, Volume 188, Issue 4, pp 641–649 | Cite as

The cannabinoid receptor agonist WIN 55,212-2 facilitates the extinction of contextual fear memory and spatial memory in rats

  • Fabrício A. Pamplona
  • Rui D. S. Prediger
  • Pablo Pandolfo
  • Reinaldo N. Takahashi
Original Investigation



Previous studies demonstrated that pharmacological blockade of CB1 cannabinoid receptors decreases the extinction of conditioned fear and spatial memory in rodents. However, the effects of CB1 cannabinoid receptor activation in this response remain unclear.


To evaluate the effects of the cannabinoid agonist WIN 55,212-2 (WIN) and the cannabinoid antagonist SR 147778 (SR) on the extinction of contextual fear memory in rats 24 h or 30 days after fear conditioning.


For fear conditioning, rats were placed in the conditioning chamber for 3 min and received a 1-s electric foot shock (1.5 mA). Retrieval testing consisted of a 3-min exposure to the conditioning chamber and extinction training consisted of successive 9-min exposures at 24-h intervals. Rats were also evaluated in the open field and water maze reversal task.


The administration of SR (1.0 mg/kg, i.p.) and WIN (0.25 mg/kg, i.p.) before extinction training disrupted and facilitated, respectively, the extinction of 24 h contextual fear memory. These effects were not related to any disturbance in memory retrieval, unconditioned freezing expression, or locomotor activity. WIN (0.25 mg/kg, i.p.) also facilitated the extinction of 30-day-old contextual fear memory, while the prior administration of SR (0.2 mg/kg, i.p.) antagonized this response. The facilitative effect of WIN on memory extinction does not seem to be specific for contextual fear memory because it was also observed in the water maze reversal task.


These results suggest cannabinoid receptor agonists as potential drugs to treat anxiety disorders related to the retrieval of aversive memories.


Fear conditioning Spatial memory Extinction Cannabinoid WIN 55,212-2 SR 147778 



The authors would like to thank Sanofi-Aventis (France) who donated SR for the present study. We also thank the anonymous reviewers for helpful comments on an earlier draft of the manuscript. F. A. P., P. P., and R. D. S. P. received a scholarship from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq-Brazil). R. N. T. is the holder of a CNPq fellowship.


  1. Blanchard RJ, Blanchard DC (1969) Crouching as an index of fear. J Comp Physiol Psychol 67:370–375PubMedCrossRefGoogle Scholar
  2. Brewin CR, Holmes EA (2003) Psychological theories of posttraumatic stress disorder. Clin Psychol Rev 23:339–376PubMedCrossRefGoogle Scholar
  3. Chhatwal JP, Davis M, Maguschak KA, Ressler KJ (2005) Enhancing cannabinoid neurotransmission augments the extinction of conditioned fear. Neuropsychopharmacology 30:516–524PubMedCrossRefGoogle Scholar
  4. Corodimas KP, Pruitt JC, Stieg JM (2000) Acute exposure to caffeine selectively disrupts context conditioning in rats. Psychopharmacology (Berl) 152:376–382CrossRefGoogle Scholar
  5. Da Silva GE, Takahashi RN (2002) SR 141716A prevents delta 9-tetrahydrocannabinol-induced spatial learning deficit in a Morris-type water maze in mice. Prog Neuropsychopharmacol Biol Psychiatry 26:321–325CrossRefGoogle Scholar
  6. Di Marzo V, Breivogel CS, Tao Q, Bridgen DT, Razdan RK, Zimmer AM, Zimmer A, Martin BR (2000) Levels, metabolism, and pharmacological activity of anandamide in CB(1) cannabinoid receptor knockout mice: evidence for non-CB(1), non-CB(2) receptor-mediated actions of anandamide in mouse brain. J Neurochem 75:2434–2444PubMedCrossRefGoogle Scholar
  7. Fanselow MS (1980) Conditioned and unconditional components of post-shock freezing. Pavlovian J Biol Sci 15:177–182Google Scholar
  8. Fernandez-Espejo E (2003) Prefrontocortical dopamine loss in rats delays long-term extinction of contextual conditioned fear, and reduces social interaction without affecting short-term social interaction memory. Neuropsychopharmacology 28:490–498PubMedCrossRefGoogle Scholar
  9. Ferrari F, Ottani A, Vivoli R, Giuliani D (1999) Learning impairment produced in rats by the cannabinoid agonist HU 210 in a water-maze task. Pharmacol Biochem Behav 64:555–561PubMedCrossRefGoogle Scholar
  10. Herkenham M, Lynn AB, Little MD, Johnson MR, Melvin LS, de Costa BR, Rice KC (1990) Cannabinoid receptor localization in brain. Proc Natl Acad Sci USA 87:1932–1936PubMedCrossRefGoogle Scholar
  11. Hohmann AG, Suplita RL, Bolton NM, Neely MH, Fegley D, Mangieri R, Krey JF, Walker JM, Holmes PV, Crystal JD, Duranti A, Tontini A, Mor M, Tarzia G, Piomelli D (2005) An endocannabinoid mechanism for stress-induced analgesia. Nature 435:1108–1112PubMedCrossRefGoogle Scholar
  12. Lichtman AH (2000) SR 141716A enhances spatial memory as assessed in a radial-arm maze task in rats. Eur J Pharmacol 404:175–179PubMedCrossRefGoogle Scholar
  13. Lichtman AH, Dimen KR, Martin BR (1995) Systemic or intrahippocampal cannabinoid administration impairs spatial memory in rats. Psychopharmacology (Berl) 119:282–290CrossRefGoogle Scholar
  14. Makriyannis A, Mechoulam R, Piomelli D (2005) Therapeutic opportunities through modulation of the endocannabinoid system. Neuropharmacology 48:1068–1071PubMedCrossRefGoogle Scholar
  15. 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 418:530–534PubMedCrossRefGoogle Scholar
  16. McKay BE, Lado WE, Martin LJ, Galic MA, Fournier NM (2002) Learning and memory in agmatine-treated rats. Pharmacol Biochem Behav 72:551–557PubMedCrossRefGoogle Scholar
  17. Pamplona FA, Takahashi RN (2006) WIN 55212-2 impairs contextual fear conditioning through the activation of CB1 cannabinoid receptors. Neurosci Lett 397:88–92PubMedCrossRefGoogle Scholar
  18. 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) 175:360–366CrossRefGoogle Scholar
  19. Quirk GJ, Russo GK, Barron JL, Lebron K (2000) The role of ventromedial prefrontal cortex in the recovery of extinguished fear. J Neurosci 20:6225–6231PubMedGoogle Scholar
  20. 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–R2PubMedCrossRefGoogle Scholar
  21. Ressler KJ, Rothbaum BO, Tannenbaum L, Anderson P, Graap K, Zimand E, Hodges L, Davis M (2004) Cognitive enhancers as adjuncts to psychotherapy: use of D-cycloserine in phobic individuals to facilitate extinction of fear. Arch Gen Psychiatry 61:1136–1144PubMedCrossRefGoogle Scholar
  22. Rinaldi-Carmona M, Barth F, Heaulme M, Alonso R, Shire D, Congy C, Soubrie P, Breliere JC, Le Fur G (1995) Biochemical and pharmacological characterisation of SR141716A, the first potent and selective brain cannabinoid receptor antagonist. Life Sci 56:1941–1947PubMedCrossRefGoogle Scholar
  23. 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 310:905–914PubMedCrossRefGoogle Scholar
  24. Sorg BA, Swindell S, Tschirgi ML (2004) Repeated low level formaldehyde exposure produces enhanced fear conditioning to odor in male, but not female, rats. Brain Res 1008:11–19PubMedCrossRefGoogle Scholar
  25. 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 24:4787–4795PubMedCrossRefGoogle Scholar
  26. Takahashi RN, Pamplona FA, Fernandes MS (2005) The cannabinoid antagonist SR141716A facilitates memory acquisition and consolidation in the mouse elevated T-maze. Neurosci Lett 380:270–275PubMedCrossRefGoogle Scholar
  27. Terranova JP, Storme JJ, Lafon N, Perio A, Rinaldi-Carmona M, Le Fur G, Soubrie P (1996) Improvement of memory in rodents by the selective CB1 cannabinoid receptor antagonist, SR 141716. Psychopharmacology (Berl) 126:165–172CrossRefGoogle Scholar
  28. Varvel SA, Lichtman AH (2002) Evaluation of CB1 receptor knockout mice in the Morris water maze. J Pharmacol Exp Ther 301:915–924PubMedCrossRefGoogle Scholar
  29. Varvel SA, Anum EA, Lichtman AH (2005) Disruption of CB(1) receptor signaling impairs extinction of spatial memory in mice. Psychopharmacology (Berl) 179:863–872CrossRefGoogle Scholar
  30. Walker DL, Ressler KJ, Lu KT, Davis M (2002) Facilitation of conditioned fear extinction by systemic administration or intra-amygdala infusions of D-cycloserine as assessed with fear-potentiated startle in rats. J Neurosci 22:2343–2351PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Fabrício A. Pamplona
    • 1
  • Rui D. S. Prediger
    • 1
  • Pablo Pandolfo
    • 1
  • Reinaldo N. Takahashi
    • 1
  1. 1.Departamento de Farmacologia, Centro de Ciências BiológicasUniversidade Federal de Santa Catarina, Campus Universitário TrindadeFlorianópolisBrazil

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