The Endocannabinoid System and Extinction Learning

Molecular Neurobiology volume 36, pages92–101(2007)Cite this article

Abstract

The endocannabinoid system has emerged as a versatile neuromodulatory system, implicated in a plethora of physiological and pathophysiological processes. Cannabinoid receptor type 1 (CB1 receptor) and endocannabinoids are widely distributed in the brain. Their roles in learning and memory have been well documented, using rodents in various memory tests. Depending on the test, the endocannabinoid system is required in the acquisition and/or extinction of memory. In particular, the activation of CB1 receptor-mediated signaling is centrally involved in the facilitation of behavioral adaptation after the acquisition of aversive memories. As several human psychiatric disorders, such as phobia, generalized anxiety disorders, and posttraumatic stress disorder (PTSD) appear to involve aberrant memory processing and impaired adaptation to changed environmental conditions, the hope has been fuelled that the endocannabinoid system might be a valuable therapeutic target for the treatment of these disorders. This review summarizes the current data on the role of the endocannabinoid system in the modulation of extinction learning.

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References

  1. 1.

    Piomelli D (2003) The molecular logic of endocannabinoid signalling. Nat Rev Neurosci 4:873–884

    PubMed  CAS  Google Scholar 

  2. 2.

    Di Marzo V, De Petrocellis L, Bisogno T (2005) The biosynthesis, fate and pharmacological properties of endocannabinoids. Handb Exp Pharmacol 168:147–185

    PubMed  CAS  Article  Google Scholar 

  3. 3.

    Pertwee RG (2005) Pharmacological actions of cannabinoids. Handb Exp Pharmacol 168:1–51

    PubMed  CAS  Google Scholar 

  4. 4.

    Valverde O, Karsak M, Zimmer A (2005) Analysis of the endocannabinoid system by using CB1 cannabinoid receptor knockout mice. Handb Exp Pharmacol 168:117–145

    PubMed  CAS  Google Scholar 

  5. 5.

    Pagotto U, Marsicano G, Cota D, Lutz B, Pasquali R (2006) The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endocr Rev 27:73–100

    PubMed  CAS  Google Scholar 

  6. 6.

    Mackie K (2006) Cannabinoid receptors as therapeutic targets. Annu Rev Pharmacol Toxicol 46:101–122

    PubMed  CAS  Google Scholar 

  7. 7.

    Matias I, Di Marzo V (2007) Endocannabinoids and the control of energy balance. Trends Endocrinol Metab 18:27–37

    PubMed  CAS  Google Scholar 

  8. 8.

    Harkany T, Guzman M, Galve-Roperh I, Berghuis P, Devi LA, Mackie K (2007) The emerging functions of endocannabinoid signaling during CNS development. Trends Pharmacol Sci 28:83–92

    PubMed  CAS  Google Scholar 

  9. 9.

    Wotjak CT (2005) Role of endogenous cannabinoids in cognition and emotionality. Mini Rev Med Chem 5:659–670

    PubMed  CAS  Google Scholar 

  10. 10.

    Sullivan JM (2000) Cellular and molecular mechanisms underlying learning and memory impairments produced by cannabinoids. Learn Mem 7:132–139

    PubMed  CAS  Google Scholar 

  11. 11.

    Riedel G, Davies SN (2005) Cannabinoid function in learning, memory and plasticity. Handb Exp Pharmacol 168:445–477

    PubMed  CAS  Google Scholar 

  12. 12.

    Ranganathan M, D’Souza DC (2006) The acute effects of cannabinoids on memory in humans: a review. Psychopharmacology (Berl) 188:425–444

    CAS  Google Scholar 

  13. 13.

    Lichtman AH, Varvel SA, Martin BR (2002) Endocannabinoids in cognition and dependence. Prostaglandins Leukot. Essent Fatty Acids 66:269–285

    CAS  Google Scholar 

  14. 14.

    Robbe D, Montgomery SM, Thome A, Rueda-Orozco PE, McNaughton BL, Buzsaki G (2006) Cannabinoids reveal importance of spike timing coordination in hippocampal function. Nat Neurosci 9:1526–1533

    PubMed  CAS  Google Scholar 

  15. 15.

    Freund TF, Katona I, Piomelli D (2003) Role of endogenous cannabinoids in synaptic signaling. Physiol Rev 83:1017–1066

    PubMed  CAS  Google Scholar 

  16. 16.

    Mackie K (2005) Distribution of cannabinoid receptors in the central and peripheral nervous system. Handb Exp Pharmacol 168:299–325

    PubMed  CAS  Google Scholar 

  17. 17.

    Marsicano G, Lutz B (1999) Expression of the cannabinoid receptor CB1 in distinct neuronal subpopulations in the adult mouse forebrain. Eur J Neurosci 11:4213–4225

    PubMed  CAS  Google Scholar 

  18. 18.

    Lutz B (2002) Molecular biology of cannabinoid receptors. Prostaglandins Leukot Essent Fatty Acids 66:123–142

    PubMed  CAS  Google Scholar 

  19. 19.

    Zimmer A, Zimmer AM, Hohmann AG, Herkenham M, Bonner TI (1999) Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice. Proc Natl Acad Sci USA 96:5780–5785

    PubMed  CAS  Google Scholar 

  20. 20.

    Ledent C, Valverde O, Cossu G, Petitet F, Aubert JF, Beslot F, Bohme GA, Imperato A, Pedrazzini T, Roques BP, Vassart G, Fratta W, Parmentier M (1999) Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice. Science 283:401–404

    PubMed  CAS  Google Scholar 

  21. 21.

    Marsicano G, Wotjak CT, Azad SC, Bisogno T, Rammes G, Cascio MG, Hermann H, Tang J, Hofmann C, Zieglgansberger W, Di Marzo V, Lutz B (2002) The endogenous cannabinoid system controls extinction of aversive memories. Nature 418:530–534

    PubMed  CAS  Google Scholar 

  22. 22.

    Marsicano G, Goodenough S, Monory K, Hermann H, Eder M, Cannich A, Azad SC, Cascio MG, Gutierrez SO, van der Stelt M, Lopez-Rodriguez ML, Casanova E, Schütz G, Zieglgänsberger W, Di Marzo V, Behl C, Lutz B (2003) CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science 302:84–88

    PubMed  CAS  Google Scholar 

  23. 23.

    Monory K, Massa F, Egertova M, Eder M, Blaudzun H, Westenbroek R, Kelsch W, Jacob W, Marsch R, Ekker M, Long J, Rubenstein JL, Goebbels S, Nave KA, During M, Klugmann M, Wolfel B, Dodt HU, Zieglgänsberger W, Wotjak CT, Mackie K, Elphick MR, Marsicano G, Lutz B (2006) The endocannabinoid system controls key epileptogenic circuits in the hippocampus. Neuron 51:455–466

    PubMed  CAS  Google Scholar 

  24. 24.

    Chevaleyre V, Takahashi KA, Castillo PE (2006) Endocannabinoid-mediated synaptic plasticity in the CNS. Annu Rev Neurosci 29:37–76

    PubMed  CAS  Google Scholar 

  25. 25.

    Marsicano G, Lutz B (2006) Neuromodulatory functions of the endocannabinoid system. J Endocrinol Invest 29:27–46

    PubMed  CAS  Google Scholar 

  26. 26.

    Klein TW (2005) Cannabinoid-based drugs as anti-inflammatory therapeutics. Nat Rev Immunol 5:400–411

    PubMed  CAS  Google Scholar 

  27. 27.

    Cravatt BF, Demarest K, Patricelli MP, Bracey MH, Giang DK, Martin BR, Lichtman AH (2001) Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase. Proc Natl Acad Sci USA 98:9371–9376

    PubMed  CAS  Google Scholar 

  28. 28.

    Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J, Petersen-Zeitz KR, Koltzenburg M, Basbaum AI, Julius D (2000) Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 288:306–313

    PubMed  CAS  Google Scholar 

  29. 29.

    Rinaldi-Carmona M, Barth F, Heaulme M, Shire D, Calandra B, Congy C, Martinez S, Maruani J, Neliat G, Caput D, Ferrara P, Soubrié P, Brelière JC, Le Fur G (1994) SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett 350:240–244

    PubMed  CAS  Google Scholar 

  30. 30.

    Gatley SJ, Gifford AN, Volkow ND, Lan R, Makriyannis A (1996) 123I-labeled AM251: a radioiodinated ligand which binds in vivo to mouse brain cannabinoid CB1 receptors. Eur J Pharmacol 307:331–338

    PubMed  CAS  Google Scholar 

  31. 31.

    Rinaldi-Carmona M, Barth F, Congy C, Martinez S, Oustric D, Perio A, Poncelet M, Maruani J, Arnone M, Finance O, Soubrie P, Le Fur G (2004) SR147778 [5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-N-(1-piperidinyl)-1H-pyr azole-3-carboxamide], a new potent and selective antagonist of the CB1 cannabinoid receptor: biochemical and pharmacological characterization. J Pharmacol Exp Ther 310:905–914

    PubMed  CAS  Google Scholar 

  32. 32.

    Kathuria S, Gaetani S, Fegley D, Valino F, Duranti A, Tontini A, Mor M, Tarzia G, Rana GL, Calignano A, Giustino A, Tattoli M, Palmery M, Cuomo V, Piomelli D (2003) Modulation of anxiety through blockade of anandamide hydrolysis. Nat Med 9:76–81

    PubMed  CAS  Google Scholar 

  33. 33.

    Beltramo M, Stella N, Calignano A, Lin SY, Makriyannis A, Piomelli D (1997) Functional role of high-affinity anandamide transport, as revealed by selective inhibition. Science 277:1094–1097

    PubMed  CAS  Google Scholar 

  34. 34.

    De Petrocellis L, Bisogno T, Davis JB, Pertwee RG, Di Marzo V (2000) Overlap between the ligand recognition properties of the anandamide transporter and the VR1 vanilloid receptor: inhibitors of anandamide uptake with negligible capsaicin-like activity. FEBS Lett 483:52–56

    PubMed  Google Scholar 

  35. 35.

    Lopez-Rodriguez ML, Viso A, Ortega-Gutierrez S, Lastres-Becker I, Gonzalez S, Fernandez-Ruiz J, Ramos JA (2001) Design, synthesis and biological evaluation of novel arachidonic acid derivatives as highly potent and selective endocannabinoid transporter inhibitors. J Med Chem 44:4505–4508

    PubMed  CAS  Google Scholar 

  36. 36.

    de Sousa N, Almeida OF, Wotjak CT (2006) A hitchhiker’s guide to behavioral analysis in laboratory rodents. Genes Brain Behav 5(Suppl 2):5–24

    PubMed  Google Scholar 

  37. 37.

    Reibaud M, Obinu MC, Ledent C, Parmentier M, Bohme GA, Imperato A (1999) Enhancement of memory in cannabinoid CB1 receptor knock-out mice. Eur J Pharmacol 379:R1–R2

    PubMed  CAS  Google Scholar 

  38. 38.

    Maccarrone M, Valverde O, Barbaccia ML, Castane A, Maldonado R, Ledent C, Parmentier M, Finazzi-Agro A (2002) Age-related changes of anandamide metabolism in CB1 cannabinoid receptor knockout mice: correlation with behaviour. Eur J Neurosci 15:1178–1186

    PubMed  Google Scholar 

  39. 39.

    Martin M, Ledent C, Parmentier M, Maldonado R, Valverde O (2002) Involvement of CB1 cannabinoid receptors in emotional behaviour. Psychopharmacology (Berl) 159:379–387

    CAS  Google Scholar 

  40. 40.

    Bilkei-Gorzo A, Racz I, Valverde O, Otto M, Michel K, Sastre M, Zimmer A (2005) Early age-related cognitive impairment in mice lacking cannabinoid CB1 receptors. Proc Natl Acad Sci USA 102:15670–15675

    PubMed  CAS  Google Scholar 

  41. 41.

    Lutz B (2004) On-demand activation of the endocannabinoid system in the control of neuronal excitability and epileptiform seizures. Biochem Pharmacol 68:1691–1698

    PubMed  CAS  Google Scholar 

  42. 42.

    van der Stelt M, Di Marzo V (2005) Cannabinoid receptors and their role in neuroprotection. Neuromolecular Med 7:37–50

    PubMed  Google Scholar 

  43. 43.

    Terranova JP, Storme JJ, Lafon N, Perio A, Rinaldi-Carmona M, LeFur G, Soubrie P (1996) Improvement of memory in rodents by the selective CB1 cannabinoid receptor antagonist, SR141716. Psychopharmacology 126:165–172

    PubMed  CAS  Google Scholar 

  44. 44.

    Lichtman AH (2000) SR 141716A enhances spatial memory as assessed in a radial-arm maze task in rats. Eur J Pharmacol 404:175–179

    PubMed  CAS  Google Scholar 

  45. 45.

    Wolff MC, Leander JD (2003) SR141716A, a cannabinoid CB1 receptor antagonist, improves memory in a delayed radial maze task. Eur J Pharmacol 477:213–217

    PubMed  CAS  Google Scholar 

  46. 46.

    Mallet PE, Beninger RJ (1998) The cannabinoid CB1 receptor antagonist SR141716A attenuates the memory impairment produced by delta9-tetrahydrocannabinol or anandamide. Psychopharmacology (Berl) 140:11–19

    CAS  Google Scholar 

  47. 47.

    Hampson RE, Deadwyler SA (2000) Cannabinoids reveal the necessity of hippocampal neural encoding for short-term memory in rats. J Neurosci 20:8932–8942

    PubMed  CAS  Google Scholar 

  48. 48.

    Mansbach RS, Rovetti CC, Winston EN, Lowe JA III (1996) Effects of the cannabinoid CB1 receptor antagonist SR141716A on the behavior of pigeons and rats. Psychopharmacology (Berl) 124:315–322

    CAS  Google Scholar 

  49. 49.

    Kishimoto Y, Kano M (2006) Endogenous cannabinoid signaling through the CB1 receptor is essential for cerebellum-dependent discrete motor learning. J Neurosci 26:8829–8837

    PubMed  CAS  Google Scholar 

  50. 50.

    Varvel SA, Wise LE, Niyuhire F, Cravatt BF, Lichtman AH (2007) Inhibition of fatty-acid amide hydrolase accelerates acquisition and extinction rates in a spatial memory task. Neuropsychopharmacology 32:1032–1041

    PubMed  CAS  Google Scholar 

  51. 51.

    Mikics E, Dombi T, Barsvari B, Varga B, Ledent C, Freund TF, Haller J (2006) The effects of cannabinoids on contextual conditioned fear in CB1 knockout and CD1 mice. Behav Pharmacol 17:223–230

    PubMed  CAS  Google Scholar 

  52. 52.

    Marsch R, Foeller E, Rammes G, Bunck M, Kossl M, Holsboer F, Zieglgänsberger W, Landgraf R, Lutz B, Wotjak CT (2007) Reduced anxiety, conditioned fear, and hippocampal long-term potentiation in transient receptor potential vanilloid type 1 receptor-deficient mice. J Neurosci 27:832–839

    PubMed  CAS  Google Scholar 

  53. 53.

    Brewin CR (2001) A cognitive neuroscience account of posttraumatic stress disorder and its treatment. Behav Res Ther 39:373–393

    PubMed  CAS  Google Scholar 

  54. 54.

    Nemeroff CB, Bremner JD, Foa EB, Mayberg HS, North CS, Stein MB (2006) Posttraumatic stress disorder: a state-of-the-science review. J Psychiatr Res 40:1–21

    PubMed  Google Scholar 

  55. 55.

    LeDoux JE (2000) Emotion circuits in the brain. Annu Rev Neurosci 23:155–184

    PubMed  CAS  Google Scholar 

  56. 56.

    Kim JJ, Jung MW (2006) Neural circuits and mechanisms involved in Pavlovian fear conditioning: a critical review. Neurosci Biobehav Rev 30:188–202

    PubMed  Google Scholar 

  57. 57.

    Rodrigues SM, Schafe GE, LeDoux JE (2004) Molecular mechanisms underlying emotional learning and memory in the lateral amygdala. Neuron 44:75–91

    PubMed  CAS  Google Scholar 

  58. 58.

    Maren S, Quirk GJ (2004) Neuronal signalling of fear memory. Nat Rev Neurosci 5:844–852

    PubMed  CAS  Google Scholar 

  59. 59.

    Wotjak CT (2005) Learning and memory. Handb Exp Pharmacol 169:1–34

    PubMed  Google Scholar 

  60. 60.

    Myers KM, Davis M (2002) Behavioral and neural analysis of extinction. Neuron 36:567–584

    PubMed  CAS  Google Scholar 

  61. 61.

    Myers KM, Davis M (2007) Mechanisms of fear extinction. Mol Psychiatry 12:120–150

    PubMed  CAS  Google Scholar 

  62. 62.

    Barad M, Gean PW, Lutz B (2006) The role of the amygdala in the extinction of conditioned fear. Biol Psychiatry 60:322–328

    PubMed  Google Scholar 

  63. 63.

    Quirk GJ, Garcia R, Gonzalez-Lima F (2006) Prefrontal mechanisms in extinction of conditioned fear. Biol Psychiatry 60:337–343

    PubMed  Google Scholar 

  64. 64.

    Sotres-Bayon F, Cain CK, LeDoux JE (2006) Brain mechanisms of fear extinction: historical perspectives on the contribution of prefrontal cortex. Biol Psychiatry 60:329–336

    PubMed  Google Scholar 

  65. 65.

    Milad MR, Rauch SL, Pitman RK, Quirk GJ (2006) Fear extinction in rats: implications for human brain imaging and anxiety disorders. Biol Psychol 73:61–71

    PubMed  Google Scholar 

  66. 66.

    Berghuis P, Rajnicek AM, Morozov YM, Ross RA, Mulder J, Urban GM, Monory K, Marsicano G, Matteoli M, Canty A, Irving AJ, Katona I, Yanagawa Y, Rakic P, Lutz B, Mackie K, Harkany T (2007) Hardwiring the brain: endocannabinoids shape neuronal connectivity. Science 316:1212–1216

    PubMed  CAS  Google Scholar 

  67. 67.

    Kamprath K, Marsicano G, Tang J, Monory K, Bisogno T, Di Marzo V, Lutz B, Wotjak CT (2006) Cannabinoid CB1 receptor mediates fear extinction via habituation-like processes. J Neurosci 26:6677–6686

    PubMed  CAS  Google Scholar 

  68. 68.

    Seidenbecher T, Laxmi TR, Stork O, Pape HC (2003) Amygdalar and hippocampal theta rhythm synchronization during fear memory retrieval. Science 301:846–850

    PubMed  CAS  Google Scholar 

  69. 69.

    Burgos-Robles A, Vidal-Gonzalez I, Santini E, Quirk GJ (2007) Consolidation of fear extinction requires NMDA receptor-dependent bursting in the ventromedial prefrontal cortex. Neuron 53:871–880

    PubMed  CAS  Google Scholar 

  70. 70.

    Vidal-Gonzalez I, Vidal-Gonzalez B, Rauch SL, Quirk GJ (2006) Microstimulation reveals opposing influences of prelimbic and infralimbic cortex on the expression of conditioned fear. Learn Mem 13:728–733

    PubMed  Google Scholar 

  71. 71.

    Varvel SA, Lichtman AH (2002) Evaluation of CB1 receptor knockout mice in the Morris water maze. J Pharmacol Exp Ther 301:915–924

    PubMed  CAS  Google Scholar 

  72. 72.

    Varvel SA, Anum EA, Lichtman AH (2005) Disruption of CB1 receptor signaling impairs extinction of spatial memory in mice. Psychopharmacology (Berl) 179:863–872

    CAS  Google Scholar 

  73. 73.

    Chhatwal JP, Davis M, Maguschak KA, Ressler KJ (2005) Enhancing cannabinoid neurotransmission augments the extinction of conditioned fear. Neuropsychopharmacology 30:516–524

    PubMed  CAS  Google Scholar 

  74. 74.

    Suzuki A, Josselyn SA, Frankland PW, Masushige S, Silva AJ, Kida S (2004) Memory reconsolidation and extinction have distinct temporal and biochemical signatures. J Neurosci 24:4787–4795

    PubMed  CAS  Google Scholar 

  75. 75.

    Finn DP, Beckett SR, Richardson D, Kendall DA, Marsden CA, Chapman V (2004) Evidence for differential modulation of conditioned aversion and fear-conditioned analgesia by CB1 receptors. Eur J Neurosci 20:848–852

    PubMed  CAS  Google Scholar 

  76. 76.

    Cannich A, Wotjak CT, Kamprath K, Hermann H, Lutz B, Marsicano G (2004) CB1 cannabinoid receptors modulate kinase and phosphatase activity during extinction of conditioned fear in mice. Learn Mem 11:625–632

    PubMed  Google Scholar 

  77. 77.

    Chhatwal JP, Stanek-Rattiner L, Davis M, Ressler KJ (2006) Amygdala BDNF signaling is required for consolidation but not encoding of extinction. Nat Neurosci 9:870–872

    PubMed  CAS  Google Scholar 

  78. 78.

    Lin HC, Mao SC, Gean PW (2006) Effects of intra-amygdala infusion of CB1 receptor agonists on the reconsolidation of fear-potentiated startle. Learn Mem 13:316–321

    PubMed  CAS  Google Scholar 

  79. 79.

    Pamplona FA, Prediger RD, Pandolfo P, Takahashi RN (2006) The cannabinoid receptor agonist WIN 55,212-2 facilitates the extinction of contextual fear memory and spatial memory in rats. Psychopharmacology (Berl) 188:641–649

    CAS  Google Scholar 

  80. 80.

    Niyuhire F, Varvel SA, Thorpe AJ, Stokes RJ, Wiley JL, Lichtman AH (2007) The disruptive effects of the CB(1) receptor antagonist rimonabant on extinction learning in mice are task-specific. Psychopharmacology (Berl) 191:223–231

    CAS  Google Scholar 

  81. 81.

    Shiflett MW, Rankin AZ, Tomaszycki ML, DeVoogd TJ (2004) Cannabinoid inhibition improves memory in food-storing birds, but with a cost. Proc R Soc Lond B Biol Sci 271:2043–2048

    CAS  Google Scholar 

  82. 82.

    Hölter SM, Kallnik M, Wurst W, Marsicano G, Lutz B, Wotjak CT (2005) Cannabinoid CB1 receptor is dispensable for memory extinction in an appetitively-motivated learning task. Eur J Pharmacol 510:69–74

    PubMed  Google Scholar 

  83. 83.

    Sanchis-Segura C, Cline BH, Marsicano G, Lutz B, Spanagel R (2004) Reduced sensitivity to reward in CB1 knockout mice. Psychopharmacology (Berl) 176:223–232

    CAS  Google Scholar 

  84. 84.

    Thornton-Jones ZD, Kennett GA, Vickers SP, Clifton PG (2007) A comparison of the effects of the CB(1) receptor antagonist SR141716A, pre-feeding and changed palatability on the microstructure of ingestive behaviour. Psychopharmacology (Berl) 193:1–9

    CAS  Google Scholar 

  85. 85.

    Thornton-Jones ZD, Vickers SP, Clifton PG (2005) The cannabinoid CB1 receptor antagonist SR141716A reduces appetitive and consummatory responses for food. Psychopharmacology (Berl) 179:452–460

    CAS  Google Scholar 

  86. 86.

    Lin CH, Yeh SH, Leu TH, Chang WC, Wang ST, Gean PW (2003) Identification of calcineurin as a key signal in the extinction of fear memory. J Neurosci 23:1574–1579

    PubMed  CAS  Google Scholar 

  87. 87.

    Lu KT, Walker DL, Davis M (2001) Mitogen-activated protein kinase cascade in the basolateral nucleus of amygdala is involved in extinction of fear-potentiated startle. J Neurosci 21:RC162

    PubMed  CAS  Google Scholar 

  88. 88.

    Kamprath K, Wotjak CT (2004) Nonassociative learning processes determine expression and extinction of conditioned fear in mice. Learn Mem 11:770–786

    PubMed  Google Scholar 

  89. 89.

    McSweeney FK, Swindell S (2002) Common processes may contribute to extinction and habituation. J Gen Psychol 129:364–400

    PubMed  Article  Google Scholar 

  90. 90.

    Viveros MP, Marco EM, File SE (2005) Endocannabinoid system and stress and anxiety responses. Pharmacol Biochem Behav 81:331–342

    PubMed  CAS  Google Scholar 

  91. 91.

    Hill MN, Gorzalka BB (2005) Is there a role for the endocannabinoid system in the etiology and treatment of melancholic depression? Behav Pharmacol 16:333–352

    PubMed  CAS  Google Scholar 

  92. 92.

    Witkin JM, Tzavara ET, Davis RJ, Li X, Nomikos GG (2005) A therapeutic role for cannabinoid CB1 receptor antagonists in major depressive disorders. Trends Pharmacol Sci 26:609–617

    PubMed  CAS  Google Scholar 

  93. 93.

    Cota D, Marsicano G, Tschöp M, Grübler Y, Flachskamm C, Schubert M, Auer D, Yassouridis A, Thone-Reineke C, Ortmann S, Tomassoni F, Cervino C, Nisoli E, Linthorst AC, Pasquali R, Lutz B, Stalla GK, Pagotto U (2003) The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. J Clin Invest 112:423–431

    PubMed  CAS  Google Scholar 

  94. 94.

    Cota D, Steiner MA, Marsicano G, Cervino C, Herman JP, Grubler Y, Stalla J, Pasquali R, Lutz B, Stalla GK, Pagotto U (2007) Requirement of cannabinoid receptor type 1 for the basal modulation of hypothalamic-pituitary-adrenal axis function. Endocrinology 148:1574–1581

    PubMed  CAS  Google Scholar 

  95. 95.

    Patel S, Roelke CT, Rademacher DJ, Hillard CJ (2005) Inhibition of restraint stress-induced neural and behavioural activation by endogenous cannabinoid signalling. Eur J Neurosci 21:1057–1069

    PubMed  Google Scholar 

  96. 96.

    Nader K, Schafe GE, Le Doux JE (2000) Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval. Nature 406:722–726

    PubMed  CAS  Google Scholar 

  97. 97.

    Kobilo T, Hazvi S, Dudai Y (2007) Role of cortical cannabinoid CB1 receptor in conditioned taste aversion memory. Eur J Neurosci 25:3417–3421

    PubMed  Google Scholar 

  98. 98.

    Murillo-Rodriguez E, Giordano M, Cabeza R, Henriksen SJ, Mendez DM, Navarro L, Prospero-Garcia O (2001) Oleamide modulates memory in rats. Neurosci Lett 313:61–64

    PubMed  CAS  Google Scholar 

  99. 99.

    Parker LA, Burton P, Sorge RE, Yakiwchuk C, Mechoulam R (2004) Effect of low doses of delta9-tetrahydrocannabinol and cannabidiol on the extinction of cocaine-induced and amphetamine-induced conditioned place preference learning in rats. Psychopharmacology (Berl) 175:360–366

    CAS  Google Scholar 

  100. 100.

    Azad SC, Monory K, Marsicano G, Cravatt BF, Lutz B, Zieglgansberger W, Rammes G (2004) Circuitry for associative plasticity in the amygdala involves endocannabinoid signaling. J Neurosci 24:9953–9961

    PubMed  CAS  Google Scholar 

  101. 101.

    Chevaleyre V, Heifets BD, Kaeser PS, Sudhof TC, Purpura DP, Castillo PE (2007) Endocannabinoid-mediated long-term plasticity requires cAMP/PKA signaling and RIM1alpha. Neuron 54:801–812

    PubMed  CAS  Google Scholar 

  102. 102.

    Chevaleyre V, Castillo PE (2004) Endocannabinoid-mediated metaplasticity in the hippocampus. Neuron 43:871–881

    PubMed  CAS  Google Scholar 

  103. 103.

    Wilson RI, Nicoll RA (2001) Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses. Nature 410:588–592

    PubMed  CAS  Google Scholar 

  104. 104.

    Alger E (2002) Retrograde signaling in the regulation of synaptic transmission: focus on endocannabinoids. Prog Neurobiol 68:247–286

    PubMed  CAS  Google Scholar 

  105. 105.

    Lafourcade M, Elezgarai I, Mato S, Bakiri Y, Grandes P, Manzoni OJ (2007) Molecular components and functions of the endocannabinoid system in mouse prefrontal cortex. PLoS ONE 2:e709

    PubMed  Google Scholar 

  106. 106.

    Bruchey AK, Shumake J, Gonzalez-Lima F (2007) Network model of fear extinction and renewal functional pathways. Neuroscience 145:423–437

    PubMed  CAS  Google Scholar 

  107. 107.

    Siegmund A, Wotjak CT (2007) A mouse model of posttraumatic stress disorder that distinguishes between conditioned and sensitised fear. J Psychiatr Res 41:848–860

    PubMed  Google Scholar 

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Acknowledgements

I would like to thank Drs. Krisztina Monory and Fabricio Moreira for critically reading the manuscript and the generous support by the Hübner Stiftung.

Author information

Affiliations

  1. Department of Physiological Chemistry, Johannes Gutenberg-University Mainz, Duesbergweg 6, D-55099, Mainz, Germany

    Beat Lutz

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  1. Beat Lutz
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Correspondence to Beat Lutz.

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Lutz, B. The Endocannabinoid System and Extinction Learning. Mol Neurobiol 36, 92–101 (2007). https://doi.org/10.1007/s12035-007-8004-x

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Keywords

  • Endocannabinoids
  • Cannabinoid receptor
  • THC
  • Extinction
  • Habituation
  • Anxiety
  • Posttraumatic stress disorder
  • Phobia
  • Rodent
  • Fear conditioning