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Endocannabinoid signaling as a synaptic circuit breaker in neurological disease

Abstract

Cannabis sativa is one of the oldest herbal plants in the history of medicine. It was used in various therapeutic applications from pain to epilepsy, but its psychotropic effect has reduced its usage in recent medical practice. However, renewed interest has been fueled by major discoveries revealing that cannabis-derived compounds act through a signaling pathway in the human body. Here we review recent advances showing that endocannabinoid signaling is a key regulator of synaptic communication throughout the central nervous system. Its underlying molecular architecture is highly conserved in synapses from the spinal cord to the neocortex, and as a negative feed-back signal, it provides protection against excess presynaptic activity. The endocannabinoid signaling machinery operates on demand in a synapse-specific manner; therefore, its modulation offers new therapeutic opportunities for the selective control of deleterious neuronal activity in several neurological disorders.

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Figure 1: Activation of the perisynaptic signaling machinery (PSM) evokes retrograde endocannabinoid signaling.
Figure 2: Operation of the perisynaptic signaling machinery as a synaptic circuit breaker.
Figure 3: Molecular mechanism of endocannabinoid-mediated long-term depression.

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References

  1. Herkenham, M. et al. Cannabinoid receptor localization in brain. Proc. Natl. Acad. Sci. USA 87, 1932–1936 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Devane, W.A., Dysarz, F.A., III, Johnson, M.R., Melvin, L.S. & Howlett, A.C. Determination and characterization of a cannabinoid receptor in rat brain. Mol. Pharmacol. 34, 605–613 (1988).

    CAS  PubMed  Google Scholar 

  3. Matsuda, L.A., Lolait, S.J., Brownstein, M.J., Young, A.C. & Bonner, T.I. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346, 561–564 (1990).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  5. Zimmer, A., Zimmer, A.M., Hohmann, A.G., Herkenham, M. & Bonner, T.I. Increased mortality, hypoactivity and hypoalgesia in cannabinoid CB1 receptor knockout mice. Proc. Natl. Acad. Sci. USA 96, 5780–5785 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Ledent, C. et al. Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice. Science 283, 401–404 (1999).

    CAS  PubMed  Google Scholar 

  7. Monory, K. et al. Genetic dissection of behavioural and autonomic effects of Δ9-tetrahydrocannabinol in mice. PLoS Biol. 5, e269 (2007).

    PubMed  PubMed Central  Google Scholar 

  8. Huestis, M.A. et al. Blockade of effects of smoked marijuana by the CB1-selective cannabinoid receptor antagonist SR141716. Arch. Gen. Psychiatry 58, 322–328 (2001).

    CAS  PubMed  Google Scholar 

  9. Freund, T.F., Katona, I. & Piomelli, D. Role of endogenous cannabinoids in synaptic signaling. Physiol. Rev. 83, 1017–1066 (2003).

    CAS  PubMed  Google Scholar 

  10. Katona, I. et al. Presynaptically located CB1 cannabinoid receptors regulate GABA release from axon terminals of specific hippocampal interneurons. J. Neurosci. 19, 4544–4558 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Nyiri, G., Cserep, C., Szabadits, E., Mackie, K. & Freund, T.F. CB1 cannabinoid receptors are enriched in the perisynaptic annulus and on preterminal segments of hippocampal GABAergic axons. Neuroscience 136, 811–822 (2005).

    CAS  PubMed  Google Scholar 

  12. Lafourcade, M. et al. Molecular components and functions of the endocannabinoid system in mouse prefrontal cortex. PLoS ONE 2, e709 (2007).

    PubMed  PubMed Central  Google Scholar 

  13. Kawamura, Y. et al. The CB1 cannabinoid receptor is the major cannabinoid receptor at excitatory presynaptic sites in the hippocampus and cerebellum. J. Neurosci. 26, 2991–3001 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Katona, I. et al. Molecular composition of the endocannabinoid system at glutamatergic synapses. J. Neurosci. 26, 5628–5637 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Wittmann, G. et al. Distribution of type 1 cannabinoid receptor (CB1)-immunoreactive axons in the mouse hypothalamus. J. Comp. Neurol. 503, 270–279 (2007).

    CAS  PubMed  Google Scholar 

  16. Degroot, A. et al. CB1 receptor antagonism increases hippocampal acetylcholine release: site and mechanism of action. Mol. Pharmacol. 70, 1236–1245 (2006).

    CAS  PubMed  Google Scholar 

  17. Oropeza, V.C., Mackie, K. & Van Bockstaele, E.J. Cannabinoid receptors are localized to noradrenergic axon terminals in the rat frontal cortex. Brain Res. 1127, 36–44 (2007).

    CAS  PubMed  Google Scholar 

  18. Balazsa, T., Biro, J., Gullai, N., Ledent, C. & Sperlagh, B. CB1-cannabinoid receptors are involved in the modulation of non-synaptic [3H]serotonin release from the rat hippocampus. Neurochem. Int. 52, 95–102 (2008).

    CAS  PubMed  Google Scholar 

  19. Devane, W.A. et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258, 1946–1949 (1992).

    CAS  PubMed  Google Scholar 

  20. Mechoulam, R. et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem. Pharmacol. 50, 83–90 (1995).

    CAS  PubMed  Google Scholar 

  21. Sugiura, T. et al. 2-arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem. Biophys. Res. Commun. 215, 89–97 (1995).

    CAS  PubMed  Google Scholar 

  22. Piomelli, D., Astarita, G. & Rapaka, R. A neuroscientist's guide to lipidomics. Nat. Rev. Neurosci. 8, 743–754 (2007).

    CAS  PubMed  Google Scholar 

  23. Sugiura, T., Kishimoto, S., Oka, S. & Gokoh, M. Biochemistry, pharmacology and physiology of 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand. Prog. Lipid Res. 45, 405–446 (2006).

    CAS  PubMed  Google Scholar 

  24. Makara, J.K. et al. Selective inhibition of 2-AG hydrolysis enhances endocannabinoid signaling in hippocampus. Nat. Neurosci. 8, 1139–1141 (2005).

    CAS  PubMed  Google Scholar 

  25. Melis, M. et al. Prefrontal cortex stimulation induces 2-arachidonoyl-glycerol–mediated suppression of excitation in dopamine neurons. J. Neurosci. 24, 10707–10715 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Hashimotodani, Y., Ohno-Shosaku, T. & Kano, M. Presynaptic monoacylglycerol lipase activity determines basal endocannabinoid tone and terminates retrograde endocannabinoid signaling in the hippocampus. J. Neurosci. 27, 1211–1219 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Hashimotodani, Y., Ohno-Shosaku, T., Maejima, T., Fukami, K. & Kano, M. Pharmacological evidence for the involvement of diacylglycerol lipase in depolarization-induced endocanabinoid release. Neuropharmacology 54, 58–67 (2008).

    CAS  PubMed  Google Scholar 

  28. Kim, J. & Alger, B.E. Inhibition of cyclooxygenase-2 potentiates retrograde endocannabinoid effects in hippocampus. Nat. Neurosci. 7, 697–698 (2004).

    CAS  PubMed  Google Scholar 

  29. Palomaki, V.A., Lehtonen, M., Savinainen, J.R. & Laitinen, J.T. Visualization of 2-arachidonoylglycerol accumulation and cannabinoid CB1 receptor activity in rat brain cryosections by functional autoradiography. J. Neurochem. 101, 972–981 (2007).

    CAS  PubMed  Google Scholar 

  30. Bisogno, T. et al. Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain. J. Cell Biol. 163, 463–468 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. McPartland, J.M., Norris, R.W. & Kilpatrick, C.W. Coevolution between cannabinoid receptors and endocannabinoid ligands. Gene 397, 126–135 (2007).

    CAS  PubMed  Google Scholar 

  32. Dinh, T.P. et al. Brain monoglyceride lipase participating in endocannabinoid inactivation. Proc. Natl. Acad. Sci. USA 99, 10819–10824 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Gulyas, A.I. et al. Segregation of two endocannabinoid-hydrolyzing enzymes into pre- and postsynaptic compartments in the rat hippocampus, cerebellum and amygdala. Eur. J. Neurosci. 20, 441–458 (2004).

    CAS  PubMed  Google Scholar 

  34. Uchigashima, M. et al. Subcellular arrangement of molecules for 2-arachidonoyl-glycerol–mediated retrograde signaling and its physiological contribution to synaptic modulation in the striatum. J. Neurosci. 27, 3663–3676 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Matyas, F. et al. Identification of the sites of 2-arachidonoylglycerol synthesis and action imply retrograde endocannabinoid signaling at both GABAergic and glutamatergic synapses in the ventral tegmental area. Neuropharmacology 54, 95–107 (2008).

    CAS  PubMed  Google Scholar 

  36. Maccarrone, M. et al. Anandamide inhibits metabolism and physiological actions of 2-arachidonoylglycerol in the striatum. Nat. Neurosci. 11, 152–159 (2008).

    CAS  PubMed  Google Scholar 

  37. Pertwee, R.G. Pharmacological actions of cannabinoids. Handb. Exp. Pharmacol. 168, 1–51 (2005).

    CAS  Google Scholar 

  38. Stella, N., Schweitzer, P. & Piomelli, D. A second endogenous cannabinoid that modulates long-term potentiation. Nature 388, 773–778 (1997).

    CAS  PubMed  Google Scholar 

  39. Jung, K.M. et al. Stimulation of endocannabinoid formation in brain slice cultures through activation of group I metabotropic glutamate receptors. Mol. Pharmacol. 68, 1196–1202 (2005).

    CAS  PubMed  Google Scholar 

  40. Lujan, R., Nusser, Z., Roberts, J.D., Shigemoto, R. & Somogyi, P. Perisynaptic location of metabotropic glutamate receptors mGluR1 and mGluR5 on dendrites and dendritic spines in the rat hippocampus. Eur. J. Neurosci. 8, 1488–1500 (1996).

    CAS  PubMed  Google Scholar 

  41. Drew, G.M., Mitchell, V.A. & Vaughan, C.W. Glutamate spillover modulates GABAergic synaptic transmission in the rat midbrain periaqueductal grey via metabotropic glutamate receptors and endocannabinoid signaling. J. Neurosci. 28, 808–815 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Robbe, D., Kopf, M., Remaury, A., Bockaert, J. & Manzoni, O.J. Endogenous cannabinoids mediate long-term synaptic depression in the nucleus accumbens. Proc. Natl. Acad. Sci. USA 99, 8384–8388 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Maejima, T., Hashimoto, K., Yoshida, T., Aiba, A. & Kano, M. Presynaptic inhibition caused by retrograde signal from metabotropic glutamate to cannabinoid receptors. Neuron 31, 463–475 (2001).

    CAS  PubMed  Google Scholar 

  44. Azad, S.C. et al. Circuitry for associative plasticity in the amygdala involves endocannabinoid signaling. J. Neurosci. 24, 9953–9961 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Yoshida, T. et al. 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 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Brakeman, P.R. et al. Homer: a protein that selectively binds metabotropic glutamate receptors. Nature 386, 284–288 (1997).

    CAS  PubMed  Google Scholar 

  47. Jung, K.M. et al. A key role for diacylglycerol lipase-α in metabotropic glutamate receptor–dependent endocannabinoid mobilization. Mol. Pharmacol. 72, 612–621 (2007).

    CAS  PubMed  Google Scholar 

  48. Kammermeier, P.J. & Worley, P.F. Homer 1a uncouples metabotropic glutamate receptor 5 from postsynaptic effectors. Proc. Natl. Acad. Sci. USA 104, 6055–6060 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Straiker, A. & Mackie, K. Metabotropic suppression of excitation in murine autaptic hippocampal neurons. J. Physiol. (Lond.) 578, 773–785 (2007).

    CAS  Google Scholar 

  50. Blankman, J.L., Simon, G.M. & Cravatt, B.F. A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol. Chem. Biol. 14, 1347–1356 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Ohno-Shosaku, T., Maejima, T. & Kano, M. Endogenous cannabinoids mediate retrograde signals from depolarized postsynaptic neurons to presynaptic terminals. Neuron 29, 729–738 (2001).

    CAS  PubMed  Google Scholar 

  52. Straiker, A. & Mackie, K. Depolarization-induced suppression of excitation in murine autaptic hippocampal neurones. J. Physiol. (Lond.) 569, 501–517 (2005).

    CAS  Google Scholar 

  53. Chevaleyre, V., Takahashi, K.A. & Castillo, P.E. Endocannabinoid-mediated synaptic plasticity in the CNS. Annu. Rev. Neurosci. 29, 37–76 (2006).

    CAS  PubMed  Google Scholar 

  54. Wilson, R.I., Kunos, G. & Nicoll, R.A. Presynaptic specificity of endocannabinoid signaling in the hippocampus. Neuron 31, 453–462 (2001).

    CAS  PubMed  Google Scholar 

  55. Brown, S.P., Safo, P.K. & Regehr, W.G. Endocannabinoids inhibit transmission at granule cell to Purkinje cell synapses by modulating three types of presynaptic calcium channels. J. Neurosci. 24, 5623–5631 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Chevaleyre, V., Heifets, B.D., Kaeser, P.S., Sudhof, T.C. & Castillo, P.E. Endocannabinoid-mediated long-term plasticity requires cAMP/PKA signaling and RIM1α. Neuron 54, 801–812 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Mato, S., Lafourcade, M., Robbe, D., Bakiri, Y. & Manzoni, O.J. Role of the cyclic-AMP/PKA cascade and of P/Q-type Ca++ channels in endocannabinoid-mediated long-term depression in the nucleus accumbens. Neuropharmacology 54, 87–94 (2008).

    CAS  PubMed  Google Scholar 

  58. Chevaleyre, V. & Castillo, P.E. Heterosynaptic LTD of hippocampal GABAergic synapses: a novel role of endocannabinoids in regulating excitability. Neuron 38, 461–472 (2003).

    CAS  PubMed  Google Scholar 

  59. Sjostrom, P.J., Turrigiano, G.G. & Nelson, S.B. Neocortical LTD via coincident activation of presynaptic NMDA and cannabinoid receptors. Neuron 39, 641–654 (2003).

    PubMed  Google Scholar 

  60. Heifets, B.D., Chevaleyre, V. & Castillo, P.E. Interneuron activity controls endocannabinoid-mediated presynaptic plasticity through calcineurin. Proc. Natl. Acad. Sci. USA 105, 10250–10255 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  62. Panikashvili, D. et al. An endogenous cannabinoid (2-AG) is neuroprotective after brain injury. Nature 413, 527–531 (2001).

    CAS  PubMed  Google Scholar 

  63. Wettschureck, N. et al. Forebrain-specific inactivation of Gq/G11 family G proteins results in age-dependent epilepsy and impaired endocannabinoid formation. Mol. Cell. Biol. 26, 5888–5894 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Nagayama, T. et al. Cannabinoids and neuroprotection in global and focal cerebral ischemia and in neuronal cultures. J. Neurosci. 19, 2987–2995 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Wallace, M.J., Martin, B.R. & DeLorenzo, R.J. Evidence for a physiological role of endocannabinoids in the modulation of seizure threshold and severity. Eur. J. Pharmacol. 452, 295–301 (2002).

    CAS  PubMed  Google Scholar 

  66. Wallace, M.J., Blair, R.E., Falenski, K.W., Martin, B.R. & DeLorenzo, R.J. The endogenous cannabinoid system regulates seizure frequency and duration in a model of temporal lobe epilepsy. J. Pharmacol. Exp. Ther. 307, 129–137 (2003).

    CAS  PubMed  Google Scholar 

  67. Marsicano, G. et al. CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science 302, 84–88 (2003).

    CAS  PubMed  Google Scholar 

  68. Monory, K. et al. The endocannabinoid system controls key epileptogenic circuits in the hippocampus. Neuron 51, 455–466 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Ludanyi, A. et al. Downregulation of the CB1 cannabinoid receptor and related molecular elements of the endocannabinoid system in epileptic human hippocampus. J. Neurosci. 28, 2976–2990 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Kirschstein, T. et al. Loss of metabotropic glutamate receptor–dependent long-term depression via downregulation of mGluR5 after status epilepticus. J. Neurosci. 27, 7696–7704 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Kim, D. et al. Phospholipase C isozymes selectively couple to specific neurotransmitter receptors. Nature 389, 290–293 (1997).

    CAS  PubMed  Google Scholar 

  72. Baker, D. et al. Cannabinoids control spasticity and tremor in a multiple sclerosis model. Nature 404, 84–87 (2000).

    CAS  PubMed  Google Scholar 

  73. Maresz, K. et al. Direct suppression of CNS autoimmune inflammation via the cannabinoid receptor CB1 on neurons and CB2 on autoreactive T cells. Nat. Med. 13, 492–497 (2007).

    CAS  PubMed  Google Scholar 

  74. Witting, A., Walter, L., Wacker, J., Moller, T. & Stella, N. P2X7 receptors control 2-arachidonoylglycerol production by microglial cells. Proc. Natl. Acad. Sci. USA 101, 3214–3219 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Witting, A. et al. Experimental autoimmune encephalomyelitis disrupts endocannabinoid-mediated neuroprotection. Proc. Natl. Acad. Sci. USA 103, 6362–6367 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Gerdeman, G.L., Ronesi, J. & Lovinger, D.M. Postsynaptic endocannabinoid release is critical to long-term depression in the striatum. Nat. Neurosci. 5, 446–451 (2002).

    CAS  PubMed  Google Scholar 

  77. Kreitzer, A.C. & Malenka, R.C. Endocannabinoid-mediated rescue of striatal LTD and motor deficits in Parkinson's disease models. Nature 445, 643–647 (2007).

    CAS  PubMed  Google Scholar 

  78. Maldonado, R., Valverde, O. & Berrendero, F. Involvement of the endocannabinoid system in drug addiction. Trends Neurosci. 29, 225–232 (2006).

    CAS  PubMed  Google Scholar 

  79. Baik, J.H. et al. Parkinsonian-like locomotor impairment in mice lacking dopamine D2 receptors. Nature 377, 424–428 (1995).

    CAS  PubMed  Google Scholar 

  80. Yin, H.H. & Lovinger, D.M. Frequency-specific and D2 receptor-mediated inhibition of glutamate release by retrograde endocannabinoid signaling. Proc. Natl. Acad. Sci. USA 103, 8251–8256 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Mato, S. et al. A single in-vivo exposure to Δ9-THC blocks endocannabinoid-mediated synaptic plasticity. Nat. Neurosci. 7, 585–586 (2004).

    CAS  PubMed  Google Scholar 

  82. Fourgeaud, L. et al. A single in vivo exposure to cocaine abolishes endocannabinoid-mediated long-term depression in the nucleus accumbens. J. Neurosci. 24, 6939–6945 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Pan, B., Hillard, C.J. & Liu, Q.S. Endocannabinoid signaling mediates cocaine-induced inhibitory synaptic plasticity in midbrain dopamine neurons. J. Neurosci. 28, 1385–1397 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Jo, Y.H., Chen, Y.J., Chua, S.C., Jr, Talmage, D.A. & Role, L.W. Integration of endocannabinoid and leptin signaling in an appetite-related neural circuit. Neuron 48, 1055–1066 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Di Marzo, V. et al. Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature 410, 822–825 (2001).

    CAS  PubMed  Google Scholar 

  86. Di, S., Malcher-Lopes, R., Halmos, K.C. & Tasker, J.G. Nongenomic glucocorticoid inhibition via endocannabinoid release in the hypothalamus: a fast feedback mechanism. J. Neurosci. 23, 4850–4857 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Hohmann, A.G. et al. An endocannabinoid mechanism for stress-induced analgesia. Nature 435, 1108–1112 (2005).

    CAS  PubMed  Google Scholar 

  88. Agarwal, N. et al. Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors in nociceptors. Nat. Neurosci. 10, 870–879 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Guindon, J. & Hohmann, A.G. Cannabinoid CB2 receptors: a therapeutic target for the treatment of inflammatory and neuropathic pain. Br. J. Pharmacol. 153, 319–334 (2008).

    CAS  PubMed  Google Scholar 

  90. Van Gaal, L., Pi-Sunyer, X., Despres, J.P., McCarthy, C. & Scheen, A. Efficacy and safety of rimonabant for improvement of multiple cardiometabolic risk factors in overweight/obese patients: pooled 1-year data from the rimonabant in obesity (RIO) program. Diabetes Care 31, S229–S240 (2008).

    CAS  PubMed  Google Scholar 

  91. Best, A.R. & Regehr, W.G. Serotonin evokes endocannabinoid release and retrogradely suppresses excitatory synapses. J. Neurosci. 28, 6508–6515 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Saario, S.M., Savinainen, J.R., Laitinen, J.T., Jarvinen, T. & Niemi, R. Monoglyceride lipase–like enzymatic activity is responsible for hydrolysis of 2-arachidonoylglycerol in rat cerebellar membranes. Biochem. Pharmacol. 67, 1381–1387 (2004).

    CAS  PubMed  Google Scholar 

  93. Nomura, D.K. et al. Activation of the endocannabinoid system by organophosphorus nerve agents. Nat. Chem. Biol. 4, 373–378 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Comelli, F., Giagnoni, G., Bettoni, I., Colleoni, M. & Costa, B. The inhibition of monoacylglycerol lipase by URB602 showed an anti-inflammatory and anti-nociceptive effect in a murine model of acute inflammation. Br. J. Pharmacol. 152, 787–794 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Gobbi, G. et al. Antidepressant-like activity and modulation of brain monoaminergic transmission by blockade of anandamide hydrolysis. Proc. Natl. Acad. Sci. USA 102, 18620–18625 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Kathuria, S. et al. Modulation of anxiety through blockade of anandamide hydrolysis. Nat. Med. 9, 76–81 (2003).

    CAS  PubMed  Google Scholar 

  97. Jayamanne, A. et al. Actions of the FAAH inhibitor URB597 in neuropathic and inflammatory chronic pain models. Br. J. Pharmacol. 147, 281–288 (2006).

    CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the Howard Hughes Medical Institute, the Egészségügyi Tudományos Tanács 561/2006, the János Bolyai scholarship (I.K.) and the US National Institutes of Health DA009158 and European Union Contract LSHM-CT-2004-005166. We are very grateful to N. Hájos, K. Mackie, D. Piomelli and M. Watanabe for their long-term collaborative support of our work on the endocannabinoid system and to I. Mody and N. Hájos for their comments on the manuscript. We are also indebted to B. Baksa, G. Nyiri and B. Dudok for their help with the preparation of figures.

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Correspondence to István Katona or Tamás F Freund.

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Katona, I., Freund, T. Endocannabinoid signaling as a synaptic circuit breaker in neurological disease. Nat Med 14, 923–930 (2008). https://doi.org/10.1038/nm.f.1869

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