Neural Plasticity
Volume 2009 (2009), Article ID 625469, 11 pages
doi:10.1155/2009/625469
Review Article

Antiaversive Effects of Cannabinoids: Is the Periaqueductal Gray Involved?

Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Avenida Bandeirantes 3900, 14049900 Ribeirão Preto, SP, Brazil

Received 14 May 2008; Revised 12 August 2008; Accepted 9 September 2008

Academic Editor: Robert Adamec

Copyright © 2009 F. A. Moreira et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. M. Booth, Cannabis: A History, Banton Books, London, UK, 2003.
  2. D. T. Courtwright, Forces of Habit: Drugs and the Making of the Modern World, Harvard University Press, Cambridge, Mass, USA, 2001.
  3. A. W. Zuardi, “History of cannabis as a medicine: a review,” Revista Brasileira de Psiquiatria, vol. 28, no. 2, pp. 153–157, 2006. View at Publisher · View at Google Scholar
  4. R. Mechoulam, “Marijuana chemistry,” Science, vol. 168, no. 936, pp. 1159–1166, 1970. View at Publisher · View at Google Scholar
  5. W. D. M. Paton, “Pharmacology of marijuana,” Annual Review of Pharmacology, vol. 15, pp. 191–220, 1975. View at Publisher · View at Google Scholar · View at PubMed
  6. W. A. Devane, F. A. Dysarz, III, M. R. Johnson, L. S. Melvin, and A. C. Howlett, “Determination and characterization of a cannabinoid receptor in rat brain,” Molecular Pharmacology, vol. 34, no. 5, pp. 605–613, 1988.
  7. L. A. Matsuda, S. J. Lolait, M. J. Brownstein, A. C. Young, and T. I. Bonner, “Structure of a cannabinoid receptor and functional expression of the cloned cDNA,” Nature, vol. 346, no. 6284, pp. 561–564, 1990. View at Publisher · View at Google Scholar · View at PubMed
  8. W. A. Devane, L. Hanus, A. Breuer, et al., “Isolation and structure of a brain constituent that binds to the cannabinoid receptor,” Science, vol. 258, no. 5090, pp. 1946–1949, 1992. View at Publisher · View at Google Scholar
  9. R. Mechoulam, S. Ben-Shabat, L. Hanus, et al., “Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors,” Biochemical Pharmacology, vol. 50, no. 1, pp. 83–90, 1995. View at Publisher · View at Google Scholar
  10. S. Munro, K. L. Thomas, and M. Abu-Shaar, “Molecular characterization of a peripheral receptor for cannabinoids,” Nature, vol. 365, no. 6441, pp. 61–65, 1993. View at Publisher · View at Google Scholar · View at PubMed
  11. M. Rinaldi-Carmona, F. Barth, M. Héaulme, et al., “SR141716A, a potent and selective antagonist of the brain cannabinoid receptor,” FEBS Letters, vol. 350, no. 2-3, pp. 240–244, 1994. View at Publisher · View at Google Scholar
  12. S. J. Gatley, A. N. Gifford, N. D. Volkow, R. Lan, and A. Makriyannis, “123I-labeled AM251: a radioiodinated ligand which binds in vivo to mouse brain cannabinoid CB1 receptors,” European Journal of Pharmacology, vol. 307, no. 3, pp. 331–338, 1996. View at Publisher · View at Google Scholar
  13. M. Herkenham, A. B. Lynn, M. R. Johnson, L. S. Melvin, B. R. de Costa, and K. C. Rice, “Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study,” The Journal of Neuroscience, vol. 11, no. 2, pp. 563–583, 1991.
  14. K. Tsou, S. Brown, M. C. Sañudo-Peña, K. Mackie, and J. M. Walker, “Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system,” Neuroscience, vol. 83, no. 2, pp. 393–411, 1998. View at Publisher · View at Google Scholar
  15. M. Egertov, D. K. Giang, B. F. Cravatt, and M. R. Elphick, “A new perspective on cannabinoid signalling: complementary localization of fatty acid amide hydrolase and the CB1 receptor in rat brain,” Proceedings of the Royal Society B, vol. 265, no. 1410, pp. 2081–2085, 1998. View at Publisher · View at Google Scholar · View at PubMed
  16. R. I. Wilson and R. A. Nicoll, “Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses,” Nature, vol. 410, no. 6828, pp. 588–592, 2001. View at Publisher · View at Google Scholar · View at PubMed
  17. A. C. Howlett, F. Barth, T. I. Bonner, et al., “International Union of Pharmacology. XXVII. Classification of cannabinoid receptors,” Pharmacological Reviews, vol. 54, no. 2, pp. 161–202, 2002. View at Publisher · View at Google Scholar
  18. A. Giuffrida, M. Beltramo, and D. Piomelli, “Mechanisms of endocannabinoid inactivation: biochemistry and pharmacology,” Journal of Pharmacology and Experimental Therapeutics, vol. 298, no. 1, pp. 7–14, 2001.
  19. M. K. McKinney and B. E. Cravatt, “Structure and function of fatty acid amide hydrolase,” Annual Review of Biochemistry, vol. 74, pp. 411–432, 2005. View at Publisher · View at Google Scholar · View at PubMed
  20. P. Pacher, S. Bátkai, and G. Kunos, “The endocannabinoid system as an emerging target of pharmacotherapy,” Pharmacological Reviews, vol. 58, no. 3, pp. 389–462, 2006. View at Publisher · View at Google Scholar · View at PubMed
  21. A. J. Brown, “Novel cannabinoid receptors,” British Journal of Pharmacology, vol. 152, no. 5, pp. 567–575, 2007. View at Publisher · View at Google Scholar · View at PubMed
  22. M. R. Price, G. L. Baillie, A. Thomas, et al., “Allosteric modulation of the cannabinoid CB1 receptor,” Molecular Pharmacology, vol. 68, no. 5, pp. 1484–1495, 2005. View at Publisher · View at Google Scholar · View at PubMed
  23. M. D. Van Sickle, M. Duncan, P. J. Kingsley, et al., “Identification and functional characterization of brainstem cannabinoid CB2 receptors,” Science, vol. 310, no. 5746, pp. 329–332, 2005. View at Publisher · View at Google Scholar · View at PubMed
  24. J.-P. Gong, E. S. Onaivi, H. Ishiguro, et al., “Cannabinoid CB2 receptors: immunohistochemical localization in rat brain,” Brain Research, vol. 1071, no. 1, pp. 10–23, 2006. View at Publisher · View at Google Scholar · View at PubMed
  25. M. P. Viveros, E. M. Marco, and S. E. File, “Endocannabinoid system and stress and anxiety responses,” Pharmacology Biochemistry and Behavior, vol. 81, no. 2, pp. 331–342, 2005. View at Publisher · View at Google Scholar · View at PubMed
  26. F. G. Graeff, “Neuroanatomy and neurotransmitter regulation of defensive behaviours and related emotions in mammals,” Brazilian Journal of Medical and Biological Research, vol. 27, no. 4, pp. 811–829, 1994.
  27. N. McNaughton and J. A. Gray, “Anxiolytic action on the behavioural inhibition system implies multiple types of arousal contribute to anxiety,” Journal of Affective Disorders, vol. 61, no. 3, pp. 161–176, 2000. View at Publisher · View at Google Scholar
  28. N. McNaughton and P. J. Corr, “A two-dimensional neuropsychology of defense: fear/anxiety and defensive distance,” Neuroscience & Biobehavioral Reviews, vol. 28, no. 3, pp. 285–305, 2004. View at Publisher · View at Google Scholar · View at PubMed
  29. R. Bandler, K. A. Keay, N. Floyd, and J. Price, “Central circuits mediating patterned autonomic activity during active vs. passive emotional coping,” Brain Research Bulletin, vol. 53, no. 1, pp. 95–104, 2000. View at Publisher · View at Google Scholar
  30. R. Bandler and A. Depaulis, “Elicitation of intraspecific defence reactions in the rat from midbrain periaqueductal grey by microinjection of kainic acid, without neurotoxic effects,” Neuroscience Letters, vol. 88, no. 3, pp. 291–296, 1988. View at Publisher · View at Google Scholar
  31. N. A. Patel, R. L. Moldow, J. A. Patel, G.-D. Wu, and S. L. Chang, “Arachidonylethanolamide (AEA) activation of FOS proto-oncogene protein immunoreactivity in the rat brain,” Brain Research, vol. 797, no. 2, pp. 225–233, 1998. View at Publisher · View at Google Scholar
  32. C.-L. Chin, A. E. Tovcimak, V. P. Hradil, et al., “Differential effects of cannabinoid receptor agonists on regional brain activity using pharmacological MRI,” British Journal of Pharmacology, vol. 153, no. 2, pp. 367–379, 2008. View at Publisher · View at Google Scholar · View at PubMed
  33. W. J. Martin, S. L. Patrick, P. O. Coffin, K. Tsou, and J. M. Walker, “An examination of the central sites of action of cannabinoid-induced antinociception in the rat,” Life Sciences, vol. 56, no. 23-24, pp. 2103–2109, 1995. View at Publisher · View at Google Scholar
  34. J. M. Walker, S. M. Huang, N. M. Strangman, K. Tsou, and M. C. Sañudo-Peña, “Pain modulation by release of the endogenous cannabinoid anandamide,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 21, pp. 12198–12203, 1999. View at Publisher · View at Google Scholar
  35. A. G. Hohmann and R. L. Suplita, II, “Endocannabinoid mechanisms of pain modulation,” The AAPS Journal, vol. 8, no. 4, pp. E693–E708, 2006. View at Publisher · View at Google Scholar · View at PubMed
  36. D. P. Finn, M. D. Jhaveri, S. R. G. Beckett, et al., “Effects of direct periaqueductal grey administration of a cannabinoid receptor agonist on nociceptive and aversive responses in rats,” Neuropharmacology, vol. 45, no. 5, pp. 594–604, 2003. View at Publisher · View at Google Scholar
  37. E. S. Onaivi, M. R. Green, and B. R. Martin, “Pharmacological characterization of cannabinoids in the elevated plus maze,” Journal of Pharmacology and Experimental Therapeutics, vol. 253, no. 3, pp. 1002–1009, 1990.
  38. E. Valjent, J. M. Mitchell, M.-J. Besson, J. Caboche, and R. Maldonado, “Behavioural and biochemical evidence for interactions between Δ9-tetrahydrocannabinol and nicotine,” British Journal of Pharmacology, vol. 135, no. 2, pp. 564–578, 2002. View at Publisher · View at Google Scholar · View at PubMed
  39. F. Berrendero and R. Maldonado, “Involvement of the opioid system in the anxiolytic-like effects induced by Δ9-tetrahydrocannabinol,” Psychopharmacology, vol. 163, no. 1, pp. 111–117, 2002. View at Publisher · View at Google Scholar · View at PubMed
  40. S. Patel and C. J. Hillard, “Pharmacological evaluation of cannabinoid receptor ligands in a mouse model of anxiety: further evidence for an anxiolytic role for endogenous cannabinoid signalling,” Journal of Pharmacology and Experimental Therapeutics, vol. 318, no. 1, pp. 304–311, 2006. View at Publisher · View at Google Scholar · View at PubMed
  41. D. Braida, V. Limonta, L. Malabarba, A. Zani, and M. Sala, “5-HT1A receptors are involved in the anxiolytic effect of Δ9-tetrahydrocannabinol and AM 404, the anandamide transport inhibitor, in Sprague-Dawley rats,” European Journal of Pharmacology, vol. 555, no. 2-3, pp. 156–163, 2007. View at Publisher · View at Google Scholar · View at PubMed
  42. N. L. Schramm-Sapyta, Y. M. Cha, S. Chaudhry, W. A. Wilson, H. S. Swartzwelder, and C. M. Kuhn, “Differential anxiogenic, aversive, and locomotor effects of THC in adolescent and adult rats,” Psychopharmacology, vol. 191, no. 4, pp. 867–877, 2007. View at Publisher · View at Google Scholar · View at PubMed
  43. T. Rubino, M. Sala, D. Viganò, et al., “Cellular mechanisms underlying the anxiolytic effect of low doses of peripheral Δ9-tetrahydrocannabinol in rats,” Neuropsychopharmacology, vol. 32, no. 9, pp. 2036–2045, 2007. View at Publisher · View at Google Scholar · View at PubMed
  44. F. S. Guimarães, T. M. Chiaretti, F. G. Graeff, and A. W. Zuardi, “Antianxiety effect of cannabidiol in the elevated plus-maze,” Psychopharmacology, vol. 100, no. 4, pp. 558–559, 1990. View at Publisher · View at Google Scholar
  45. F. S. Guimarães, J. C. de Aguiar, R. Mechoulam, and A. Breuer, “Anxiolytic effect of cannabidiol derivatives in the elevated plus-maze,” General Pharmacology, vol. 25, no. 1, pp. 161–164, 1994. View at Publisher · View at Google Scholar
  46. F. A. Moreira, D. C. Aguiar, and F. S. Guimarães, “Anxiolytic-like effect of cannabidiol in the rat Vogel conflict test,” Progress in Neuro-Psychopharmacology and Biological Psychiatry, vol. 30, no. 8, pp. 1466–1471, 2006. View at Publisher · View at Google Scholar · View at PubMed
  47. L. B. Resstel, S. R. L. Joca, F. A. Moreira, F. M. A. Corrêaa, and F. S. Guimarães, “Effects of cannabidiol and diazepam on behavioural and cardiovascular responses induced by contextual conditioned fear in rats,” Behavioural Brain Research, vol. 172, no. 2, pp. 294–298, 2006. View at Publisher · View at Google Scholar · View at PubMed
  48. D. Giuliani, F. Ferrari, and A. Ottani, “The cannabinoid agonist HU 210 modifies rat behavioural responses to novelty and stress,” Pharmacological Research, vol. 41, no. 1, pp. 45–51, 2000. View at Publisher · View at Google Scholar
  49. W. Jiang, Y. Zhang, L. Xiao, et al., “Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects,” The Journal of Clinical Investigation, vol. 115, no. 11, pp. 3104–3116, 2005. View at Publisher · View at Google Scholar · View at PubMed
  50. M. N. Hill and B. B. Gorzalka, “Enhancement of anxiety-like responsiveness to the cannabinoid CB1 receptor agonist HU-210 following chronic stress,” European Journal of Pharmacology, vol. 499, no. 3, pp. 291–295, 2004. View at Publisher · View at Google Scholar · View at PubMed
  51. J. Haller, B. Varga, C. Ledent, and T. F. Freund, “CB1 cannabinoid receptors mediate anxiolytic effects: convergent genetic and pharmacological evidence with CB1-specific agents,” Behavioural Pharmacology, vol. 15, no. 4, pp. 299–304, 2004. View at Publisher · View at Google Scholar
  52. J. Haller, F. Mátyás, K. Soproni, et al., “Correlated species differences in the effects of cannabinoid ligands on anxiety and on GABAergic and glutamatergic synaptic transmission,” European Journal of Neuroscience, vol. 25, no. 8, pp. 2445–2456, 2007. View at Publisher · View at Google Scholar · View at PubMed
  53. C. Arévalo, R. de Miguel, and R. Hernández-Tristán, “Cannabinoid effects on anxiety-related behaviours and hypothalamic neurotransmitters,” Pharmacology Biochemistry and Behavior, vol. 70, no. 1, pp. 123–131, 2001. View at Publisher · View at Google Scholar
  54. S. Marín, E. Marco, M. Biscaia, et al., “Involvement of the κ-opioid receptor in the anxiogenic-like effect of CP 55,940 in male rats,” Pharmacology Biochemistry and Behavior, vol. 74, no. 3, pp. 649–656, 2003. View at Publisher · View at Google Scholar
  55. E. M. Marco, L. Pérez-Alvarez, E. Borcel, et al., “Involvement of 5-HT1A receptors in behavioural effects of the cannabinoid receptor agonist CP 55,940 in male rats,” Behavioural Pharmacology, vol. 15, no. 1, pp. 21–27, 2004. View at Publisher · View at Google Scholar
  56. R. F. Genn, S. Tucci, E. Marco, M.-P. Viveros, and S. E. File, “Anxiolytic and anxiogenic effects of the cannabinoid agonist CP 55,940 in animal tests of anxiety,” Journal of Psychopharmacology, vol. 17, p. A27, 2003.
  57. R. F. Genn, S. Tucci, E. M. Marco, M. P. Viveros, and S. E. File, “Unconditioned and conditioned anxiogenic effects of the cannabinoid receptor agonist CP 55,940 in the social interaction test,” Pharmacology Biochemistry and Behavior, vol. 77, no. 3, pp. 567–573, 2004. View at Publisher · View at Google Scholar · View at PubMed
  58. A. Chakrabarti, J. E. Ekuta, and E. S. Onaivi, “Neurobehavioral effects of anandamide and cannabinoid receptor gene expression in mice,” Brain Research Bulletin, vol. 45, no. 1, pp. 67–74, 1998. View at Publisher · View at Google Scholar
  59. M. Scherma, J. Medalie, W. Fratta, et al., “The endogenous cannabinoid anandamide has effects on motivation and anxiety that are revealed by fatty acid amide hydrolase (FAAH) inhibition,” Neuropharmacology, vol. 54, no. 1, pp. 129–140, 2008. View at Publisher · View at Google Scholar · View at PubMed
  60. M. Bortolato, P. Campolongo, R. A. Mangieri, et al., “Anxiolytic-like properties of the anandamide transport inhibitor AM404,” Neuropsychopharmacology, vol. 31, no. 12, pp. 2652–2659, 2006. View at Publisher · View at Google Scholar · View at PubMed
  61. S. Kathuria, S. Gaetani, D. Fegley, et al., “Modulation of anxiety through blockade of anandamide hydrolysis,” Nature Medicine, vol. 9, no. 1, pp. 76–81, 2003. View at Publisher · View at Google Scholar · View at PubMed
  62. P. S. Naidu, S. A. Varvel, K. Ahn, B. F. Cravatt, B. R. Martin, and A. H. Lichtman, “Evaluation of fatty acid amide hydrolase inhibition in murine models of emotionality,” Psychopharmacology, vol. 192, no. 1, pp. 61–70, 2007. View at Publisher · View at Google Scholar · View at PubMed
  63. F. A. Moreira, N. Kaiser, K. Monory, and B. Lutz, “Reduced anxiety-like behaviour induced by genetic and pharmacological inhibition of the endocannabinoid-degrading enzyme fatty acid amide hydrolase (FAAH) is mediated by CB1 receptors,” Neuropharmacology, vol. 54, no. 1, pp. 141–150, 2008. View at Publisher · View at Google Scholar · View at PubMed
  64. M. Rutkowska, J. Jamontt, and H. Gliniak, “Effects of cannabinoids on the anxiety-like response in mice,” Pharmacological Reports, vol. 58, no. 2, pp. 200–206, 2006.
  65. M. Navarro, E. Hernández, R. M. Muñoz, et al., “Acute administration of the CB1 cannabinoid receptor antagonist SR 141716A induces anxiety-like responses in the rat,” NeuroReport, vol. 8, no. 2, pp. 491–496, 1997. View at Publisher · View at Google Scholar
  66. J. Haller, N. Bakos, M. Szirmay, C. Ledent, and T. F. Freund, “The effects of genetic and pharmacological blockade of the CB1 cannabinoid receptor on anxiety,” European Journal of Neuroscience, vol. 16, no. 7, pp. 1395–1398, 2002. View at Publisher · View at Google Scholar
  67. G. Griebel, J. Stemmelin, and B. Scatton, “Effects of the cannabinoid CB1 receptor antagonist rimonabant in models of emotional reactivity in rodents,” Biological Psychiatry, vol. 57, no. 3, pp. 261–267, 2005. View at Publisher · View at Google Scholar · View at PubMed
  68. R. J. Rodgers, P. M. Evans, and A. Murphy, “Anxiogenic profile of AM-251, a selective cannabinoid CB1 receptor antagonist, in plus-maze-naïve and plus-maze-experienced mice,” Behavioural Pharmacology, vol. 16, no. 5-6, pp. 405–413, 2005. View at Publisher · View at Google Scholar
  69. J. W. Kasckow, J. J. Mulchahey, and T. D. Geracioti, Jr., “Effects of the vanilloid agonist olvanil and antagonist capsazepine on rat behaviours,” Progress in Neuropsychopharmacology and Biological Psychiatry, vol. 28, no. 2, pp. 291–295, 2004. View at Publisher · View at Google Scholar · View at PubMed
  70. D. P. Finn, M. D. Jhaveri, S. R. G. Beckett, D. A. Kendall, C. A. Marsden, and V. Chapman, “Cannabinoids modulate ultrasound-induced aversive responses in rats,” Psychopharmacology, vol. 172, no. 1, pp. 41–51, 2004. View at Publisher · View at Google Scholar · View at PubMed
  71. F. A. Moreira, D. C. Aguiar, and F. S. Guimarães, “Anxiolytic-like effect of cannabinoids injected into the rat dorsolateral periaqueductal gray,” Neuropharmacology, vol. 52, no. 3, pp. 958–965, 2007. View at Publisher · View at Google Scholar · View at PubMed
  72. S. Pellow and S. E. File, “Anxiolytic and anxiogenic drug effects on exploratory activity in an elevated plus-maze: a novel test of anxiety in the rat,” Pharmacology Biochemistry and Behavior, vol. 24, no. 3, pp. 525–529, 1986. View at Publisher · View at Google Scholar
  73. S. F. Lisboa, L. B. Resstel, D. C. Aguiar, and F. S. Guimarães, “Activation of cannabinoid CB1 receptors in the dorsolateral periaqueductal gray induces anxiolytic effects in rats submitted to the Vogel conflict test,” European Journal of Pharmacology, vol. 593, no. 1–3, pp. 73–78, 2008. View at Publisher · View at Google Scholar · View at PubMed
  74. J. R. Vogel, B. Beer, and D. E. Clody, “A simple and reliable conflict procedure for testing anti-anxiety agents,” Psychopharmacologia, vol. 21, no. 1, pp. 1–7, 1971. View at Publisher · View at Google Scholar
  75. M. J. Millan, “The neurobiology and control of anxious states,” Progress in Neurobiology, vol. 70, no. 2, pp. 83–244, 2003. View at Publisher · View at Google Scholar
  76. M.-P. Viveros, E.-M. Marco, R. Llorente, and M. López-Gallardo, “Endocannabinoid system and synaptic plasticity: implications for emotional responses,” Neural Plasticity, vol. 2007, Article ID 52908, 12 pages, 2007. View at Publisher · View at Google Scholar · View at PubMed
  77. A. G. Hohmann, R. L. Suplita, N. M. Bolton, et al., “An endocannabinoid mechanism for stress-induced analgesia,” Nature, vol. 435, no. 7045, pp. 1108–1112, 2005. View at Publisher · View at Google Scholar · View at PubMed
  78. L. B. Resstel, S. F. Lisboa, D. C. Aguiar, F. M. A. Corrêa, and F. S. Guimarães, “Activation of CB1 cannabinoid receptors in the dorsolateral periaqueductal gray reduces the expression of contextual fear conditioning in rats,” Psychopharmacology, vol. 198, no. 3, pp. 405–411, 2008. View at Publisher · View at Google Scholar · View at PubMed
  79. M. S. Fanselow, “Conditional and unconditional components of post-shock freezing,” The Pavlovian Journal of Biological Science, vol. 15, no. 4, pp. 177–182, 1980.
  80. L. B. Resstel, S. R. Joca, F. G. Guimarães, and F. M. A. Corrêa, “Involvement of medial prefrontal cortex neurons in behavioural and cardiovascular responses to contextual fear conditioning,” Neuroscience, vol. 143, no. 2, pp. 377–385, 2006. View at Publisher · View at Google Scholar · View at PubMed
  81. P. Carrive, J. Lee, and A. Su, “Lidocaine blockade of amygdala output in fear-conditioned rats reduces Fos expression in the ventrolateral periaqueductal gray,” Neuroscience, vol. 95, no. 4, pp. 1071–1080, 1999. View at Publisher · View at Google Scholar
  82. P. Carrive, P. Leung, J. Harris, and G. Paxinos, “Conditioned fear to context is associated with increased Fos expression in the caudal ventrolateral region of the midbrain periaqueductal gray,” Neuroscience, vol. 78, no. 1, pp. 165–177, 1997. View at Publisher · View at Google Scholar
  83. P. Amorapanth, K. Nader, and J. E. LeDoux, “Lesions of periaqueductal gray dissociate-conditioned freezing from conditioned suppression behaviour in rats,” Learning & Memory, vol. 6, no. 5, pp. 491–499, 1999. View at Publisher · View at Google Scholar
  84. J. E. LeDoux, J. Iwata, P. Cicchetti, and D. J. Reis, “Different projections of the central amygdaloid nucleus mediate autonomic and behavioural correlates of conditioned fear,” The Journal of Neuroscience, vol. 8, no. 7, pp. 2517–2529, 1988.
  85. C. W. Vaughan, M. Connor, E. E. Bagley, and M. J. Christie, “Actions of cannabinoids on membrane properties and synaptic transmission in rat periaqueductal gray neurons in vitro,” Molecular Pharmacology, vol. 57, no. 2, pp. 288–295, 2000.
  86. A. C. Campos and F. S. Guimarães, “Involvement of 5HT1A receptors in the anxiolytic-like effects of cannabidiol injected into the dorsolateral periaqueductal gray of rats,” Psychopharmacology, vol. 199, no. 2, pp. 223–230, 2008. View at Publisher · View at Google Scholar · View at PubMed
  87. A.L. Terzian, D.C. Aguiar, F.S. Guimarães, and F.A. Moreira, “Modulation of anxiety-like behaviour by Transient Receptor Potential Vanilloid Type 1 Channel (TRPV1) located in the dorsolateral periaqueductal gray,” European Neuropsychopharmacology. In press.
  88. N. S. Canteras, “The medial hypothalamic defensive system: hodological organization and functional implications,” Pharmacology Biochemistry and Behavior, vol. 71, no. 3, pp. 481–491, 2002. View at Publisher · View at Google Scholar
  89. F. A. Moreira and B. Lutz, “The endocannabinoid system: emotion, learning and addiction,” Addiction Biology, vol. 13, no. 2, pp. 196–212, 2008. View at Publisher · View at Google Scholar · View at PubMed
  90. A. W. Zuardi, I. Shirakawa, E. Finkelfarb, and I. G. Karniol, “Action of cannabidiol on the anxiety and other effects produced by Δ9-THC in normal subjects,” Psychopharmacology, vol. 76, no. 3, pp. 245–250, 1982. View at Publisher · View at Google Scholar
  91. A. W. Zuardi, J. A. S. Crippa, J. E. C. Hallak, F. A. Moreira, and F. S. Guimarães, “Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug,” Brazilian Journal of Medical and Biological Research, vol. 39, no. 4, pp. 421–429, 2006. View at Publisher · View at Google Scholar
  92. A. W. Zuardi, R. A. Cosme, F. G. Graeff, and F. S. Guimarães, “Effects of ipsapirone and cannabidiol on human experimental anxiety,” Journal of Psychopharmacology, vol. 7, no. 1, pp. 82–88, 1993.
  93. J. A. de Souza Crippa, A. W. Zuardi, G. E. J. Garrido, et al., “Effects of cannabidiol (CBD) on regional cerebral blood flow,” Neuropsychopharmacology, vol. 29, no. 2, pp. 417–426, 2004. View at Publisher · View at Google Scholar · View at PubMed
  94. T. Bisogno, L. Hanuš, L. De Petrocellis, et al., “Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide,” British Journal of Pharmacology, vol. 134, no. 4, pp. 845–852, 2001. View at Publisher · View at Google Scholar · View at PubMed
  95. E. B. Russo, A. Burnett, B. Hall, and K. K. Parker, “Agonistic properties of cannabidiol at 5-HT1a receptors,” Neurochemical Research, vol. 30, no. 8, pp. 1037–1043, 2005. View at Publisher · View at Google Scholar · View at PubMed
  96. L. Cristino, L. de Petrocellis, G. Pryce, D. Baker, V. Guglielmotti, and V. Di Marzo, “Immunohistochemical localization of cannabinoid type 1 and vanilloid transient receptor potential vanilloid type 1 receptors in the mouse brain,” Neuroscience, vol. 139, no. 4, pp. 1405–1415, 2006.
  97. R. L. Nogueira and F. G. Graeff, “Role of 5-HT receptor subtypes in the modulation of dorsal periaqueductal gray generated aversion,” Pharmacology Biochemistry and Behavior, vol. 52, no. 1, pp. 1–6, 1995. View at Publisher · View at Google Scholar
  98. J. R. Raymond, Y. V. Mukhin, T. W. Gettys, and M. N. Garnovskaya, “The recombinant 5-HT1A receptor: G protein coupling and signalling pathways,” British Journal of Pharmacology, vol. 127, no. 8, pp. 1751–1764, 1999. View at Publisher · View at Google Scholar · View at PubMed
  99. G. A. Carrasco and L. D. Van de Kar, “Neuroendocrine pharmacology of stress,” European Journal of Pharmacology, vol. 463, no. 1–3, pp. 235–272, 2003. View at Publisher · View at Google Scholar
  100. J. M. Zanoveli, R. L. Nogueira, and H. Zangrossi, Jr., “Serotonin in the dorsal periaqueductal gray modulates inhibitory avoidance and one-way escape behaviours in the elevated T-maze,” European Journal of Pharmacology, vol. 473, no. 2-3, pp. 153–161, 2003. View at Publisher · View at Google Scholar
  101. V. de Paula Soares and H. Zangrossi, Jr., “Involvement of 5-HT1A and 5-HT2 receptors of the dorsal periaqueductal gray in the regulation of the defensive behaviours generated by the elevated T-maze,” Brain Research Bulletin, vol. 64, no. 2, pp. 181–188, 2004. View at Publisher · View at Google Scholar · View at PubMed
  102. M. J. Caterina, M. A. Schumacher, M. Tominaga, T. A. Rosen, J. D. Levine, and D. Julius, “The capsaicin receptor: a heat-activated ion channel in the pain pathway,” Nature, vol. 389, no. 6653, pp. 816–824, 1997. View at Publisher · View at Google Scholar · View at PubMed
  103. A. Szallasi and P. M. Blumberg, “Vanilloid (Capsaicin) receptors and mechanisms,” Pharmacology Reviews, vol. 51, no. 2, pp. 159–212, 1999.
  104. M. van der Stelt and V. Di Marzo, “Endovanilloids: putative endogenous ligands of transient receptor potential vanilloid 1 channels,” European Journal of Biochemistry, vol. 271, no. 10, pp. 1827–1834, 2004. View at Publisher · View at Google Scholar · View at PubMed
  105. S. Marinelli, V. Di Marzo, F. Florenzano, et al., “N-arachidonoyl-dopamine tunes synaptic transmission onto dopaminergic neurons by activating both cannabinoid and vanilloid receptors,” Neuropsychopharmacology, vol. 32, no. 2, pp. 298–308, 2007. View at Publisher · View at Google Scholar · View at PubMed
  106. É. Mezey, Z. E. Tóth, D. N. Cortright, et al., “Distribution of mRNA for vanilloid receptor subtype 1 (VR1), and VR1-like immunoreactivity, in the central nervous system of the rat and human,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 7, pp. 3655–3660, 2000. View at Publisher · View at Google Scholar · View at PubMed
  107. S. McGaraughty, K. L. Chu, R. S. Bitner, et al., “Capsaicin infused into the PAG affects rat tail flick responses to noxious heat and alters neuronal firing in the RVM,” Journal of Neurophysiology, vol. 90, no. 4, pp. 2702–2710, 2003. View at Publisher · View at Google Scholar · View at PubMed
  108. E. Palazzo, V. de Novellis, I. Marabese, et al., “Interaction between vanilloid and glutamate receptors in the central modulation of nociception,” European Journal of Pharmacology, vol. 439, no. 1–3, pp. 69–75, 2002. View at Publisher · View at Google Scholar
  109. J. Xing and J. Li, “TRPV1 receptor mediates glutamatergic synaptic input to dorsolateral periaqueductal gray (dl-PAG) neurons,” Journal of Neurophysiology, vol. 97, no. 1, pp. 503–511, 2007. View at Publisher · View at Google Scholar · View at PubMed
  110. M. L. Molchanov and F. S. Guimarães, “Anxiolytic-like effects of AP7 injected into the dorsolateral or ventrolateral columns of the periaqueductal gray of rats,” Psychopharmacology, vol. 160, no. 1, pp. 30–38, 2002. View at Publisher · View at Google Scholar · View at PubMed
  111. R. Marsch, E. Foeller, G. Rammes, et al., “Reduced anxiety, conditioned fear, and hippocampal long-term potentiation in transient receptor potential vanilloid type 1 receptor-deficient mice,” The Journal of Neuroscience, vol. 27, no. 4, pp. 832–839, 2007. View at Publisher · View at Google Scholar · View at PubMed
  112. V. Micale, L. Cristino, A. Tamburella, et al., “Anxiolytic effects in mice of a dual blocker of fatty acid amide hydrolase and transient receptor potential vanilloid type-1 channels,” Neuropsychopharmacology. In press. View at Publisher · View at Google Scholar · View at PubMed
  113. T. Rubino, N. Realini, C. Castiglioni, et al., “Role in anxiety behavior of the endocannabinoid system in the prefrontal cortex,” Cerebral Cortex, vol. 18, no. 6, pp. 292–301, 2008. View at Publisher · View at Google Scholar · View at PubMed
  114. T. Rubino, C. Guidali, D. Vigano, et al., “CB1 receptor stimulation in specific brain areas differently modulate anxiety-related behaviour,” Neuropharmacology, vol. 54, no. 1, pp. 151–160, 2008. View at Publisher · View at Google Scholar · View at PubMed
  115. E. S. Onaivi, A. Chakrabarti, E. T. Gwebu, and G. Chaudhuri, “Neurobehavioral effects of Δ9-THC and cannabinoid (CB1) receptor gene expression in mice,” Behavioural Brain Research, vol. 72, no. 1-2, pp. 115–125, 1996. View at Publisher · View at Google Scholar