, Volume 232, Issue 15, pp 2811–2825 | Cite as

2-AG promotes the expression of conditioned fear via cannabinoid receptor type 1 on GABAergic neurons

  • Alvaro Llorente-Berzal
  • Ana Luisa B. Terzian
  • Vincenzo di Marzo
  • Vincenzo Micale
  • Maria Paz Viveros
  • Carsten T. WotjakEmail author
Original Investigation



The contribution of two major endocannabinoids, 2-arachidonoylglycerol (2-AG) and anandamide (AEA), in the regulation of fear expression is still unknown.


We analyzed the role of different players of the endocannabinoid system on the expression of a strong auditory-cued fear memory in male mice by pharmacological means.


The cannabinoid receptor type 1 (CB1) antagonist SR141716 (3 mg/kg) caused an increase in conditioned freezing upon repeated tone presentation on three consecutive days. The cannabinoid receptor type 2 (CB2) antagonist AM630 (3 mg/kg), in contrast, had opposite effects during the first tone presentation, with no effects of the transient receptor potential vanilloid receptor type 1 (TRPV1) antagonist SB366791 (1 and 3 mg/kg). Administration of the CB2 agonist JWH133 (3 mg/kg) failed to affect the acute freezing response, whereas the CB1 agonist CP55,940 (50 μg/kg) augmented it. The endocannabinoid uptake inhibitor AM404 (3 mg/kg), but not VDM11 (3 mg/kg), reduced the acute freezing response. Its co-administration with SR141716 or SB366791 confirmed an involvement of CB1 and TRPV1. AEA degradation inhibition by URB597 (1 mg/kg) decreased, while 2-AG degradation inhibition by JZL184 (4 and 8 mg/kg) increased freezing response. As revealed in conditional CB1-deficient mutants, CB1 on cortical glutamatergic neurons alleviates whereas CB1 on GABAergic neurons slightly enhances fear expression. Moreover, 2-AG fear-promoting effects depended on CB1 signaling in GABAergic neurons, while an involvement of glutamatergic neurons remained inconclusive due to the high freezing shown by vehicle-treated Glu-CB1-KO.


Our findings suggest that increased AEA levels mediate acute fear relief, whereas increased 2-AG levels promote the expression of conditioned fear primarily via CB1 on GABAergic neurons.


Fear extinction TRPV1 CB1 CB2 URB597 JZL184 AM404 Anandamide 



This study is supported by the Instituto de Salud Carlos III, Redes temáticas de Investigación Cooperativa en salud (ISCIII y FEDER): Red de trastornos adictivos RD06/0001/1013 and RD2012/0028/0021; GRUPOS UCM-BSCH (GRUPO UCM 951579); Plan Nacional sobre Drogas: SAS/1250/2009. ALB received a travel grant from Boehringer Ingelheim Fonds. ALBT is supported by a CNPq scholarship (process 290008/2009-3). In addition, this work was supported by the project “CEITEC—Central European Institute of Technology” (CZ.1.05/1.1.00/02.0068) from the European Regional Development Fund (to VM).

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

213_2015_3917_MOESM1_ESM.pdf (66 kb)
Supplemental Figure 1 Consequences of pharmacological treatment on locomotor activity in C57BL/6N mice. The animals were treated in the same manner as done before re-exposure to the tone at d1-d3 (cf. Fig. 1 + 2), 16 days after fear conditioning. The following behavioral measures were scored during the subsequent 15-min exposure to the activity chambers and analyzed in 3-min bins: (i) movement time (left), distance (middle) and number of vertical explorations (rearings, right). I > II – significant group differences (p < 0.05, ANOVA, followed by Newman-Keuls post-hoc test); * p < 0.05 (significant group x time interval interaction, followed by Newman-Keuls test). (PDF 65 kb)
213_2015_3917_MOESM2_ESM.pdf (32 kb)
Supplemental Figure 2 Consequences of JZL184 on locomotor activity in GABA-CB1-KO. GABA-CB1-KO and WT controls were treated with JZL184 (4 mg/kg) or vehicle in the same manner as done before re-exposure to the tone at d1-d3 (cf. Fig. 4A-C), 16 days after fear conditioning. The following behavioral measures were scored during the subsequent 15-min exposure to the activity chambers and analyzed in 3-min bins: (i) movement time (left), distance (middle) and number of vertical explorations (rearings, right). (PDF 32 kb)
213_2015_3917_MOESM3_ESM.rtf (93 kb)
Suppl. Tab. 01 (RTF 93 kb)


  1. Aguiar DC, Moreira FA, Terzian AL, Fogaça MV, Lisboa SF, Wotjak CT et al (2014) Modulation of defensive behavior by transient receptor potential vanilloid type-1 (TRPV1) channels. Neurosci Biobehav Rev. doi: 10.1016/j.neubiorev.2014.03.026 PubMedGoogle Scholar
  2. Alger BE, Kim J (2011) Supply and demand for endocannabinoids. Trends Neurosci 34:304–315. doi: 10.1016/j.tins.2011.03.003 PubMedCentralPubMedCrossRefGoogle Scholar
  3. Aliczki M, Zelena D, Mikics E, Varga ZK, Pinter O, Bakos NV et al (2013) Monoacylglycerol lipase inhibition-induced changes in plasma corticosterone levels, anxiety and locomotor activity in male CD1 mice. Horm Behav 63:752–758. doi: 10.1016/j.yhbeh.2013.03.017 PubMedCrossRefGoogle Scholar
  4. Almeida-Santos AF, Gobira PH, Rosa LC, Guimaraes FS, Moreira FA, Aguiar DC (2013) Modulation of anxiety-like behavior by the endocannabinoid 2-arachidonoylglycerol (2-AG) in the dorsolateral periaqueductal gray. Behav Brain Res 252:10–17. doi: 10.1016/j.bbr.2013.05.027 PubMedCrossRefGoogle Scholar
  5. Andero R, Ressler KJ (2012) Fear extinction and BDNF: translating animal models of PTSD to the clinic. Genes Brain Behav 11:503–512. doi: 10.1111/j.1601-183X.2012.00801.x PubMedCentralPubMedCrossRefGoogle Scholar
  6. Atwood BK, Mackie K (2010) CB2: a cannabinoid receptor with an identity crisis. Br J Pharmacol 160:467–479Google Scholar
  7. Bellocchio L, Lafenêtre P, Cannich A, Cota D, Puente N, Grandes P et al (2010) Bimodal control of stimulated food intake by the endocannabinoid system. Nat Neurosci 13:281–283. doi: 10.1038/nn.2494 PubMedCrossRefGoogle Scholar
  8. Beltramo M, Piomelli D (2000) Carrier-mediated transport and enzymatic hydrolysis of the endogenous cannabinoid 2-arachidonylglycerol. Neuroreport 11:1231–1235PubMedCrossRefGoogle Scholar
  9. Bisogno T, MacCarrone M, De Petrocellis L, Jarrahian A, Finazzi-Agrò A, Hillard C et al (2001) The uptake by cells of 2-arachidonoylglycerol, an endogenous agonist of cannabinoid receptors. Eur J Biochem 268:1982–1989PubMedCrossRefGoogle Scholar
  10. Bitencourt RM, Pamplona FA, Takahashi RN (2008) Facilitation of contextual fear memory extinction and anti-anxiogenic effects of AM404 and cannabidiol in conditioned rats. Eur Neuropsychopharmacol 18:849–859. doi: 10.1016/j.euroneuro.2008.07.001 PubMedCrossRefGoogle Scholar
  11. Busquets-Garcia A, Puighermanal E, Pastor A, de la Torre R, Maldonado R, Ozaita A (2011) Differential role of anandamide and 2-arachidonoylglycerol in memory and anxiety-like responses. Biol Psychiatry 70:479–486. doi: 10.1016/j.biopsych.2011.04.022 PubMedCrossRefGoogle Scholar
  12. Chhatwal JP, Davis M, Maguschak KA, Ressler KJ (2005) Enhancing cannabinoid neurotransmission augments the extinction of conditioned fear. Neuropsychopharmacology 30:516–524. doi: 10.1038/sj.npp.1300655 PubMedCrossRefGoogle Scholar
  13. de Bitencourt RM, Pamplona FA, Takahashi RN (2013) A current overview of cannabinoids and glucocorticoids in facilitating extinction of aversive memories: potential extinction enhancers. Neuropharmacology 64:389–395. doi: 10.1016/j.neuropharm.2012.05.039 PubMedCrossRefGoogle Scholar
  14. 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 483:52–56PubMedCrossRefGoogle Scholar
  15. Deussing JM (2013) Targeted mutagenesis tools for modelling psychiatric disorders. Cell Tissue Res 354:9–25. doi: 10.1007/s00441-013-1708-5 PubMedCrossRefGoogle Scholar
  16. Dhopeshwarkar A, Mackie K (2014) CB2 Cannabinoid receptors as a therapeutic target—what does the future hold? Mol Pharmacol 86:430–437. doi: 10.1124/mol.114.094649 PubMedCrossRefGoogle Scholar
  17. Di Marzo V (2011) Endocannabinoid signaling in the brain: biosynthetic mechanisms in the limelight. Nat Neurosci 14:9–15. doi: 10.1038/nn.2720 PubMedCrossRefGoogle Scholar
  18. Dias BG, Banerjee SB, Goodman JV, Ressler KJ (2013) Towards new approaches to disorders of fear and anxiety. Curr Opin Neurobiol 23:346–352. doi: 10.1016/j.conb.2013.01.013 PubMedCentralPubMedCrossRefGoogle Scholar
  19. Edwards JG, Gibson HE, Jensen T, Nugent F, Walther C, Blickenstaff J et al (2012) A novel non-CB1/TRPV1 endocannabinoid-mediated mechanism depresses excitatory synapses on hippocampal CA1 interneurons. Hippocampus 22:209–221. doi: 10.1002/hipo.20884 PubMedCentralPubMedCrossRefGoogle Scholar
  20. Fowler CJ (2012) Anandamide uptake explained? Trends Pharmacol Sci 33:181–185. doi: 10.1016/ PubMedCrossRefGoogle Scholar
  21. Fowler CJ (2013) Transport of endocannabinoids across the plasma membrane and within the cell. FEBS J 280:1895–1904. doi: 10.1111/febs.12212 PubMedCrossRefGoogle Scholar
  22. Fu J, Bottegoni G, Sasso O, Bertorelli R, Rocchia W, Masetti M et al (2012) A catalytically silent FAAH-1 variant drives anandamide transport in neurons. Nat Neurosci 15:64–69. doi: 10.1038/nn.2986 CrossRefGoogle Scholar
  23. Ganon-Elazar E, Akirav I (2013) Cannabinoids and traumatic stress modulation of contextual fear extinction and GR expression in the amygdala-hippocampal-prefrontal circuit. Psychoneuroendocrinology 38:1675–1687. doi: 10.1016/j.psyneuen.2013.01.014 PubMedCrossRefGoogle Scholar
  24. Gao Y, Vasilyev DV, Goncalves MB, Howell FV, Hobbs C, Reisenberg M et al (2010) Loss of retrograde endocannabinoid signaling and reduced adult neurogenesis in diacylglycerol lipase knock-out mice. J Neurosci 30:2017–2024. doi: 10.1523/JNEUROSCI. 5693-09.2010 PubMedCrossRefGoogle Scholar
  25. Glaser ST, Abumrad NA, Fatade F, Kaczocha M, Studholme KM, Deutsch DG (2003) Evidence against the presence of an anandamide transporter. Proc Natl Acad Sci U S A 100:4269–4274. doi: 10.1073/pnas.0730816100 PubMedCentralPubMedCrossRefGoogle Scholar
  26. Golub Y, Mauch CP, Dahlhoff M, Wotjak CT (2009) Consequences of extinction training on associative and non-associative fear in a mouse model of posttraumatic stress disorder (PTSD). Behav Brain Res 205:544–549. doi: 10.1016/j.bbr.2009.08.019 PubMedCrossRefGoogle Scholar
  27. Graham BM, Milad MR (2011) The study of fear extinction: implications for anxiety disorders. Am J Psychiatry 168:1255–1265. doi: 10.1176/appi.ajp.2011.11040557 PubMedCentralPubMedCrossRefGoogle Scholar
  28. Gulyas AI, Cravatt BF, Bracey MH, Dinh TP, Piomelli D, Boscia F et al (2004) Segregation of two endocannabinoid-hydrolyzing enzymes into pre- and postsynaptic compartments in the rat hippocampus, cerebellum and amygdala. Eur J Neurosci 20:441–458. doi: 10.1111/j.1460-9568.2004.03428.x PubMedCrossRefGoogle Scholar
  29. Gunduz-Cinar O, Hill MN, McEwen BS, Holmes A (2013a) Amygdala FAAH and anandamide: mediating protection and recovery from stress. Trends Pharmacol Sci 34:637–644. doi: 10.1016/ PubMedCentralPubMedCrossRefGoogle Scholar
  30. Gunduz-Cinar O, MacPherson KP, Cinar R, Gamble-George J, Sugden K, Williams B et al (2013b) Convergent translational evidence of a role for anandamide in amygdala-mediated fear extinction, threat processing and stress-reactivity. Mol Psychiatry 18:813–823. doi: 10.1038/mp.2012.72 PubMedCentralPubMedCrossRefGoogle Scholar
  31. Haller J, Varga B, Ledent C, Freund TF (2004) CB1 cannabinoid receptors mediate anxiolytic effects: convergent genetic and pharmacological evidence with CB1-specific agents. Behav Pharmacol 15:299–304PubMedCrossRefGoogle Scholar
  32. Han J, Kesner P, Metna-Laurent M, Duan T, Xu L, Georges F et al (2012) Acute cannabinoids impair working memory through astroglial CB1 receptor modulation of hippocampal LTD. Cell 148:1039–1050. doi: 10.1016/j.cell.2012.01.037 PubMedCrossRefGoogle Scholar
  33. Hariri AR, Gorka A, Hyde LW, Kimak M, Halder I, Ducci F et al (2009) Divergent effects of genetic variation in endocannabinoid signaling on human threat- and reward-related brain function. Biol Psychiatry 66:9–16. doi: 10.1016/j.biopsych.2008.10.047 PubMedCentralPubMedCrossRefGoogle Scholar
  34. Hashimotodani Y, Ohno-Shosaku T, Kano M (2007) Presynaptic monoacylglycerol lipase activity determines basal endocannabinoid tone and terminates retrograde endocannabinoid signaling in the hippocampus. J Neurosci 27:1211–1219. doi: 10.1523/JNEUROSCI. 4159-06.2007 PubMedCrossRefGoogle Scholar
  35. Heitland I, Klumpers F, Oosting RS, Evers DJ, Leon Kenemans J, Baas JM (2012) Failure to extinguish fear and genetic variability in the human cannabinoid receptor 1. Transl Psychiatry 2:e162. doi: 10.1038/tp.2012.90 PubMedCentralPubMedCrossRefGoogle Scholar
  36. Heldt SA, Mou L, Ressler KJ (2012) In vivo knockdown of GAD67 in the amygdala disrupts fear extinction and the anxiolytic-like effect of diazepam in mice. Transl Psychiatry 2:e181. doi: 10.1038/tp.2012.101 PubMedCentralPubMedCrossRefGoogle Scholar
  37. Hill MN, Patel S, Campolongo P, Tasker JG, Wotjak CT, Bains JS (2010) Functional interactions between stress and the endocannabinoid system: from synaptic signaling to behavioral output. J Neurosci 30:14980–14986. doi: 10.1523/JNEUROSCI. 4283-10.2010 PubMedCentralPubMedCrossRefGoogle Scholar
  38. Hillard CJ (2014) Stress regulates endocannabinoid-CB1 receptor signaling. Semin Immunol. doi: 10.1016/j.smim.2014.04.001 PubMedGoogle Scholar
  39. Hillard CJ, Weinlander KM, Stuhr KL (2012) Contributions of endocannabinoid signaling to psychiatric disorders in humans: genetic and biochemical evidence. Neuroscience 204:207–229. doi: 10.1016/j.neuroscience.2011.11.020 PubMedCentralPubMedCrossRefGoogle Scholar
  40. Holmes A, Singewald N (2013) Individual differences in recovery from traumatic fear. Trends Neurosci 36:23–31. doi: 10.1016/j.tins.2012.11.003 PubMedCentralPubMedCrossRefGoogle Scholar
  41. Jacob W, Yassouridis A, Marsicano G, Monory K, Lutz B, Wotjak CT (2009) Endocannabinoids render exploratory behaviour largely independent of the test aversiveness: role of glutamatergic transmission. Genes Brain Behav 8:685–698. doi: 10.1111/j.1601-183X.2009.00512.x PubMedCrossRefGoogle Scholar
  42. Jacob W, Marsch R, Marsicano G, Lutz B, Wotjak CT (2012) Cannabinoid CB1 receptor deficiency increases contextual fear memory under highly aversive conditions and long-term potentiation in vivo. Neurobiol Learn Mem 98:47–55. doi: 10.1016/j.nlm.2012.04.008 PubMedCrossRefGoogle Scholar
  43. Kamprath K, Wotjak CT (2004) Nonassociative learning processes determine expression and extinction of conditioned fear in mice. Learn Mem 11:770–786. doi: 10.1101/lm.86104 PubMedCentralPubMedCrossRefGoogle Scholar
  44. Kamprath K, Marsicano G, Tang J, Monory K, Bisogno T, Di Marzo V et al (2006) Cannabinoid CB1 receptor mediates fear extinction via habituation-like processes. J Neurosci 26:6677–6686. doi: 10.1523/JNEUROSCI. 0153-06.2006 PubMedCrossRefGoogle Scholar
  45. Kamprath K, Plendl W, Marsicano G, Deussing JM, Wurst W, Lutz B et al (2009) Endocannabinoids mediate acute fear adaptation via glutamatergic neurons independently of corticotropin-releasing hormone signaling. Genes Brain Behav 8:203–211. doi: 10.1111/j.1601-183X.2008.00463.x PubMedCrossRefGoogle Scholar
  46. Kathuria S, Gaetani S, Fegley D, Valiño F, Duranti A, Tontini A et al (2003) Modulation of anxiety through blockade of anandamide hydrolysis. Nat Med 9:76–81. doi: 10.1038/nm803 PubMedCrossRefGoogle Scholar
  47. Kearns MC, Ressler KJ, Zatzick D, Rothbaum BO (2012) Early interventions for PTSD: a review. Depress Anxiety 29:833–842. doi: 10.1002/da.21997 PubMedCentralPubMedCrossRefGoogle Scholar
  48. Kim J, Alger BE (2004) Inhibition of cyclooxygenase-2 potentiates retrograde endocannabinoid effects in hippocampus. Nat Neurosci 7:697–698. doi: 10.1038/nn1262 PubMedCrossRefGoogle Scholar
  49. Kinsey SG, O’Neal ST, Long JZ, Cravatt BF, Lichtman AH (2011) Inhibition of endocannabinoid catabolic enzymes elicits anxiolytic-like effects in the marble burying assay. Pharmacol Biochem Behav 98:21–27. doi: 10.1016/j.pbb.2010.12.002 PubMedCentralPubMedCrossRefGoogle Scholar
  50. Lafenêtre P, Chaouloff F, Marsicano G (2009) Bidirectional regulation of novelty-induced behavioral inhibition by the endocannabinoid system. Neuropharmacology 57:715–721. doi: 10.1016/j.neuropharm.2009.07.014 PubMedCrossRefGoogle Scholar
  51. Llorente-Berzal A, Fuentes S, Gagliano H, López-Gallardo M, Armario A, Viveros MP et al (2011) Sex-dependent effects of maternal deprivation and adolescent cannabinoid treatment on adult rat behaviour. Addict Biol 16:624–637. doi: 10.1111/j.1369-1600.2011.00318.x PubMedCrossRefGoogle Scholar
  52. Long JZ, Li W, Booker L, Burston JJ, Kinsey SG, Schlosburg JE et al (2009) Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects. Nat Chem Biol 5:37–44. doi: 10.1038/nchembio.129 PubMedCentralPubMedCrossRefGoogle Scholar
  53. Luchicchi A, Pistis M (2012) Anandamide and 2-arachidonoylglycerol: pharmacological properties, functional features, and emerging specificities of the two major endocannabinoids. Mol Neurobiol 46:374–392. doi: 10.1007/s12035-012-8299-0 PubMedCrossRefGoogle Scholar
  54. Maccarrone M, Rossi S, Bari M, De Chiara V, Fezza F, Musella A et al (2008) Anandamide inhibits metabolism and physiological actions of 2-arachidonoylglycerol in the striatum. Nat Neurosci 11:152–159. doi: 10.1038/nn2042 PubMedCrossRefGoogle Scholar
  55. Maione S, Bisogno T, de Novellis V, Palazzo E, Cristino L, Valenti M et al (2006) Elevation of endocannabinoid levels in the ventrolateral periaqueductal grey through inhibition of fatty acid amide hydrolase affects descending nociceptive pathways via both cannabinoid receptor type 1 and transient receptor potential vanilloid type-1 receptors. J Pharmacol Exp Ther 316:969–982. doi: 10.1124/jpet.105.093286 PubMedCrossRefGoogle Scholar
  56. Maione S, Costa B, Piscitelli F, Morera E, De Chiaro M, Comelli F et al (2013) Piperazinyl carbamate fatty acid amide hydrolase inhibitors and transient receptor potential channel modulators as “dual-target” analgesics. Pharmacol Res 76C:98–105. doi: 10.1016/j.phrs.2013.07.003 CrossRefGoogle Scholar
  57. Manwell LA, Satvat E, Lang ST, Allen CP, Leri F, Parker LA (2009) FAAH inhibitor, URB-597, promotes extinction and CB(1) antagonist, SR141716, inhibits extinction of conditioned aversion produced by naloxone-precipitated morphine withdrawal, but not extinction of conditioned preference produced by morphine in rats. Pharmacol Biochem Behav 94:154–162. doi: 10.1016/j.pbb.2009.08.002 PubMedCrossRefGoogle Scholar
  58. Marsch R, Foeller E, Rammes G, Bunck M, Kössl M, Holsboer F et al (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. doi: 10.1523/JNEUROSCI. 3303-06.2007 PubMedCrossRefGoogle Scholar
  59. Marsicano G, Lutz B (1999) Expression of the cannabinoid receptor CB1 in distinct neuronal subpopulations in the adult mouse forebrain. Eur J Neurosci 11:4213–4225PubMedCrossRefGoogle Scholar
  60. Marsicano G, Wotjak CT, Azad SC, Bisogno T, Rammes G, Cascio MG et al (2002) The endogenous cannabinoid system controls extinction of aversive memories. Nature 418:530–534. doi: 10.1038/nature00839 PubMedCrossRefGoogle Scholar
  61. McGregor IS, Issakidis CN, Prior G (1996) Aversive effects of the synthetic cannabinoid CP 55,940 in rats. Pharmacol Biochem Behav 53:657–664PubMedCrossRefGoogle Scholar
  62. Mechoulam R, Parker LA (2013) The endocannabinoid system and the brain. Annu Rev Psychol 64:21–47. doi: 10.1146/annurev-psych-113011-143739 PubMedCrossRefGoogle Scholar
  63. Metna-Laurent M, Soria-Gómez E, Verrier D, Conforzi M, Jégo P, Lafenêtre P et al (2012) Bimodal control of fear-coping strategies by CB1 cannabinoid receptors. J Neurosci 32:7109–7118. doi: 10.1523/JNEUROSCI.1054-12.2012 PubMedCrossRefGoogle Scholar
  64. Micale V, Di Marzo V, Sulcova A, Wotjak CT, Drago F (2013) Endocannabinoid system and mood disorders: priming a target for new therapies. Pharmacol Ther 138:18–37. doi: 10.1016/j.pharmthera.2012.12.002 PubMedCrossRefGoogle Scholar
  65. Monory K, Massa F, Egertová M, Eder M, Kelsch W, Blaudzun H, Westenbroek R, Kelsch W, Jacob W, Marsch R, Ekker M, Long J, Rubenstein J, Goebbels S, Nave KA, During M, Klugmann M, Wölfel B, Dodt HU, Zieglgänsberger W, Wotjak CT, Mackie K, Elphick MR, Marsicano G, Lutz B (2006) The endocannabinoid system controls a key epileptogenic circuit in the hippocampus. Neuron 51:455–466Google Scholar
  66. Moreira FA, Wotjak CT (2010) Cannabinoids and anxiety. Curr Top Behav Neurosci 2:429–450PubMedCrossRefGoogle Scholar
  67. Moreira FA, Aguiar DC, Terzian AL, Guimarães FS, Wotjak CT (2012) Cannabinoid type 1 receptors and transient receptor potential vanilloid type 1 channels in fear and anxiety—two sides of one coin? Neuroscience 204:186–192. doi: 10.1016/j.neuroscience.2011.08.046 PubMedCrossRefGoogle Scholar
  68. Morena M, Roozendaal B, Trezza V, Ratano P, Peloso A, Hauer D et al (2014) Endogenous cannabinoid release within prefrontal-limbic pathways affects memory consolidation of emotional training. Proc Natl Acad Sci U S A 111:18333–18338PubMedCentralPubMedCrossRefGoogle Scholar
  69. Naidu PS, Varvel SA, Ahn K, Cravatt BF, Martin BR, Lichtman AH (2007) Evaluation of fatty acid amide hydrolase inhibition in murine models of emotionality. Psychopharmacology (Berl) 192:61–70. doi: 10.1007/s00213-006-0689-4 CrossRefGoogle Scholar
  70. Niyuhire F, Varvel SA, Martin BR, Lichtman AH (2007) Exposure to marijuana smoke impairs memory retrieval in mice. J Pharmacol Exp Ther 322:1067–1075. doi: 10.1124/jpet.107.119594 PubMedCrossRefGoogle Scholar
  71. 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. doi: 10.1007/s00213-006-0514-0 CrossRefGoogle Scholar
  72. Pamplona FA, Bitencourt RM, Takahashi RN (2008) Short- and long-term effects of cannabinoids on the extinction of contextual fear memory in rats. Neurobiol Learn Mem 90:290–293. doi: 10.1016/j.nlm.2008.04.003 PubMedCrossRefGoogle Scholar
  73. Pan B, Wang W, Zhong P, Blankman JL, Cravatt BF, Liu QS (2011) Alterations of endocannabinoid signaling, synaptic plasticity, learning, and memory in monoacylglycerol lipase knock-out mice. J Neurosci 31:13420–13430. doi: 10.1523/JNEUROSCI. 2075-11.2011 PubMedCentralPubMedCrossRefGoogle Scholar
  74. Pardini M, Krueger F, Koenigs M, Raymont V, Hodgkinson C, Zoubak S et al (2012) Fatty-acid amide hydrolase polymorphisms and post-traumatic stress disorder after penetrating brain injury. Transl Psychiatry 2:e75. doi: 10.1038/tp.2012.1 PubMedCentralPubMedCrossRefGoogle Scholar
  75. Parsons RG, Ressler KJ (2013) Implications of memory modulation for post-traumatic stress and fear disorders. Nat Neurosci 16:146–153. doi: 10.1038/nn.3296 PubMedCentralPubMedCrossRefGoogle Scholar
  76. 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. doi: 10.1111/j.1460-9568.2005.03916.x PubMedCrossRefGoogle Scholar
  77. Plendl W, Wotjak CT (2010) Dissociation of within- and between-session extinction of conditioned fear. J Neurosci 30:4990–4998. doi: 10.1523/JNEUROSCI. 6038-09.2010 PubMedCrossRefGoogle Scholar
  78. Ralevic V, Kendall DA, Jerman JC, Middlemiss DN, Smart D (2001) Cannabinoid activation of recombinant and endogenous vanilloid receptors. Eur J Pharmacol 424:211–219PubMedCrossRefGoogle Scholar
  79. Rea K, Ford GK, Olango WM, Harhen B, Roche M, Finn DP (2014) Microinjection of 2-arachidonoyl glycerol into the rat ventral hippocampus differentially modulates contextually induced fear, depending on a persistent pain state. Eur J Neurosci 39:435–443PubMedCrossRefGoogle Scholar
  80. Rey AA, Purrio M, Viveros MP, Lutz B (2012) Biphasic effects of cannabinoids in anxiety responses: CB1 and GABA(B) receptors in the balance of GABAergic and glutamatergic neurotransmission. Neuropsychopharmacology 37:2624–2634. doi: 10.1038/npp.2012.123 PubMedCentralPubMedCrossRefGoogle Scholar
  81. Riebe CJ, Pamplona FA, Pamplona F, Kamprath K, Wotjak CT (2012) Fear relief—toward a new conceptual frame work and what endocannabinoids gotta do with it. Neuroscience 204:159–185. doi: 10.1016/j.neuroscience.2011.11.057 PubMedCrossRefGoogle Scholar
  82. Ross RA, Gibson TM, Brockie HC, Leslie M, Pashmi G, Craib SJ et al (2001) Structure-activity relationship for the endogenous cannabinoid, anandamide, and certain of its analogues at vanilloid receptors in transfected cells and vas deferens. Br J Pharmacol 132:631–640. doi: 10.1038/sj.bjp.0703850 PubMedCentralPubMedCrossRefGoogle Scholar
  83. Savinainen JR, Saario SM, Laitinen JT (2012) The serine hydrolases MAGL, ABHD6 and ABHD12 as guardians of 2-arachidonoylglycerol signalling through cannabinoid receptors. Acta Physiol (Oxf) 204:267–276. doi: 10.1111/j.1748-1716.2011.02280.x CrossRefGoogle Scholar
  84. Schlosburg JE, Blankman JL, Long JZ, Nomura DK, Pan B, Kinsey SG et al (2010) Chronic monoacylglycerol lipase blockade causes functional antagonism of the endocannabinoid system. Nat Neurosci 13:1113–1119. doi: 10.1038/nn.2616 PubMedCentralPubMedCrossRefGoogle Scholar
  85. Sciolino NR, Zhou W, Hohmann AG (2011) Enhancement of endocannabinoid signaling with JZL184, an inhibitor of the 2-arachidonoylglycerol hydrolyzing enzyme monoacylglycerol lipase, produces anxiolytic effects under conditions of high environmental aversiveness in rats. Pharmacol Res 64:226–234. doi: 10.1016/j.phrs.2011.04.010 PubMedCentralPubMedCrossRefGoogle Scholar
  86. 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. doi: 10.1016/j.jpsychires.2006.07.017 PubMedCrossRefGoogle Scholar
  87. Siegmund A, Langnaese K, Wotjak CT (2005) Differences in extinction of conditioned fear in C57BL/6 substrains are unrelated to expression of alpha-synuclein. Behav Brain Res 157:291–298. doi: 10.1016/j.bbr.2004.07.007 PubMedCrossRefGoogle Scholar
  88. Suárez J, Ortíz O, Puente N, Bermúdez-Silva FJ, Blanco E, Fernández-Llebrez P et al (2011) Distribution of diacylglycerol lipase alpha, an endocannabinoid synthesizing enzyme, in the rat forebrain. Neuroscience 192:112–131. doi: 10.1016/j.neuroscience.2011.06.062 PubMedCrossRefGoogle Scholar
  89. Tambaro S, Bortolato M (2012) Cannabinoid-related agents in the treatment of anxiety disorders: current knowledge and future perspectives. Recent Pat CNS Drug Discov 7:25–40PubMedCentralPubMedCrossRefGoogle Scholar
  90. Tanimura A, Yamazaki M, Hashimotodani Y, Uchigashima M, Kawata S, Abe M et al (2010) The endocannabinoid 2-arachidonoylglycerol produced by diacylglycerol lipase alpha mediates retrograde suppression of synaptic transmission. Neuron 65:320–327. doi: 10.1016/j.neuron.2010.01.021 PubMedCrossRefGoogle Scholar
  91. Trezza V, Campolongo P (2013) The endocannabinoid system as a possible target to treat both the cognitive and emotional features of post-traumatic stress disorder (PTSD). Front Behav Neurosci 7:100. doi: 10.3389/fnbeh.2013.00100 PubMedCentralPubMedCrossRefGoogle Scholar
  92. Uchigashima M, Yamazaki M, Yamasaki M, Tanimura A, Sakimura K, Kano M et al (2011) Molecular and morphological configuration for 2-arachidonoylglycerol-mediated retrograde signaling at mossy cell-granule cell synapses in the dentate gyrus. J Neurosci 31:7700–7714. doi: 10.1523/JNEUROSCI. 5665-10.2011 PubMedCrossRefGoogle Scholar
  93. Wiskerke J, Irimia C, Cravatt BF, De Vries TJ, Schoffelmeer AN, Pattij T et al (2012) Characterization of the effects of reuptake and hydrolysis inhibition on interstitial endocannabinoid levels in the brain: an in vivo microdialysis study. ACS Chem Neurosci 3:407–417. doi: 10.1021/cn300036b PubMedCentralPubMedCrossRefGoogle Scholar
  94. Yoshida T, Fukaya M, Uchigashima M, Miura E, Kamiya H, Kano M et al (2006) Localization of diacylglycerol lipase-alpha around postsynaptic spine suggests close proximity between production site of an endocannabinoid, 2-arachidonoyl-glycerol, and presynaptic cannabinoid CB1 receptor. J Neurosci 26:4740–4751. doi: 10.1523/JNEUROSCI. 0054-06.2006 PubMedCrossRefGoogle Scholar
  95. Yoshino H, Miyamae T, Hansen G, Zambrowicz B, Flynn M, Pedicord D et al (2011) Postsynaptic diacylglycerol lipase mediates retrograde endocannabinoid suppression of inhibition in mouse prefrontal cortex. J Physiol 589:4857–4884. doi: 10.1113/jphysiol.2011.212225 PubMedCentralPubMedCrossRefGoogle Scholar
  96. Zygmunt PM, Chuang H, Movahed P, Julius D, Högestätt ED (2000) The anandamide transport inhibitor AM404 activates vanilloid receptors. Eur J Pharmacol 396:39–42PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Alvaro Llorente-Berzal
    • 1
    • 6
  • Ana Luisa B. Terzian
    • 2
    • 3
  • Vincenzo di Marzo
    • 4
  • Vincenzo Micale
    • 2
    • 5
  • Maria Paz Viveros
    • 1
    • 6
  • Carsten T. Wotjak
    • 2
    Email author
  1. 1.Departamento de Fisiología (Fisiología Animal II), Facultad de BiologíaUniversidad Complutense de MadridMadridSpain
  2. 2.RG “Neuronal Plasticity”, Department of Stress Neurobiology and NeurogeneticsMax Planck Institute of PsychiatryMunichGermany
  3. 3.Graduate School of Systemic NeuroscienceLudwig-Maximilians-UniversitätMunichGermany
  4. 4.Endocannabinoid Research Group, Institute of Biomolecular ChemistryC.N.R.PozzuoliItaly
  5. 5.CEITEC—Central European Institute of TechnologyMasaryk UniversityBrnoCzech Republic
  6. 6.Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC)MadridSpain

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