  243. Yokel RA (1987) Intravenous self-administration: response rates, the effects of pharmacological challenges, and drug preference. In: Bozarth MA (ed) Methods of assessing the reinforcing properties of abused drugs. Springer, New York, pp 1–33Google Scholar
  244. Young AM, Herling S (1986) Drugs as reinforcers: studies in laboratory animals. In: Goldberg SR, Stolerman IP (eds) Behavioral analysis of drug dependence. Academic Press, Orlando, pp 9–67Google Scholar
  245. Young AM, Woods JH (1981) Maintenance of behavior by ketamine and related compounds in rhesus monkeys with different self-administration histories. J Pharmacol Exp Ther 218: 720–727PubMedGoogle Scholar
  246. Young AM, Herling S, Woods JH (1981) History of drug exposure as a determinant of drug self-administration. NIDA Res Monogr 37:75–88PubMedGoogle Scholar
  247. Zangen A, Solinas M, Ikemoto S et al. (2006) Two brain sites for cannabinoid reward. J Neurosci 26:4901–4907PubMedGoogle Scholar
  248. Zimmer A, Valjent E, Konig M et al. (2001) Absence of delta -9-tetrahydrocannabinol dysphoric effects in dynorphin-deficient mice. J Neurosci 21:9499–9505Google Scholar
  249. Zhang PW, Ishiguro H, Ohtsuki T et al. (2004) Human cannabinoid receptor 1: 5' exons, candidate regulatory regions, polymorphisms, haplotypes and association with polysubstance abuse. Mol Psychiatry 9:916–931PubMedGoogle Scholar
  250. Zuo L, Kranzler HR, Luo X et al. (2007) CNR1 variation modulates risk for drug and alcohol dependence. Biol Psychiatry 62:616–626PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2009

Authors and Affiliations

  • Zuzana Justinova
    • 1
  • Leigh V. Panlilio
    • 1
  • Steven R. Goldberg
    • 1
    Email author
  1. 1.Department of Health and Human Services, Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research ProgramNational Institute on Drug Abuse, National Institutes of HealthBaltimoreUSA

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