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New Insights into the Endocannabinoid System by Using Cannabinoid Receptor Knockout Mice

  • Chapter
The Cannabinoid Receptors

Part of the book series: The Receptors ((REC))

Abstract

Considering the profound effects of cannabinoids on the brain, it is perhaps not surprising that much of the efforts in the endocannabinoid field have been devoted to the elucidation of the function of the neuronal CB1 cannabinoid receptor and its ligands. Recent findings, however, have revealed some unexpected new roles of cannabinoid receptors in non-neuronal tissues such as the liver and bone and, consequently, the whole field has experienced a dramatic expansion. This chapter will to a large extend focus on these latest results obtained using cannabinoid receptor knockout mice.

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References

  1. Ledent C, Valverde O, Cossu G, et al. Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice. Science. ;283:401–4.

    Google Scholar 

  2. Zimmer A, Zimmer AM, Hohmann AG, Herkenham M, Bonner TI. Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice. Proc Natl Acad Sci USA. 1999;96:5780–5.

    Article  CAS  PubMed  Google Scholar 

  3. Robbe D, Kopf M, Remaury A, Bockaert J, Manzoni OJ. Endogenous cannabinoids mediate long-term synaptic depression in the nucleus accumbens. Proc Natl Acad Sci USA. 2002;99:8384–8.

    Article  CAS  PubMed  Google Scholar 

  4. Marsicano G, Wotjak CT, Azad SC, et al. The endogenous cannabinoid system controls extinction of aversive memories. Nature. 2002;418:530–4.

    Article  CAS  PubMed  Google Scholar 

  5. Sauer B. Inducible gene targeting in mice using the Cre/lox system. Methods. 1998;14(4):381–92.

    Article  CAS  PubMed  Google Scholar 

  6. Buckley NE, McCoy KL, Mezey E, et al. Immunomodulation by cannabinoids is absent in mice deficient for the cannabinoid CB(2) receptor. Eur J Pharmacol. 2000;396:141–9.

    Article  CAS  PubMed  Google Scholar 

  7. Kaplan BL, Ouyang Y, Rockwell CE, Rao GK, Kaminski NE. 2-Arachidonoyl-glycerol suppresses interferon-gamma production in phorbol ester/ionomycin-activated mouse splenocytes independent of CB1 or CB2. J Leukoc Biol. 2005;77:966–74.

    Article  CAS  PubMed  Google Scholar 

  8. Zygmunt PM, Andersson DA, Hogestatt ED. Delta-9-tetrahydrocannabinol and cannabinol activate capsaicin-sensitive sensory nerves via a CB1 and CB2 cannabinoid receptor-independent mechanism. J Neurosci. 2002;22:4720–7.

    CAS  PubMed  Google Scholar 

  9. Jarai Z, Wagner JA, Varga K, et al. Cannabinoid-induced mesenteric vasodilation through an endothelial site distinct from CB1 or CB2 receptors. Proc Natl Acad Sci USA. 1999;96:14136–41.

    Article  CAS  PubMed  Google Scholar 

  10. Marsicano G, Goodenough S, Monory K, et al. CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science. 2003;302:84–8.

    Article  CAS  PubMed  Google Scholar 

  11. Van Der Stelt M, Di Marzo V. Cannabinoid receptors and their role in neuroprotection. Neuromolecular Med. 2005;7:37–50.

    Article  PubMed  Google Scholar 

  12. Mechoulam R, Spatz M, Shohami E. Endocannabinoids and neuroprotection. Sci STKE. 2002;129:RE5.

    Google Scholar 

  13. Panikashvili D, Simeonidou C, Ben-Shabat S, et al. An endogenous cannabinoid (2-AG) is neuroprotective after brain injury. Nature. 2001;413:527–31.

    Article  CAS  PubMed  Google Scholar 

  14. Bilkei-Gorzo A, Racz I, Valverde O, et al. Early age-related cognitive impairment in mice lacking cannabinoid CB1 receptors. Proc Natl Acad Sci USA. 2005;102:15670–5.

    Article  CAS  PubMed  Google Scholar 

  15. Lichtman AH, Martin BR. Marijuana withdrawal syndrome in the animal model. J Clin Pharmacol. 2002;42:20S–7S.

    CAS  PubMed  Google Scholar 

  16. Maldonado R, Rodriguez De Fonseca F. Cannabinoid addiction: behavioral models and neural correlates. J Neurosci. 2002;22:3326–31.

    CAS  PubMed  Google Scholar 

  17. Martin TJ, Kim SA, Lyupina Y, Smith JE. Differential involvement of mu-opioid receptors in the rostral versus caudal nucleus accumbens in the reinforcing effects of heroin in rats: evidence from focal injections of beta-funaltrexamine. Psychopharmacology (Berl). 2002;161:152–9.

    Article  CAS  Google Scholar 

  18. Cossu G, Ledent C, Fattore L, et al. Cannabinoid CB1 receptor knockout mice fail to self-administer morphine but not other drugs of abuse. Behav Brain Res. 2001;118:61–5.

    Article  CAS  PubMed  Google Scholar 

  19. Mascia MS, Obinu MC, Ledent C, et al. Lack of morphine-induced dopamine release in the nucleus accumbens of cannabinoid CB(1) receptor knockout mice. Eur J Pharmacol. 1999;383:R1–2.

    Article  CAS  PubMed  Google Scholar 

  20. Lichtman AH, Sheikh SM, Loh HH, Martin BR. Opioid and cannabinoid modulation of precipitated withdrawal in delta-9-tetrahydrocannabinol and morphine-dependent mice. J Pharmacol Exp Ther. 2001;298:1007–14.

    CAS  PubMed  Google Scholar 

  21. Zimmer A, Valjent E, Konig M, et al. Absence of delta-9-tetrahydrocannabinol dysphoric effects in dynorphin-deficient mice. J Neurosci. 2001;21:9499–505.

    CAS  PubMed  Google Scholar 

  22. Ghozland S, Matthes HW, Simonin F, Filliol D, Kieffer BL, Maldonado R. Motivational effects of cannabinoids are mediated by mu-opioid and kappa-opioid receptors. J Neurosci. 2002;22:1146–54.

    CAS  PubMed  Google Scholar 

  23. Castane A, Robledo P, Matifas A, Kieffer BL, Maldonado R. Cannabinoid withdrawal syndrome is reduced in double mu and delta opioid receptor knockout mice. Eur J Neurosci. 2003;17:155–9.

    Article  PubMed  Google Scholar 

  24. Mechoulam R, Parker L. Cannabis and alcohol – a close friendship. Trends Pharmacol Sci. 2003;24:266–8.

    Article  CAS  PubMed  Google Scholar 

  25. Basavarajappa BS, Hungund BL. Neuromodulatory role of the endocannabinoid signaling system in alcoholism: an overview. Prostaglandins Leukot Essent Fatty Acids. 2002;66:287–99.

    Article  CAS  PubMed  Google Scholar 

  26. Arnone M, Maruani J, Chaperon F, et al. Selective inhibition of sucrose and ethanol intake by SR 141716, an antagonist of central cannabinoid (CB1) receptors. Psychopharmacology (Berl). 1997;132:104–6.

    Article  CAS  Google Scholar 

  27. Freedland CS, Sharpe AL, Samson HH, Porrino LJ. Effects of SR141716A on ethanol and sucrose self-administration. Alcohol Clin Exp Res. 2001;25:277–82.

    Article  CAS  PubMed  Google Scholar 

  28. Hungund BL, Szakall I, Adam A, Basavarajappa BS, Vadasz C. Cannabinoid CB1 receptor knockout mice exhibit markedly reduced voluntary alcohol consumption and lack alcohol-induced dopamine release in the nucleus accumbens. J Neurochem. 2003;84:698–704.

    Article  CAS  PubMed  Google Scholar 

  29. Wang L, Liu J, Harvey-White J, Zimmer A, Kunos G. Endocannabinoid signaling via cannabinoid receptor 1 is involved in ethanol preference and its age-dependent decline in mice. Proc Natl Acad Sci USA. 2003;100:1393–8.

    Article  CAS  PubMed  Google Scholar 

  30. Racz I, Bilkei-Gorzo A, Toth ZE, Michel K, Palkovits M, Zimmer A. A critical role for the cannabinoid CB1 receptors in alcohol dependence and stress-stimulated ethanol drinking. J Neurosci. 2003;23:2453–8.

    CAS  PubMed  Google Scholar 

  31. Schmidt LG, Samochowiec J, Finckh U, et al. Association of a CB1 cannabinoid receptor gene (CNR1) polymorphism with severe alcohol dependence. Drug Alcohol Depend. 2002;65:221–4.

    Article  CAS  PubMed  Google Scholar 

  32. Valjent E, Mitchell JM, Besson MJ, Caboche J, Maldonado R. Behavioural and biochemical evidence for interactions between delta-9-tetrahydrocannabinol and nicotine. Br J Pharmacol. 2002;135:564–78.

    Article  CAS  PubMed  Google Scholar 

  33. Castane A, Valjent E, Ledent C, Parmentier M, Maldonado R, Valverde O. Lack of CB1 cannabinoid receptors modifies nicotine behavioural responses, but not nicotine abstinence. Neuropharmacology. 2002;43:857–67.

    Article  CAS  PubMed  Google Scholar 

  34. Bloch E, Thysen B, Morrill GA, Gardner E, Fujimoto G. Effects of cannabinoids on reproduction and development. Vitam Horm. 1978;36:203–58.

    Article  CAS  PubMed  Google Scholar 

  35. Schuel H, Chang MC, Berkery D, Schuel R, Zimmerman AM, Zimmerman S. Cannabinoids inhibit fertilization in Sea Urchins by reducing the fertilizing capacity of sperm. Pharmacol Biochem Behav. 1991;40:609–15.

    Article  CAS  PubMed  Google Scholar 

  36. Chang MC, Berkery D, Schuel R, et al. Evidence for a cannabinoid receptor in Sea Urchin sperm and its role in blockade of the acrosome reaction. Mol Reprod Dev. 1993;36:507–16.

    Article  CAS  PubMed  Google Scholar 

  37. Fride E. The endocannabinoid-CB(1) receptor system in pre- and postnatal life. Eur J Pharmacol. 2004;500:289–97.

    Article  CAS  PubMed  Google Scholar 

  38. Wang H, Matsumoto H, Guo Y, Paria BC, Roberts RL, Dey SK. Differential G protein-coupled cannabinoid receptor signaling by anandamide directs blastocyst activation for implantation. Proc Natl Acad Sci USA. 2003;100:14914–9.

    Article  CAS  PubMed  Google Scholar 

  39. Paria BC, Deutsch DD, Dey SK. The uterus is a potential site for anandamide synthesis and hydrolysis: differential profiles of anandamide synthase and hydrolase activities in the mouse uterus during the periimplantation period. Mol Reprod Dev. 1996;45:183–92.

    Article  CAS  PubMed  Google Scholar 

  40. Paria BC, Das SK, Dey SK. The preimplantation mouse embryo is a target for cannabinoid ligand-receptor signaling. Proc Natl Acad Sci USA. 1995;92:9460–4.

    Article  CAS  PubMed  Google Scholar 

  41. Guo Y, Wang H, Okamoto Y, et al. N-Acylphosphatidylethanolamine-hydrolyzing phospholipase D is an important determinant of uterine anandamide levels during implantation. J Biol Chem. 2005;280:23429–32.

    Article  CAS  PubMed  Google Scholar 

  42. Wang H, Guo Y, Wang D, et al. Aberrant cannabinoid signaling impairs oviductal transport of embryos. Nat Med. 2004;10:1074–80.

    Article  CAS  PubMed  Google Scholar 

  43. Schmid PC, Paria BC, Krebsbach RJ, Schmid HH, Dey SK. Changes in anandamide levels in mouse uterus are associated with uterine receptivity for embryo implantation. Proc Natl Acad Sci USA. 1997;94:4188–92.

    Article  CAS  PubMed  Google Scholar 

  44. Wang H, Xie H, Dey SK. Endocannabinoid signaling directs periimplantation events. AAPS J. 2006;8:E425–32.

    PubMed  Google Scholar 

  45. Paria BC, Song H, Wang X, et al. Dysregulated cannabinoid signaling disrupts uterine receptivity for embryo implantation. J Biol Chem. 2001;276:20523–8.

    Article  CAS  PubMed  Google Scholar 

  46. Izzo AA, Fezza F, Capasso R, et al. Cannabinoid CB1-receptor mediated regulation of gastrointestinal motility in mice in a model of intestinal inflammation. Br J Pharmacol. 2001;134:563–70.

    Article  CAS  PubMed  Google Scholar 

  47. Izzo AA, Mascolo N, Capasso F. The gastrointestinal pharmacology of cannabinoids. Curr Opin Pharmacol. 2001;1:597–603.

    Article  CAS  PubMed  Google Scholar 

  48. Di Carlo G, Izzo AA. Cannabinoids for gastrointestinal diseases: potential therapeutic applications. Expert Opin Investig Drugs. 2003;12:39–49.

    Article  PubMed  Google Scholar 

  49. Pertwee RG. Cannabinoids and the gastrointestinal tract. Gut. 2001;48:859–67.

    Article  CAS  PubMed  Google Scholar 

  50. Mcvey DC, Schmid PC, Schmid HH, Vigna SR. Endocannabinoids induce ileitis in rats via the capsaicin receptor (VR1). J Pharmacol Exp Ther. 2003;304:713–22.

    Article  CAS  PubMed  Google Scholar 

  51. Massa F, Marsicano G, Hermann H, et al. The endogenous cannabinoid system protects against colonic inflammation. J Clin Invest. 2004;113:1202–9.

    CAS  PubMed  Google Scholar 

  52. Linden DR, Sharkey KA, Mawe GM. Enhanced excitability of myenteric AH neurones in the inflamed guinea-pig distal colon. J Physiol. 2003;547:589–601.

    Article  CAS  PubMed  Google Scholar 

  53. Batkai S, Jarai Z, Wagner JA, et al. Endocannabinoids acting at vascular CB1 receptors mediate the vasodilated state in advanced liver cirrhosis. Nat Med. 2001;7:827–32.

    Article  CAS  PubMed  Google Scholar 

  54. Julien B, Grenard P, Teixeira-Clerc F, et al. Antifibrogenic role of the cannabinoid receptor CB2 in the liver. Gastroenterology. 2005;128:742–55.

    Article  CAS  PubMed  Google Scholar 

  55. Knittel T, Kobold D, Saile B, et al. Rat liver myofibroblasts and hepatic stellate cells: different cell populations of the fibroblast lineage with fibrogenic potential. Gastroenterology. 1999;117:1205–21.

    Article  CAS  PubMed  Google Scholar 

  56. Cassiman D, Roskams T. Beauty is in the eye of the beholder: emerging concepts and pitfalls in hepatic stellate cell research. J Hepatol. 2002;37:527–35.

    Article  PubMed  Google Scholar 

  57. Prosser CC, Yen RD, Wu J. Molecular therapy for hepatic injury and fibrosis: where are we? World J Gastroenterol. 2006;12:509–15.

    CAS  PubMed  Google Scholar 

  58. Elsharkawy AM, Oakley F, Mann DA. The role and regulation of hepatic stellate cell apoptosis in reversal of liver fibrosis. Apoptosis. 2005;10:927–39.

    Article  CAS  PubMed  Google Scholar 

  59. Bataller R, Brenner DA. Liver fibrosis. J Clin Invest. 2005;115:209–18.

    CAS  PubMed  Google Scholar 

  60. Perez Tamayo R. Is cirrhosis of the liver experimentally produced by CCl4 and adequate model of human cirrhosis? Hepatology. 1983;3:112–20.

    Article  CAS  PubMed  Google Scholar 

  61. Siegmund SV, Uchinami H, Osawa Y, Brenner DA, Schwabe RF. Anandamide induces necrosis in primary hepatic stellate cells. Hepatology. 2005;41:1085–95.

    Article  CAS  PubMed  Google Scholar 

  62. Teixeira-Clerc F, Julien B, Grenard P, et al. CB1 Cannabinoid receptor antagonism: a new strategy for the treatment of liver fibrosis. Nat Med. 2006;12:671–6.

    Article  CAS  PubMed  Google Scholar 

  63. Hezode C, Roudot-Thoraval F, Nguyen S, et al. Daily cannabis smoking as a risk factor for progression of fibrosis in chronic Hepatitis C. Hepatology. 2005;42:63–71.

    Article  CAS  PubMed  Google Scholar 

  64. Libby P. Inflammation in atherosclerosis. Nature. 2002;420:868–74.

    Article  CAS  PubMed  Google Scholar 

  65. Steffens S, Veillard NR, Arnaud C, et al. Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice. Nature. 2005;434:782–6.

    Article  CAS  PubMed  Google Scholar 

  66. Breslow JL. Mouse models of atherosclerosis. Science. 1996;272:685–8.

    Article  CAS  PubMed  Google Scholar 

  67. Brenneisen R, Egli A, Elsohly MA, Henn V, Spiess Y. The effect of orally and rectally administered delta-9-tetrahydrocannabinol on spasticity: a pilot study with 2 patients. Int J Clin Pharmacol Ther. 1996;34:446–52.

    CAS  PubMed  Google Scholar 

  68. Chesher GB, Bird KD, Jackson DM, Perrignon A, Starmer GA. The effects of orally administered delta-9-tetrahydrocannabinol in man on mood and performance measures: a dose-response study. Pharmacol Biochem Behav. 1990;35:861–4.

    Article  CAS  PubMed  Google Scholar 

  69. Lichtman AH, Poklis JL, Poklis A, Wilson DM, Martin BR. The pharmacological activity of inhalation exposure to marijuana smoke in mice. Drug Alcohol Depend. 2001;63:107–16.

    Article  CAS  PubMed  Google Scholar 

  70. Varvel SA, Hamm RJ, Martin BR, Lichtman AH. Differential effects of delta-9-tetrahydrocannabinol on spatial reference and working memory in mice. Psychopharmacology (Berl). 2001;157:142–50.

    Article  CAS  Google Scholar 

  71. Moeller F, Nielsen LB. Aortic recruitment of blood lymphocytes is most pronounced in early stages of lesion formation in apolipoprotein-E-deficient mice. Atherosclerosis. 2003;168:49–56.

    Article  CAS  PubMed  Google Scholar 

  72. Song L, Leung C, Schindler C. Lymphocytes are important in early atherosclerosis. J Clin Invest. 2001;108:251–9.

    CAS  PubMed  Google Scholar 

  73. Takeda S, Elefteriou F, Levasseur R, et al. Leptin regulates bone formation via the sympathetic nervous system. Cell. 2002;111:305–17.

    Article  CAS  PubMed  Google Scholar 

  74. Elefteriou F, Ahn JD, Takeda S, et al. Leptin regulation of bone resorption by the sympathetic nervous system and CART. Nature. 2005;434:514–20.

    Article  CAS  PubMed  Google Scholar 

  75. Di Marzo V, Goparaju SK, Wang L, et al. Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature. 2001;410:822–5.

    Article  PubMed  Google Scholar 

  76. Ofek O, Karsak M, Leclerc N, et al. Peripheral cannabinoid receptor, CB2, regulates bone mass. Proc Natl Acad Sci USA. 2006;103:696–701.

    Article  CAS  PubMed  Google Scholar 

  77. Idris AI, Van ’T Hof RJ, Greig IR, et al. Regulation of bone mass, bone loss and osteoclast activity by cannabinoid receptors. Nat Med. 2005;11:774–9.

    Article  CAS  PubMed  Google Scholar 

  78. Tam J, Ofek O, Fride E, et al. Involvement of neuronal cannabinoid receptor CB1 in regulation of bone mass and bone remodeling. Mol Pharmacol. 2006;70:786–92.

    Article  CAS  PubMed  Google Scholar 

  79. Karsak M, Cohen-Solal M, Freudenberg J, et al. Cannabinoid receptor type 2 gene is associated with human osteoporosis. Hum Mol Genet. 2005;14:3389–96.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Institute of Molecular Psychiatry, Life & Brain Centre, University of Bonn, Sigmund-Freud-Strasse 25, D-53127 Bonn, Germany

    Meliha Karsak

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  1. Meliha Karsak
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  2. Itai Bab
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  3. Andreas Zimmer
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Correspondence to Meliha Karsak .

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  1. University of North Carolina, Greensboro, NC, USA

    Patricia H. Reggio

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Karsak, M., Bab, I., Zimmer, A. (2009). New Insights into the Endocannabinoid System by Using Cannabinoid Receptor Knockout Mice. In: Reggio, P.H. (eds) The Cannabinoid Receptors. The Receptors. Humana Press. https://doi.org/10.1007/978-1-59745-503-9_11

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