Advertisement

Molecular Neurobiology

, Volume 54, Issue 1, pp 768–778 | Cite as

Role of the Endocannabinoid System in the Pathophysiology of Schizophrenia

  • Marc Fakhoury
Article

Abstract

The endocannabinoid system (ECS) is a group of neuromodulatory lipids, enzymes, and receptors involved in numerous behavioral and physiological processes such as mood, memory, and appetite. Recently, longitudinal and postmortem studies have shown that the ECS might be involved in neuropsychiatric disorders like schizophrenia. However, despite the large amount of research, our knowledge of the ECS and its implication in this debilitating disorder is still largely limited. This review aims at providing a comprehensive overview of the current state of knowledge of the ECS in schizophrenia and presenting some potential antipsychotic compounds that modulate this system. Findings from animal and human studies, and their implications for pharmacotherapy, will be integrated and discussed in this paper. A closer look will be given at the roles of the cannabinoid receptors type 1 (CB1) and type 2 (CB2), as well as the endogenous ligand N-arachidonoylethanolamine (AEA) and 2-arachidonylglycerol (2-AG), in the development of psychotic and schizophrenia-like symptoms.

Keywords

Antipsychotics Cannabis Cannabinoid receptor Endocannabinoid Psychosis Schizophrenia 

Notes

Acknowledgments

The author acknowledges the financial support from the Natural Sciences and Engineering Research Council (NSERC) of Canada and would like to thank Dr. Giovanni Hernandez for providing critical reviews of early versions of the manuscript.

Compliance with Ethical Standards

For this type of study, formal consent is not required.

Conflict of Interest

The author declares that he has no competing interests.

References

  1. 1.
    Fervaha G, Zakzanis KK, Foussias G, Graff-Guerrero A, Agid O, Remington G (2014) Motivational deficits and cognitive test performance in schizophrenia. JAMA Psychiatry 71:1058–1065PubMedCrossRefGoogle Scholar
  2. 2.
    Karam CS, Ballon JS, Bivens NM, Freyberg Z, Girgis RR, Lizardi-Ortiz JE, Markx S, Lieberman JA et al (2010) Signaling pathways in schizophrenia: emerging targets and therapeutic strategies. Trends Pharmacol Sci 31:381–390PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Muguruza C, Lehtonen M, Aaltonen N, Morentin B, Meana JJ, Callado LF (2013) Quantification of endocannabinoids in postmortem brain of schizophrenic subjects. Schizophr Res 148:145–50PubMedCrossRefGoogle Scholar
  4. 4.
    Howes OD, Kapur S (2009) The dopamine hypothesis of schizophrenia: version III—the final common pathway. Schizophr Bull 35:549–562PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    van Rossum JM (1966) The significance of dopamine-receptor blockade for the mechanism of action of neuroleptic drugs. Arch Int Pharmacodyn Ther 160(2):492–4PubMedGoogle Scholar
  6. 6.
    Seeman P, Lee T (1975) Antipsychotic drugs: direct correlation between clinical potency and presynaptic action on dopamine neurons. Science 188:1217–9PubMedCrossRefGoogle Scholar
  7. 7.
    Seeman P (2002) Atypical antipsychotics: mechanism of action. Can J Psychiatry 47:27–38PubMedGoogle Scholar
  8. 8.
    Dold M, Samara MT, Li C, Tardy M, Leucht S (2015) Haloperidol versus first-generation antipsychotics for the treatment of schizophrenia and other psychotic disorders. Cochrane Database Syst Rev 1:CD009831PubMedGoogle Scholar
  9. 9.
    Ginovart N, Kapur S (2012) Role of dopamine D(2) receptors for antipsychotic activity. Handb Exp Pharmacol 212:27–52CrossRefGoogle Scholar
  10. 10.
    Crossley NA, Constante M, McGuire P, Power P (2010) Efficacy of atypical v. typical antipsychotics in the treatment of early psychosis: meta-analysis. Br J Psychiatry 196:434–439PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Leo RJ, Regno PD (2000) Atypical antipsychotic use in the treatment of psychosis in primary care. Prim Care Companion J Clin Psychiatry 2:194–204PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Higashi K, Medic G, Littlewood KJ, Diez T, Granström O, De Hert M (2013) Medication adherence in schizophrenia: factors influencing adherence and consequences of nonadherence, a systematic literature review. Ther Adv Psychopharmacol 3:200–218PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Morken G, Widen JH, Grawe RW (2008) Non-adherence to antipsychotic medication, relapse and rehospitalisation in recent-onset schizophrenia. BMC Psychiatry 8:32PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Kucerova J, Tabiova K, Drago F, Micale V (2014) Therapeutic potential of cannabinoids in schizophrenia. Recent Pat CNS Drug Discov 9:13–25PubMedCrossRefGoogle Scholar
  15. 15.
    Ulugöl (2014) The endocannabinoid system as a potential therapeutic target for pain modulation. Balkan Med J 31:115–20PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Bossong MG, van Hell HH, Jager G, Kahn RS, Ramsey NF, Jansma JM (2013) The endocannabinoid system and emotional processing: a pharmacological fMRI study with ∆9-tetrahydrocannabinol. Eur Neuropsychopharmacol 23:1687–1697PubMedCrossRefGoogle Scholar
  17. 17.
    Jager G, Witkamp RF (2014) The endocannabinoid system and appetite: relevance for food reward. Nutr Res Rev 27:172–185PubMedCrossRefGoogle Scholar
  18. 18.
    Silvestri C, Di Marzo V (2013) The endocannabinoid system in energy homeostasis and the etiopathology of metabolic disorders. Cell Metab 17:475–490PubMedCrossRefGoogle Scholar
  19. 19.
    Hill MN, Gorzalka BB (2009) The endocannabinoid system and the treatment of mood and anxiety disorders. CNS Neurol Disord Drug Targets 8:451–458PubMedCrossRefGoogle Scholar
  20. 20.
    Morena M, Campolongo P (2014) The endocannabinoid system: an emotional buffer in the modulation of memory function. Neurobiol Learn Mem 112:30–43PubMedCrossRefGoogle Scholar
  21. 21.
    Seillier A, Advani T, Cassano T, Hensler JG, Giuffrida A (2010) Inhibition of fatty-acid amide hydrolase and CB1 receptor antagonism differentially affect behavioural responses in normal and PCP-treated rats. Int J Neuropsychopharmacol 13:373–386PubMedCrossRefGoogle Scholar
  22. 22.
    Vigano D, Guidali C, Petrosino S, Realini N, Rubino T, Di Marzo V, Parolaro D (2009) Involvement of the endocannabinoid system in phencyclidine-induced cognitive deficits modelling schizophrenia. Int J Neuropsychopharmacol 12:599–614PubMedCrossRefGoogle Scholar
  23. 23.
    Ishiguro H, Horiuchi Y, Ishikawa M, Koga M, Imai K, Suzuki Y, Morikawa M, Inada T et al (2010) Brain cannabinoid CB2 receptor in schizophrenia. Biol Psychiatry 67:974–982PubMedCrossRefGoogle Scholar
  24. 24.
    Malone DT, Hill MN, Rubino T (2010) Adolescent cannabis use and psychosis: epidemiology and neurodevelopmental models. Br J Pharmacol 160:511–522PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Shrivastava A, Johnston M, Tsuang M (2011) Cannabis use and cognitive dysfunction. Indian J Psychiatry 53:187–191PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Hall W, Degenhardt L (2008) Cannabis use and the risk of developing a psychotic disorder. World Psychiatry 7:68–71PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Müller-Vahl KR, Emrich HM (2008) Cannabis and schizophrenia: towards a cannabinoid hypothesis of schizophrenia. Expert Rev Neurother 8:1037–1048PubMedCrossRefGoogle Scholar
  28. 28.
    Arseneault L, Cannon M, Poulton R, Murray R, Caspi A, Moffitt TE (2002) Cannabis use in adolescence and risk for adult psychosis: longitudinal prospective study. BMJ 325:1212–1213PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Pertwee RG (2008) The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol 153:199–215PubMedCrossRefGoogle Scholar
  30. 30.
    Zamberletti E, Beggiato S, Steardo L Jr, Prini P, Antonelli T, Ferraro L, Rubino T, Parolaro D (2014) Alterations of prefrontal cortex GABAergic transmission in the complex psychotic-like phenotype induced by adolescent delta-9-tetrahydrocannabinol exposure in rats. Neurobiol Dis 63:35–47PubMedCrossRefGoogle Scholar
  31. 31.
    Renard J, Krebs MO, Le Pen G, Jay TM (2014) Long-term consequences of adolescent cannabinoid exposure in adult psychopathology. Front Neurosci 8:361PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Fernandez-Espejo E, Viveros MP, Núñez L, Ellenbroek BA, Rodriguez de Fonseca F (2009) Role of cannabis and endocannabinoids in the genesis of schizophrenia. Psychopharmacol (Berl) 206:531–549CrossRefGoogle Scholar
  33. 33.
    D’Souza DC, Sewell RA, Ranganathan M (2009) Cannabis and psychosis/schizophrenia: human studies. Eur Arch Psychiatry Clin Neurosci 259:413–31PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Ames F (1958) A clinical and metabolic study of acute intoxication with Cannabis sativa and its role in the model psychoses. J Ment Sci 104:972–999PubMedGoogle Scholar
  35. 35.
    Andréasson S, Allebeck P, Engström A, Rydberg U (1987) Cannabis and schizophrenia. A longitudinal study of Swedish conscripts. Lancet 2:1483–1486PubMedCrossRefGoogle Scholar
  36. 36.
    Tien AY, Anthony JC (1990) Epidemiological analysis of alcohol and drug use as risk factors for psychotic experiences. J Nerv Ment Dis 178:473–480PubMedCrossRefGoogle Scholar
  37. 37.
    van Os J, Bak M, Hanssen M, Bijl RV, de Graaf R, Verdoux H (2002) Cannabis use and psychosis: a longitudinal population-based study. Am J Epidemiol 156:319–327PubMedCrossRefGoogle Scholar
  38. 38.
    Zammit S, Spurlock G, Williams H, Norton N, Williams N, O’Donovan MC, Owen MJ (2007) Genotype effects of CHRNA7, CNR1 and COMT in schizophrenia: interactions with tobacco and cannabis use. Br J Psychiatry 191:402–7PubMedCrossRefGoogle Scholar
  39. 39.
    Fergusson DM, Horwood LJ, Swain-Campbell NR (2003) Cannabis dependence and psychotic symptoms in young people. Psychol Med 33:15–21PubMedGoogle Scholar
  40. 40.
    Weiser M, Reichenberg A, Rabinowitz J, Kaplan Z, Caspi A, Yasvizky R, Mark M, Knobler HY et al (2003) Self-reported drug abuse in male adolescents with behavioral disturbances, and follow-up for future schizophrenia. Biol Psychiatry 54:655–660PubMedCrossRefGoogle Scholar
  41. 41.
    Stefanis NC, Delespaul P, Henquet C, Bakoula C, Stefanis CN, Van Os J (2004) Early adolescent cannabis exposure and positive and negative dimensions of psychosis. Addiction 99(10):1333–41PubMedCrossRefGoogle Scholar
  42. 42.
    Henquet C, Krabbendam L, Spauwen J, Kaplan C, Lieb R, Wittchen HU, van Os J (2005) Prospective cohort study of cannabis use, predisposition for psychosis, and psychotic symptoms in young people. BMJ 330:11PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Ferdinand RF, Sondeijker F, van der Ende J, Selten JP, Huizink A, Verhulst FC (2005) Cannabis use predicts future psychotic symptoms, and vice versa. Addiction 100(5):612–8PubMedCrossRefGoogle Scholar
  44. 44.
    Wiles NJ, Zammit S, Bebbington P, Singleton N, Meltzer H, Lewis G (2006) Self-reported psychotic symptoms in the general population: results from the longitudinal study of the British National Psychiatric Morbidity Survey. Br J Psychiatry 188:519–526PubMedCrossRefGoogle Scholar
  45. 45.
    Miettunen J, Törmänen S, Murray GK, Jones PB, Mäki P, Ebeling H, Moilanen I, Taanila A et al (2008) Association of cannabis use with prodromal symptoms of psychosis in adolescence. Br J Psychiatry 192:470–471PubMedCrossRefGoogle Scholar
  46. 46.
    Quickfall J, Crockford D (2006) Brain neuroimaging in cannabis use: a review. J Neuropsychiatry Clin Neurosci 18(3):318–32PubMedCrossRefGoogle Scholar
  47. 47.
    Rapp C, Bugra H, Riecher-Rössler A, Tamagni C, Borgwardt S (2012) Effects of cannabis use on human brain structure in psychosis: a systematic review combining in vivo structural neuroimaging and post mortem studies. Curr Pharm Des 18(32):5070–80PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Gaoni Y, Mechoulam R (1964) Isolation, structure and partial synthesis of an active constituent of hashish. J Am Chem Soc 86(8):1646–1647CrossRefGoogle Scholar
  49. 49.
    Devane WA, Dysarz FA 3rd, Johnson MR, Melvin LS, Howlett AC (1988) Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol 34:605–13PubMedGoogle Scholar
  50. 50.
    Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI (1990) Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346:561–564PubMedCrossRefGoogle Scholar
  51. 51.
    Schubart CD, Sommer IE, Fusar-Poli P, de Witte L, Kahn RS, Boks MP (2014) Cannabidiol as a potential treatment for psychosis. Eur Neuropsychopharmacol 24:51–64PubMedCrossRefGoogle Scholar
  52. 52.
    Dalton VS, Long LE, Weickert CS, Zavitsanou K (2011) Paranoid schizophrenia is characterized by increased CB1 receptor binding in the dorsolateral prefrontal cortex. Neuropsychopharmacology 36:1620–1630PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Chiu CQ, Puente N, Grandes P, Castillo PE (2010) Dopaminergic modulation of endocannabinoid-mediated plasticity at GABAergic synapses in the prefrontal cortex. J Neurosci 30(21):7236–48PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Eggan SM, Lewis DA (2007) Immunocytochemical distribution of the cannabinoid CB1 receptor in the primate neocortex: a regional and laminar analysis. Cereb Cortex 17:175–191PubMedCrossRefGoogle Scholar
  55. 55.
    Eggan SM, Stoyak SR, Verrico CD, Lewis DA (2010) Cannabinoid CB1 receptor immunoreactivity in the prefrontal cortex: comparison of schizophrenia and major depressive disorder. Neuropsychopharmacology 35:2060–2071PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Munro S, Thomas KL, Abu-Shaar M (1993) Molecular characterization of a peripheral receptor for cannabinoids. Nature 365(6441):61–5PubMedCrossRefGoogle Scholar
  57. 57.
    Brusco A, Tagliaferro P, Saez T, Onaivi ES (2008) Postsynaptic localization of CB2 cannabinoid receptors in the rat hippocampus. Synapse 62:944–949PubMedCrossRefGoogle Scholar
  58. 58.
    Roche M, Finn DP (2010) Brain CB2 receptors: implications for neuropsychiatric disorders. Pharm 3:2517–2553Google Scholar
  59. 59.
    Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, Gibson D, Mandelbaum A et al (1992) Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258:1946–1949PubMedCrossRefGoogle Scholar
  60. 60.
    Desfossés J, Stip E, Bentaleb LA, Potvin S (2010) Endocannabinoids and schizophrenia. Pharm 3:3101–3126Google Scholar
  61. 61.
    Trezza V, Damsteegt R, Manduca A, Petrosino S, Van Kerkhof LW, Pasterkamp RJ, Zhou Y, Campolongo P et al (2012) Endocannabinoids in amygdala and nucleus accumbens mediate social play reward in adolescent rats. J Neurosci 32:14899–14908PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Morena M, Roozendaal B, Trezza V, Ratano P, Peloso A, Hauer D, Atsak P, Trabace L et al (2014) Endogenous cannabinoid release within prefrontal-limbic pathways affects memory consolidation of emotional training. Proc Natl Acad Sci U S A 111:18333–18338PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Pava MJ, den Hartog CR, Blanco-Centurion C, Shiromani PJ, Woodward JJ (2014) Endocannabinoid modulation of cortical up-states and NREM sleep. PLoS ONE 9:e88672PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Sugiura T, Kondo S, Sukagawa A, Nakane S, Shinoda A, Itoh K, Yamashita A, Waku K (1995) 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem Biophys Res Commun 215:89–97PubMedCrossRefGoogle Scholar
  65. 65.
    Sugiura T, Kobayashi Y, Oka S, Waku K (2002) Biosynthesis and degradation of anandamide and 2-arachidonoylglycerol and their possible physiological significance. Prostaglandins Leukot Essent Fatty Acids 66:173–192PubMedCrossRefGoogle Scholar
  66. 66.
    Buczynski MW, Parsons LH (2010) Quantification of brain endocannabinoid levels: methods, interpretations and pitfalls. Br J Pharmacol 160:423–442PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Wang J, Ueda N (2009) Biology of endocannabinoid synthesis system. Prostaglandins Lipid Mediat 89:112–119CrossRefGoogle Scholar
  68. 68.
    Alhouayek M, Muccioli GG (2012) The endocannabinoid system in inflammatory bowel diseases: from pathophysiology to therapeutic opportunity. Trends Mol Med 18:615–625PubMedCrossRefGoogle Scholar
  69. 69.
    Basavarajappa BS (2007) Neuropharmacology of the endocannabinoid signaling system-molecular mechanisms. Biological actions and synaptic plasticity. Curr Neuropharmacol 5:81–97PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Leweke FM, Piomelli D, Pahlisch F, Muhl D, Gerth CW, Hoyer C, Klosterkötter J, Hellmich M et al (2012) Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry 2:e94PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Hwang J, Adamson C, Butler D, Janero DR, Makriyannis A, Bahr BA (2010) Enhancement of endocannabinoid signaling by fatty acid amide hydrolase inhibition: a neuroprotective therapeutic modality. Life Sci 86:615–623PubMedCrossRefGoogle Scholar
  72. 72.
    Ueda N, Tsuboi K, Uyama T (2010) N-acylethanolamine metabolism with special reference to N-acylethanolamine-hydrolyzing acid amidase (NAAA). Prog Lipid Res 49(4):299–315PubMedCrossRefGoogle Scholar
  73. 73.
    Rahn EJ, Hohmann AG (2009) Cannabinoids as pharmacotherapies for neuropathic pain: from the bench to the bedside. Neurotherapeutics 6:713–737PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    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) 204:267–76CrossRefGoogle Scholar
  75. 75.
    Malone DT, Kearn CS, Chongue L, Mackie K, Taylor DA (2008) Effect of social isolation on CB1 and D2 receptor and fatty acid amide hydrolase expression in rats. Neuroscience 152(1):265–72PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Lovelace JW, Vieira PA, Corches A, Mackie K, Korzus E (2014) Impaired fear memory specificity associated with deficient endocannabinoid-dependent long-term plasticity. Neuropsychopharmacology 39(7):1685–93PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Marsicano G, Wotjak CT, Azad SC, Bisogno T, Rammes G, Cascio MG, Hermann H, Tang J et al (2002) The endogenous cannabinoid system controls extinction of aversive memories. Nature 418:530–4PubMedCrossRefGoogle Scholar
  78. 78.
    Bioque M, García-Bueno B, Macdowell KS, Meseguer A, Saiz PA, Parellada M, Gonzalez-Pinto A, Rodriguez-Jimenez R et al (2013) Peripheral endocannabinoid system dysregulation in first-episode psychosis. Neuropsychopharmacology 38:2568–2577PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    De Marchi N, De Petrocellis L, Orlando P, Daniele F, Fezza F, Di Marzo V (2003) Endocannabinoid signalling in the blood of patients with schizophrenia. Lipids Health Dis 2:5PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Ujike H, Takaki M, Nakata K, Tanaka Y, Takeda T, Kodama M, Fujiwara Y, Sakai A et al (2002) CNR1, central cannabinoid receptor gene, associated with susceptibility to hebephrenic schizophrenia. Mol Psychiatry 7(5):515–8PubMedCrossRefGoogle Scholar
  81. 81.
    Martínez-Gras I, Hoenicka J, Ponce G, Rodríguez-Jiménez R, Jiménez-Arriero MA, Pérez-Hernandez E, Ampuero I, Ramos-Atance JA et al (2006) (AAT)n repeat in the cannabinoid receptor gene, CNR1: association with schizophrenia in a Spanish population. Eur Arch Psychiatry Clin Neurosci 256(7):437–41PubMedCrossRefGoogle Scholar
  82. 82.
    Chavarría-Siles I, Contreras-Rojas J, Hare E, Walss-Bass C, Quezada P, Dassori A, Contreras S, Medina R et al (2008) Cannabinoid receptor 1 gene (CNR1) and susceptibility to a quantitative phenotype for hebephrenic schizophrenia. Am J Med Genet B Neuropsychiatr Genet 147(3):279–84PubMedCrossRefGoogle Scholar
  83. 83.
    Seifert J, Ossege S, Emrich HM, Schneider U, Stuhrmann M (2007) No association of CNR1 gene variations with susceptibility to schizophrenia. Neurosci Lett 426(1):29–33PubMedCrossRefGoogle Scholar
  84. 84.
    Tsai SJ, Wang YC, Hong CJ (2000) Association study of a cannabinoid receptor gene (CNR1) polymorphism and schizophrenia. Psychiatr Genet 10(3):149–51PubMedCrossRefGoogle Scholar
  85. 85.
    Ho BC, Wassink TH, Ziebell S, Andreasen NC (2011) Cannabinoid receptor 1 gene polymorphisms and marijuana misuse interactions on white matter and cognitive deficits in schizophrenia. Schizophr Res 128(1–3):66–75PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Ortega-Alvaro A, Aracil-Fernandez A, Garcia-Gutierrez MS, Navarrete F, Manzanares J (2011) Deletion of CB2 cannabinoid receptor induces schizophrenia-related behaviors in mice. Neuropsychopharmacology 36:1489–1504PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Dean B, Sundram S, Bradbury R, Scarr E, Copolov D (2001) Studies on [3H]CP-55940 binding in the human central nervous system: regional specific changes in density of cannabinoid-1 receptors associated with schizophrenia and cannabis use. Neuroscience 103:9–15PubMedCrossRefGoogle Scholar
  88. 88.
    Jenko KJ, Hirvonen J, Henter ID, Anderson KB, Zoghbi SS, Hyde TM, Deep-Soboslay A, Innis RB et al (2012) Binding of a tritiated inverse agonist to cannabinoid CB1 receptors is increased in patients with schizophrenia. Schizophr Res 141(2–3):185–8PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Newell KA, Deng C, Huang XF (2006) Increased cannabinoid receptor density in the posterior cingulate cortex in schizophrenia. Exp Brain Res 172(4):556–60PubMedCrossRefGoogle Scholar
  90. 90.
    Zavitsanou K, Garrick T, Huang XF (2004) Selective antagonist [3H]SR141716A binding to cannabinoid CB1 receptors is increased in the anterior cingulate cortex in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 28(2):355–60PubMedCrossRefGoogle Scholar
  91. 91.
    Ceccarini J, De Hert M, van Winkel R, Koethe D, Bormans G, Leweke M, Peuskens J, Van Laere K (2010) In vivo PET imaging of cerebral type 1 cannabinoid receptor availability in patients with schizophrenia. Schizophrenia Res 117:170CrossRefGoogle Scholar
  92. 92.
    Wong DF, Kuwabara H, Horti AG, Raymont V, Brasic J, Guevara M, Ye W, Dannals RF et al (2010) Quantification of cerebral cannabinoid receptors subtype 1 (CB1) in healthy subjects and schizophrenia by the novel PET radioligand [11C]OMAR. Neuroimage 52(4):1505–13PubMedCrossRefGoogle Scholar
  93. 93.
    Eggan SM, Hashimoto T, Lewis DA (2008) Reduced cortical cannabinoid 1 receptor messenger RNA and protein expression in schizophrenia. Arch Gen Psychiatry 65(7):772–84PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Urigüen L, García-Fuster MJ, Callado LF, Morentin B, La Harpe R, Casadó V, Lluis C, Franco R et al (2009) Immunodensity and mRNA expression of A2A adenosine, D2 dopamine, and CB1 cannabinoid receptors in postmortem frontal cortex of subjects with schizophrenia: effect of antipsychotic treatment. Psychopharmacol (Berl) 206(2):313–24CrossRefGoogle Scholar
  95. 95.
    Potvin S, Kouassi E, Lipp O, Bouchard RH, Roy MA, Demers MF, Gendron A, Astarita G et al (2008) Endogenous cannabinoids in patients with schizophrenia and substance use disorder during quetiapine therapy. J Psychopharmacol 22(3):262–9PubMedCrossRefGoogle Scholar
  96. 96.
    Leweke FM, Giuffrida A, Wurster U, Emrich HM, Piomelli D (1999) Elevated endogenous cannabinoids in schizophrenia. Neuroreport 10:1665–1669PubMedCrossRefGoogle Scholar
  97. 97.
    Ujike H, Morita Y (2004) New perspectives in the studies on endocannabinoid and cannabis: cannabinoid receptors and schizophrenia. J Pharmacol Sci 96:376–381PubMedCrossRefGoogle Scholar
  98. 98.
    Giuffrida A, Leweke FM, Gerth CW, Schreiber D, Koethe D, Faulhaber J, Klosterkötter J, Piomelli D (2004) Cerebrospinal anandamide levels are elevated in acute schizophrenia and are inversely correlated with psychotic symptoms. Neuropsychopharmacology 29:2108–2114PubMedCrossRefGoogle Scholar
  99. 99.
    Guidali C, Viganò D, Petrosino S, Zamberletti E, Realini N, Binelli G, Rubino T, Di Marzo V et al (2011) Cannabinoid CB1 receptor antagonism prevents neurochemical and behavioural deficits induced by chronic phencyclidine. Int J Neuropsychopharmacol 14:17–28PubMedCrossRefGoogle Scholar
  100. 100.
    Katona I, Urbán GM, Wallace M, Ledent C, Jung KM, Piomelli D, Mackie K, Freund TF (2006) Molecular composition of the endocannabinoid system at glutamatergic synapses. J Neurosci 26(21):5628–37PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Melis M, Pistis M, Perra S, Muntoni AL, Pillolla G, Gessa GL (2004) Endocannabinoids mediate presynaptic inhibition of glutamatergic transmission in rat ventral tegmental area dopamine neurons through activation of CB1 receptors. J Neurosci 24:53–62PubMedCrossRefGoogle Scholar
  102. 102.
    Morrison PD, Nottage J, Stone JM, Bhattacharyya S, Tunstall N, Brenneisen R, Holt D, Wilson D et al (2011) Disruption of frontal θ coherence by Δ9-tetrahydrocannabinol is associated with positive psychotic symptoms. Neuropsychopharmacology 36:827–836PubMedCrossRefGoogle Scholar
  103. 103.
    Thomas A, Baillie GL, Phillips AM, Razdan RK, Ross RA, Pertwee RG (2007) Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro. Br J Pharmacol 150:613–623PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Moreira FA, Guimarães FS (2005) Cannabidiol inhibits the hyperlocomotion induced by psychotomimetic drugs in mice. Eur J Pharmacol 512:199–205PubMedCrossRefGoogle Scholar
  105. 105.
    Bergamaschi MM, Queiroz RH, Zuardi AW, Crippa JA (2011) Safety and side effects of cannabidiol, a Cannabis sativa constituent. Curr Drug Saf 6(4):237–49PubMedCrossRefGoogle Scholar
  106. 106.
    Huestis MA, Gorelick DA, Heishman SJ, Preston KL, Nelson RA, Moolchan ET, Frank RA (2001) Blockade of effects of smoked marijuana by the CB1-selective cannabinoid receptor antagonist SR141716. Arch Gen Psychiatry 58(4):322–8PubMedCrossRefGoogle Scholar
  107. 107.
    Poncelet M, Barnouin MC, Brelière JC, Le Fur G, Soubrié P (1999) Blockade of cannabinoid (CB1) receptors by 141716 selectively antagonizes drug-induced reinstatement of exploratory behaviour in gerbils. Psychopharmacol (Berl) 144(2):144–50CrossRefGoogle Scholar
  108. 108.
    Martin RS, Secchi RL, Sung E, Lemaire M, Bonhaus DW, Hedley LR, Lowe DA (2003) Effects of cannabinoid receptor ligands on psychosis-relevant behavior models in the rat. Psychopharmacol (Berl) 165(2):128–35CrossRefGoogle Scholar
  109. 109.
    Black MD, Stevens RJ, Rogacki N, Featherstone RE, Senyah Y, Giardino O, Borowsky B, Stemmelin J et al (2011) AVE1625, a cannabinoid CB1 receptor antagonist, as a co-treatment with antipsychotics for schizophrenia: improvement in cognitive function and reduction of antipsychotic-side effects in rodents. Psychopharmacol (Berl) 215(1):149–63CrossRefGoogle Scholar
  110. 110.
    Du H, Kwon IK, Kim J (2013) Neuregulin-1 impairs the long-term depression of hippocampal inhibitory synapses by facilitating the degradation of endocannabinoid 2-AG. J Neurosci 33(38):15022–31PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Pan B, Wang W, Long JZ, Sun D, Hillard CJ, Cravatt BF, Liu QS (2009) Blockade of 2-arachidonoylglycerol hydrolysis by selective monoacylglycerol lipase inhibitor 4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184) enhances retrograde endocannabinoid signaling. J Pharmacol Exp Ther 331(2):591–7PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Seillier A, Martinez AA, Giuffrida A (2013) Phencyclidine-induced social withdrawal results from deficient stimulation of cannabinoid CB1 receptors: implications for schizophrenia. Neuropsychopharmacology 38(9):1816–24PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Beltramo M, de Fonseca FR, Navarro M, Calignano A, Gorriti MA, Grammatikopoulos G, Sadile AG, Giuffrida A et al (2000) Reversal of dopamine D(2) receptor responses by an anandamide transport inhibitor. J Neurosci 20(9):3401–7PubMedGoogle Scholar
  114. 114.
    Almeida V, Peres FF, Levin R, Suiama MA, Calzavara MB, Zuardi AW, Hallak JE, Crippa JA et al (2014) Effects of cannabinoid and vanilloid drugs on positive and negative-like symptoms on an animal model of schizophrenia: the SHR strain. Schizophr Res 153(1–3):150–9PubMedCrossRefGoogle Scholar
  115. 115.
    Levin R, Peres FF, Almeida V, Calzavara MB, Zuardi AW, Hallak JE, Crippa JA, Abílio VC (2014) Effects of cannabinoid drugs on the deficit of prepulse inhibition of startle in an animal model of schizophrenia: the SHR strain. Front Pharmacol 5:10PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Fernandez-Espejo E, Galan-Rodriguez B (2004) Sensorimotor gating in mice is disrupted after AM404, an anandamide reuptake and degradation inhibitor. Psychopharmacol (Berl) 175(2):220–4CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Department of Neurosciences, Faculty of MedicineUniversité de MontréalMontrealCanada

Personalised recommendations