The Endocannabinoid System is a Major Player in Schizophrenia

  • Attila Köfalvi
  • Markus Fritzsche

Converging lines of evidence point to an inextricable role of the endocannabinoid system in schizophrenia. Marijuana consumption (1) elicits psychotic symptoms similar to schizophrenia; (2) precipitates schizophrenia in susceptible individuals; (3) worsens psychosis; and (4) is more prevalent among schizophrenia patients. (5) Genetic linkage studies have mapped a locus around the CB1 cannabinoid receptor gene (CNR1), which potentially confers susceptibility to schizophrenia, and (6) within CNR1, several polymorphisms reportedly associate with this disease. (7) The endocannabinoid system controls brain areas and signalling systems implicated in schizophrenia, (8) and is overactive in patients, (9). It correlates with symptom severity and is reversible with certain antipsychotics. Finally, (10) the naturally occurring CB1 receptor antagonist cannabidiol exhibits a promising antipsychotic profile in pharmacological model-psychoses and schizophrenia. In summarizing the pertinent epidemiological and molecular data, we define schizophrenia as a manifestation of aberrant circuitry formation at the synaptic level and propose that the liability to develop psychosis is driven by imbalanced co-signalling between endocannabinoids and other neuromodulatory pathways already implicated in schizophrenia.


Schizophrenic Patient Schizophrenia Patient Cannabis Abuse Marijuana Abuse Cannabis Psychosis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Adler LE, Olincy A, Waldo M, Harris JG, Griffith J, Stevens K, Flach K, Nagamoto H, Bickford P, Leonard S, Freedman R (1998) Schizophrenia, sensory gating, and nicotinic receptors. Schizophr Bull 24:189–202.PubMedGoogle Scholar
  2. Aldrich MR (1977) Tantric cannabis use in India. J Psychedelic Drugs 9:227–233.Google Scholar
  3. Andersson M, Usiello A, Borgkvist A, Pozzi L, Dominguez C, Fienberg AA, Svenningsson P, Fredholm BB, Borrelli E, Greengard P, Fisone G (2005) Cannabinoid action depends on phosphorylation of dopamine- and cAMP-regulated phosphoprotein of 32 kDa at the protein kinase A site in striatal projection neurons. J Neurosci 25:8432–8438.PubMedCrossRefGoogle Scholar
  4. Andreasson S, Allebeck P, Engstrom A, Rydberg U (1987) Cannabis and schizophrenia. A longitudinal study of Swedish conscripts. Lancet 2:1483–1486.PubMedCrossRefGoogle Scholar
  5. 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 325:1212–1213.PubMedCrossRefGoogle Scholar
  6. Arseneault L, Cannon M, Witton J, Murray RM (2004) Causal association between cannabis and psychosis: examination of the evidence. Br J Psychiatry 184:110–117.PubMedCrossRefGoogle Scholar
  7. Arvindakshan M, Sitasawad S, Debsikdar V, Ghate M, Evans D, Horrobin DF, Bennett C, Ranjekar PK, Mahadik SP (2003) Essential polyunsaturated fatty acid and lipid peroxide levels in never-medicated and medicated schizophrenia patients. Biol Psychiatry 53:56–64.PubMedCrossRefGoogle Scholar
  8. Baldelli P, Hernandez-Guijo JM, Carabelli V, Carbone E (2005) Brain-derived neurotrophic factor enhances GABA release probability and nonuniform distribution of N- and P/Q-type channels on release sites of hippocampal inhibitory synapses. J Neurosci 25:3358–3368.PubMedCrossRefGoogle Scholar
  9. Ballmaier M, Bortolato M, Rizzetti C, Zoli M, Gessa G, Heinz A, Spano P (2007) Cannabinoid receptor antagonists counteract sensorimotor gating deficits in the phencyclidine model of psychosis. Neuropsychopharmacology 32:2098–2107.PubMedCrossRefGoogle Scholar
  10. Bär KJ, Letzsch A, Jochum T, Wagner G, Greiner W, Sauer H (2005) Loss of efferent vagal activity in acute schizophrenia. J Psychiatr Res 39:519–527.PubMedCrossRefGoogle Scholar
  11. Baudelaire C (1966) Les Paradis Artificiels. Paris: Garnier-Flammarion.Google Scholar
  12. Berghuis P, Dobszay MB, Wang X, Spano S, Ledda F, Sousa KM, Schulte G, Ernfors P, Mackie K, Paratcha G, Hurd YL, Harkany T (2005) Endocannabinoids regulate interneuron migration and morphogenesis by transactivating the TrkB receptor. Proc Natl Acad Sci USA 102:19115–191120.PubMedCrossRefGoogle Scholar
  13. Berghuis P, Rajnicek AM, Morozov YM, Ross RA, Mulder J, Urban GM, Monory K, Marsicano G, Matteoli M, Canty A, Irving AJ, Katona I, Yanagawa Y, Rakic P, Lutz B, Mackie K, Harkany T (2007) Hardwiring the brain: endocannabinoids shape neuronal connectivity. Science 316:1212–1216.PubMedCrossRefGoogle Scholar
  14. Bergson C, Levenson R, Goldman-Rakic PS, Lidow MS (2003) Dopamine receptor-interacting proteins: the Ca2+ connection in dopamine signaling. Trends Pharmacol Sci 24:486–492.PubMedCrossRefGoogle Scholar
  15. Berridge MJ (1998) Neuronal calcium signaling. Neuron 21:13–26.PubMedCrossRefGoogle Scholar
  16. Betz VA (1875) Two centers in the human brain cortex.Google Scholar
  17. Blackwood D (2000) P300, a state and a trait marker in schizophrenia. Lancet 355:771–72.PubMedCrossRefGoogle Scholar
  18. Bleuler E (1911) Handbuch der Psychiatrie. Dementia praecox oder Gruppe der Schizophrenien. Leipzig: Deuticke.Google Scholar
  19. Blum J, Braverman ER, Dinardo MJ, Wood RC, Sheridan PJ (1994) Prolonged P300 latency in a neuropsychiatric population with the D2 dopamine receptor A1 allele. Pharmacogenetics 4:313–322.PubMedCrossRefGoogle Scholar
  20. Boksa P (2007) Of rats and schizophrenia. J Psychiatry Neurosci 32:8–10.PubMedGoogle Scholar
  21. Boucher AA, Arnold JC, Duffy L, Schofield PR, Micheau J, Karl T (2007) Heterozygous neuregulin 1 mice are more sensitive to the behavioural effects of Delta9-tetrahydrocannabinol. Psychopharmacology (Berl) 192:325–336.CrossRefGoogle Scholar
  22. Boydell J, van Os J, Caspi A, Kennedy N, Giouroukou E, Fearon P, Farrell M, Murray RM (2006) Trends in cannabis use prior to first presentation with schizophrenia, in South-East London between 1965 and 1999. Psychol Med 36:1441–1446.PubMedCrossRefGoogle Scholar
  23. Brakeman PR, Lanahan AA, O’Brien R, Roche K, Barnes CA, Huganir RL, Worley PF (1997) Homer: a protein that selectively binds metabotropic glutamate receptors. Nature 368:284–288.CrossRefGoogle Scholar
  24. Brown P, Williams D, Aziz T, Mazzone P, Oliviero A, Insola A, Tonali P, Di Lazzaro V (2002) Pallidal activity recorded in patients with implanted electrodes predictively correlates with eventual performance in a timing task. Neurosci Lett 330:188–192.PubMedCrossRefGoogle Scholar
  25. Buhusi CV, Meck WH (2005) What makes us tick? Functional and neural mechanisms of interval timing. Nat Rev Neurosci 6:755–765.PubMedCrossRefGoogle Scholar
  26. Burgoyne RD, O’Callaghan DW, Hasdemir B, Haynes LP, Tepikin AV (2004) Neuronal Ca2+-sensor proteins: multitalented regulators of neuronal function. Trends Neurosci 27:203–209.PubMedCrossRefGoogle Scholar
  27. Cannon TD, Thompson PM, van Erp TG, Toga AW, Poutanen VP, Huttunen M, Lonnqvist J, Standerskjold-Nordenstam CG, Narr KL, Khaledy M, Zoumalan CI, Dail R, Kaprio J (2002) Cortex mapping reveals regionally specific patterns of genetic and disease-specific gray-matter deficits in twins discordant for schizophrenia. Proc Natl Acad Sci USA 99:3228–3233.PubMedCrossRefGoogle Scholar
  28. Cao Q, Martinez M, Zhang J, Sanders AR, Badner JA, Cravchik A, Markey CJ, Beshah E, Guroff JJ, Maxwell ME, Kazuba DM, Whiten R, Goldin LR, Gershon ES, Gejman PV (1997) Suggestive evidence for a schizophrenia susceptibility locus on chromosome 6q and a confirmation in an independent series of pedigrees. Genomics 43:1–8.PubMedCrossRefGoogle Scholar
  29. Carr DB, Surmeier DJ (2007) M1 Muscarinic receptor modulation of kir2 channels enhances temporal summation of excitatory synaptic potentials in prefrontal cortex pyramidal neurons. J Neurophysiol 97:3432–3438.PubMedCrossRefGoogle Scholar
  30. Carriba P, Ortiz O, Patkar K, Justinova Z, Stroik J, Themann A, Müller C, Woods AS, Hope BT, Ciruela F, Casadó V, Canela EI, Lluis C, Goldberg SR, Moratalla R, Franco R, Ferré S (2007) Striatal adenosine A2A and cannabinoid CB1 receptors form functional heteromeric complexes that mediate the motor effects of cannabinoids. Neuropsychopharmacol doi:10.1038/sj.npp. 1301375.Google Scholar
  31. Chapman J (1966) The early symptoms of schizophrenia. Br J Psychiatry 112:225–251.PubMedCrossRefGoogle Scholar
  32. Chaudry HR, Moss HB, Bashir A, Suliman T (1991) Cannabis psychosis following bhang ingestion. Br J Addict 86:1075–1081.PubMedCrossRefGoogle Scholar
  33. Cheer JF, Cadogan AK, Marsden CA, Fone KC, Kendall DA (1999) Modification of 5-HT2 receptor mediated behaviour in the rat by oleamide and the role of cannabinoid receptors. Neuropharmacology 38:533–541.PubMedCrossRefGoogle Scholar
  34. Cheer JF, Wassum KM, Heien ML, Phillips PE, Wightman RM (2004) Cannabinoids enhance subsecond dopamine release in the nucleus accumbens of awake rats. J Neurosci 24:4393–4400.PubMedCrossRefGoogle Scholar
  35. Cheer JF, Wassum KM, Sombers LA, Heien ML, Ariansen JL, Aragona BJ, Phillips PE, Wightman RM (2007) Phasic dopamine release evoked by abused substances requires cannabinoid receptor activation. J Neurosci 27:791–795.PubMedCrossRefGoogle Scholar
  36. Chen N, Appell M, Berfield JL, Reith ME (2003) Inhibition by arachidonic acid and other fatty acids of dopamine uptake at the human dopamine transporter. Eur J Pharmacol 478:89–95.PubMedCrossRefGoogle Scholar
  37. Chen L, Bohanick JD, Nishihara M, Seamans JK, Yang CR (2007) Dopamine D1/5 receptor-mediated long-term potentiation of intrinsic excitability in rat prefrontal cortical neurons: Ca2+-dependent intracellular signaling. J Neurophysiol 97:2448–2464.PubMedCrossRefGoogle Scholar
  38. Chen ZY, Patel PD, Sant G, Meng CX, Teng KK, Hempstead BL, Lee FS (2004) Variant brain-derived neurotrophic factor(BDNF)(Met66) alters the intracellular trafficking and activity-dependent secretion of wild-type BDNF in neurosecretory cells and cortical neurons. J Neurosci 24:4401–4411.PubMedCrossRefGoogle Scholar
  39. Chevaleyre V, Takahashi KA, Castillo PE (2006) Endocannabinoid-mediated synaptic plasticity in the CNS. Annu Rev Neurosci 29:37–76.PubMedCrossRefGoogle Scholar
  40. Comings DE, Muhleman D, Gade R, Johnson P, Verde R, Saucier G, MacMurray J (1997) Cannabinoid receptor gene (CNR1): association with i.v. drug use. Mol Psychiatry 2:161–168.PubMedCrossRefGoogle Scholar
  41. Cuffel BJ (1992) Prevalence estimates of substance abuse in schizophrenia and their correlates. J Nerv Ment Dis 180:589–592.PubMedCrossRefGoogle Scholar
  42. Cui G, Bernier BE, Harnett MT, Morikawa H (2007) Differential regulation of action potential- and metabotropic glutamate receptor-induced Ca2+ signals by inositol 1, 4, 5-trisphosphate in dopaminergic neurons. J Neurosci 27:4776–4785.PubMedCrossRefGoogle Scholar
  43. Damasio AR (1999) The Feeling of What Happens–Body and Emotion in the Making of Consciousness. New York: Harcourt Brace.Google Scholar
  44. Damasio AR, Grabowski TJ, Bechara A, Damasio H, Ponto LL, Parvizi J, Hichwa RD (2000) Subcortical and cortical brain activity during the feeling of self-generated emotions. Nat Neurosci 3:1049–1056.PubMedCrossRefGoogle Scholar
  45. Dawson E (1995) Identification of a polymorphic triplet repeat marker for the brain cannabinoid receptor gene: use in linkage and association studies. Psychiatr Genet 5(S50–S51):850.CrossRefGoogle Scholar
  46. De Marchi N, De Petrocellis L, Orlando P, Daniele F, Fezza F, Di Marzo V (2003) Endocannabinoid signaling in the blood of patients with schizophrenia. Lipids Health Dis 2:5.PubMedCrossRefGoogle Scholar
  47. 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 103:9–15.PubMedCrossRefGoogle Scholar
  48. Degroot A, Köfalvi A, Wade MR, Davis RJ, Rodrigues RJ, Rebola N, Cunha RA, Nomikos GG (2006) CB1 receptor antagonism increases hippocampal acetylcholine release: site and mechanism of action. Mol Pharmacol 70:1236–1245.PubMedCrossRefGoogle Scholar
  49. Delmas P, Crest M, Brown DA (2004) Functional organization of PLC signaling microdomains in neurons. Trends Neurosci 27:41–47.PubMedCrossRefGoogle Scholar
  50. Devlin MG, Christopoulos A (2002) Modulation of cannabinoid agonist binding by 5-HT in the rat cerebellum. J Neurochem 80:1095–1102.PubMedCrossRefGoogle Scholar
  51. Drewe M, Drewe J, Riecher-Rossler A (2004) Cannabis and risk of psychosis. Swiss Med Wkly 134:659–663.PubMedGoogle Scholar
  52. D’Souza DC (2007) Cannabinoids and psychosis. Int Rev Neurobiol 78:289–326.PubMedCrossRefGoogle Scholar
  53. Duarte JM, Nogueira C, Mackie K, Oliveira CR, Cunha RA, Köfalvi A (2007) Increase of cannabinoid CB1 receptor density in the hippocampus of streptozotocin-induced diabetic rats. Exp Neurol 204:479–484.PubMedCrossRefGoogle Scholar
  54. Eblen F, Graybiel AM (1995) Highly restricted origin of prefrontal cortical inputs to striosomes in the macaque monkey. J Neurosci 15:5999–6013.PubMedGoogle Scholar
  55. Ellert-Miklaszewska A, Kaminska B, Konarska L (2005) Cannabinoids down-regulate PI3K/Akt and Erk signaling pathways and activate proapoptotic function of Bad protein. Cell Signal 17:25–37.PubMedCrossRefGoogle Scholar
  56. Elvevag B, McCormack T, Gilbert A, Brown GD, Weinberger DR, Goldberg TE (2003) Duration judgements in patients with schizophrenia. Psychol Med 33:1249–1261.PubMedCrossRefGoogle Scholar
  57. Emrich HM, Leweke FM, Schneider U (1997) Towards a cannabinoid hypothesis of schizophrenia: cognitive impairments due to dysregulation of the endogenous cannabinoid system. Pharmacol Biochem Behav 56:803–807.PubMedCrossRefGoogle Scholar
  58. Freud S (1915) The unconscious. In: Strachey J (ed.), Complete Psychological Works, Vol. 14, translated in 1964. London: Hogarth.Google Scholar
  59. Frith CD, Blakemore S, Wolpert DM (2000) Explaining the symptoms of schizophrenia: abnormalities in the awareness of action. Brain Res Brain Res Rev 31:357–363.PubMedCrossRefGoogle Scholar
  60. Fritzsche M, Fritzsche LN, Kosidubova SM, Prognimak AB, Mayorov OY (2006) Asymmetric information-processing in development, evolution and psychopathology. In: Hellige JB, Bogen JE (eds.), Cognition, Brain, Behavior, Special Issue. Napoca: CBB, pp. 311–342.Google Scholar
  61. Fujii N, Graybiel AM (2005) Time-varying covariance of neural activities recorded in striatum and frontal cortex as monkeys perform sequential-saccade tasks. Proc Natl Acad Sci USA 102:9032–9037.PubMedCrossRefGoogle Scholar
  62. Fuster JM (1989) The Prefrontal Cortex, Anatomy, Physiology, and Neuropsychology of the Frontal Lobe. New York: Raven.Google Scholar
  63. Gardner EL (2002) Addictive potential of cannabinoids: the underlying neurobiology. Chem Phys Lipids 121:267–290.PubMedCrossRefGoogle Scholar
  64. Gerfen CR (2004) Basal ganglia. In: Paxinos G (ed.), The Rat Nervous System. Amsterdam: Elsevier, pp. 455–508.CrossRefGoogle Scholar
  65. Giuffrida A, Leweke FM, Gerth CW, Schreiber D, Koethe D, Faulhaber J, Klosterkotter J, Piomelli D (2004) Cerebrospinal anandamide levels are elevated in acute schizophrenia and are inversely correlated with psychotic symptoms. Neuropsychopharmacology 29:2108–2114.PubMedCrossRefGoogle Scholar
  66. Gladkevich A, Kauffman HF, Korf J (2004) Lymphocytes as a neural probe: potential for studying psychiatric disorders. Prog Neuropsychopharmacol Biol Psychiatry 28:559–576.PubMedCrossRefGoogle Scholar
  67. Glass M, Felder CC (1997) Concurrent stimulation of cannabinoid CB1 and dopamine D2 receptors augments cAMP accumulation in striatal neurons: evidence for a Gs linkage to the CB1 receptor. J Neurosci 17:5327–5333.PubMedGoogle Scholar
  68. Goldman-Rakic PS (2005) Working memory dysfunction in schizophrenia. In: Salloway SP, Malloy PF, Duffy JD (eds.), The Frontal Lobes and Neuropsychiatric Illness. Washington, DC: American Psychiatric PI, pp. 71–82.Google Scholar
  69. Goto Y, Grace AA (2005a) Dopamine-dependent interactions between limbic and prefrontal cortical plasticity in the nucleus accumbens: disruption by cocaine sensitization. Neuron 47:255–266.PubMedCrossRefGoogle Scholar
  70. Goto Y, Grace AA (2005b) Dopaminergic modulation of limbic and cortical drive of nucleus accumbens in goal-directed behavior. Nat Neurosci 8:805–812.PubMedCrossRefGoogle Scholar
  71. Gottesmann C (2006) The dreaming sleep stage: a new neurobiological model of schizophrenia? Neuroscience 140:1105–1115.PubMedCrossRefGoogle Scholar
  72. Green AL, Wang S, Owen SL, Aziz TZ (2007) The periaqueductal grey area and the cardiovascular system. Acta Neurochir Suppl 97:521–528.PubMedCrossRefGoogle Scholar
  73. Gross A, Joutsiniemi SL, Rimon R, Appelberg B (2006) Correlation of symptom clusters of schizophrenia with absolute powers of main frequency bands in quantitative EEG. Behav Brain Funct 2:23.PubMedCrossRefGoogle Scholar
  74. Gu Z, Jiang Q, Yan Z (2007) RGS4 modulates serotonin signaling in prefrontal cortex and links to serotonin dysfunction in a rat model of schizophrenia. Mol Pharmacol 71:1030–1039.PubMedCrossRefGoogle Scholar
  75. Halikas JA, Goodwin DW, Guze SB (1972) Marihuana use and psychiatric illness. Arch Gen Psychiatry 27:162–165.PubMedGoogle Scholar
  76. Hampson AJ, Bornheim LM, Scanziani M, Yost CS, Gray AT, Hansen BM, Leonoudakis DJ, Bickler PE (1998) Dual effects of anandamide on NMDA receptor-mediated responses and neurotransmission. J Neurochem 70:671–676.PubMedCrossRefGoogle Scholar
  77. Hanson DR, Gottesman II (2005) Theories of schizophrenia: a genetic-inflammatory-vascular synthesis. BMC Med Genet 6:7.PubMedCrossRefGoogle Scholar
  78. Häring M, Marsicano G, Lutz B, Monory K (2007) Identification of the cannabinoid receptor type 1 in serotonergic cells of raphe nuclei in mice. Neuroscience 146:1212–1219.PubMedCrossRefGoogle Scholar
  79. Harkány T, Guzman M, Galve-Roperh I, Berghuis P, Devi LA, Mackie K (2007) The emerging functions of endocannabinoid signaling during CNS development. Trends Pharmacol Sci 28:83–92.PubMedCrossRefGoogle Scholar
  80. Hashimoto T, Bergen SE, Nguyen QL, Xu B, Monteggia LM, Pierri JN, Sun Z, Sampson AR, Lewis DA (2005) Relationship of brain-derived neurotrophic factor and its receptor TrkB to altered inhibitory prefrontal circuitry in schizophrenia. J Neurosci 25:372–383.PubMedCrossRefGoogle Scholar
  81. Hashimoto T, Lewis DA (2006) BDNF Val66Met polymorphism and GAD67 mRNA expression in the prefrontal cortex of subjects with schizophrenia. Am J Psychiatry 163:534–537.PubMedCrossRefGoogle Scholar
  82. Haznedar MM, Buchsbaum MS, Hazlett EA, Shihabuddin L, New A, Siever LJ (2004) Cingulate gyrus volume and metabolism in the schizophrenia spectrum. Schizophr Res 71:249–262.PubMedCrossRefGoogle Scholar
  83. Heath RG (1954) Studies in Schizophrenia. A Multidisciplinary Approach to Mind-Brain Relationships. Cambridge: Harvard University Press.Google Scholar
  84. Heath RG (1962) Common characteristics of epilepsy and schizophrenia: clinical observation and depth electrode studies. Am J Psychiatry 118:1013–1026.PubMedGoogle Scholar
  85. Henquet C, Murray R, Linszen D, van Os J (2005) The environment and schizophrenia: the role of cannabis use. Schizophr Bull 31:608–612.PubMedCrossRefGoogle Scholar
  86. Herkenham M, Lynn AB, Little MD, Johnson MR, Melvin LS, de Costa BR, Rice KC (1990) Cannabinoid receptor localization in brain. Proc Natl Acad Sci USA 87:1932–1936.PubMedCrossRefGoogle Scholar
  87. Herrero MT, Barcia C, Navarro JM (2202) Functional anatomy of thalamus and basal ganglia. Childs Nerv Syst 18:386–404.CrossRefGoogle Scholar
  88. Hicks RE, Gualtieri CT, Mayo JP, Perez-Reyes M (1984) Cannabis, atropine, and temporal information processing. Neuropsychobiology 12:229–237.PubMedCrossRefGoogle Scholar
  89. Hill EL, Gallopin T, Ferezou I, Cauli B, Rossier J, Schweitzer P, Lambolez B (2007) Functional CB1 receptors are broadly expressed in neocortical GABAergic and glutamatergic neurons. J Neurophysiol 97:2580–2589.PubMedCrossRefGoogle Scholar
  90. Hoehe MR, Caenazzo L, Martinez MM, Hsieh WT, Modi WS, Gershon ES, Bonner TI (1991) Genetic and physical mapping of the human cannabinoid receptor gene to chromosome 6q14–q15. New Biol 3:880–885.PubMedGoogle Scholar
  91. Hoffman DC (1992) Typical and atypical neuroleptics antagonize MK-801-induced locomotion and stereotypy in rats. J Neural Transm Gen Sect 89:1–10.PubMedCrossRefGoogle Scholar
  92. Holstege G, Mouton LJ, Gerrits N (2004). Emotional motor system. In: Paxinos G (ed.), The Human Nervous System. Amsterdam: Elsevier, pp. 1306–1325.CrossRefGoogle Scholar
  93. Hyman SE, Malenka RC, Nestler EJ (2006) Neural mechanisms of addiction: the role of reward-related learning and memory, Annu Rev Neurosci. 2006; 29:565–98.PubMedCrossRefGoogle Scholar
  94. Isohanni M, Miettunen J, Maki P, Murray GK, Ridler K, Lauronen E, Moilanen K, Alaraisanen A, Haapea M, Isohanni I, Ivleva E, Tamminga C, McGrath J, Koponen H (2006) Risk factors for schizophrenia. Follow-up data from the Northern Finland 1966 Birth Cohort Study. World Psychiatry 5:168–171.PubMedGoogle Scholar
  95. Iversen L (2003) Cannabis and the brain. Brain 126:1252–1270.PubMedCrossRefGoogle Scholar
  96. Jackson JH (1932) In: Taylor J (ed.), Selected Writings of John Hughlings Jackson. London: Hodder & Stoughton.Google Scholar
  97. Jarrahian A, Watts VJ, Barker EL (2004) D2 dopamine receptors modulate G -subunit coupling of the CB1 cannabinoid receptor. J Pharmacol Exp Ther 308:880–886.PubMedCrossRefGoogle Scholar
  98. Jiang W, Zhang Y, Xiao L, Van Cleemput J, Ji SP, Bai G, Zhang X (2005) Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects. J Clin Invest 115:3104–3116.PubMedCrossRefGoogle Scholar
  99. Jin K, Xie L, Kim SH, Parmentier-Batteur S, Sun Y, Mao XO, Childs J, Greenberg DA (2004) Defective adult neurogenesis in CB1 cannabinoid receptor knockout mice. Mol Pharmacol 66:204–208.PubMedCrossRefGoogle Scholar
  100. Jockers-Scherubl MC, Danker-Hopfe H, Mahlberg R, Selig F, Rentzsch J, Schurer F, Lang UE, Hellweg R (2004) Brain-derived neurotrophic factor serum concentrations are increased in drug-naive schizophrenic patients with chronic cannabis abuse and multiple substance abuse. Neurosci Lett 371:79–83.PubMedCrossRefGoogle Scholar
  101. Jockers-Scherubl MC, Matthies U, Danker-Hopfe H, Lang UE, Mahlberg R, Hellweg R (2003) Chronic cannabis abuse raises nerve growth factor serum concentrations in drug-naive schizophrenic patients. J Psychopharmacol 17:439–445.PubMedCrossRefGoogle Scholar
  102. Jockers-Scherubl MC, Rentzsch J, Danker-Hopfe H, Radzei N, Schurer F, Bahri S, Hellweg R (2006) Adequate antipsychotic treatment normalizes serum nerve growth factor concentrations in schizophrenia with and without cannabis or additional substance abuse. Neurosci Lett 400:262–266.PubMedCrossRefGoogle Scholar
  103. Johns A (2001) Psychiatric effects of cannabis. Br J Psychiatry 178:116–122.PubMedCrossRefGoogle Scholar
  104. Johnson JP, Muhleman D, Mc Murray J, Gade R, Verde R, Ask M, Kelley J, Comings DE (1997) Association between the cannabinoid receptor gene (CNR1) and the P300 event-related potential. Mol Psychiatry 2:169–171.PubMedCrossRefGoogle Scholar
  105. Jones EG (2007) The Thalamus. California: Cambridge University Press.Google Scholar
  106. Joyce JN, Gurevich EV (1999) D3 receptors and the actions of neuroleptics in the ventral striatopallidal system of schizophrenics. Ann NY Acad Sci 877:595–613.PubMedCrossRefGoogle Scholar
  107. Kaiya H, Nishida A, Imai A, Nakashima S, Nozawa Y (1989) Accumulation of diacylgylcerol in platelet phosphoinositide turnover in schizophrenia: a biological marker of good prognosis? Biol Psychiatry 26:669–676.PubMedCrossRefGoogle Scholar
  108. Kalkman HO (2006) The role of the phosphatidylinositide 3-kinase-protein kinase B pathway in schizophrenia. Pharmacol Ther 110:117–134.PubMedCrossRefGoogle Scholar
  109. Kang H, Schuman EM (1995) Long-lasting neurotrophin-induced enhancement of synaptic transmission in the adult hippocampus. Science 267:1658–1662.PubMedCrossRefGoogle Scholar
  110. Kapur S, Remington G (2001) Atypical antipsychotics: new directions and new challenges in the treatment of schizophrenia. Annu Rev Med 52:503–517.PubMedCrossRefGoogle Scholar
  111. Kapur S, Remington G (1996) Serotonin-dopamine interaction and its relevance to schizophrenia. Am J Psychiatry 153:466–476.PubMedGoogle Scholar
  112. Kapur S, Zipursky R, Jones C, Shammi CS, Remington G, Seeman P (2000) A positron emission tomography study of quetiapine in schizophrenia: a preliminary finding of an antipsychotic effect with only transiently high dopamine D2 receptor occupancy. Arch Gen Psychiatry 57:553–559.PubMedCrossRefGoogle Scholar
  113. Katona I, Sperlágh B, Magloczky Z, Santha E, Köfalvi A, Czirjak S, Mackie K, Vizi ES, Freund TF (2000) GABAergic interneurons are the targets of cannabinoid actions in the human hippocampus. Neuroscience 100:797–804.PubMedCrossRefGoogle Scholar
  114. Katona I, Sperlágh B, Sík A, Köfalvi A, Vizi ES, Mackie K, Freund TF (1999) Presynaptically located CB1 cannabinoid receptors regulate GABA release from axon terminals of specific hippocampal interneurons. J Neurosci 19:4544–4558.PubMedGoogle Scholar
  115. Kearn CS, Blake-Palmer K, Daniel E, Mackie K, Glass M (2004) Concurrent stimulation of cannabinoid CB1 and dopamine D2 receptors enhances heterodimer formation: a mechanism for receptor cross-talk? Mol Pharmacol 67:1697–1704.CrossRefGoogle Scholar
  116. Keay KA, Bandler R (2004) Periaqueductal gray. In: Paxinos G (ed.), The Rat Nervous System. Amsterdam: Elsevier, pp. 244–257.Google Scholar
  117. Kim D, Thayer SA (2001) Cannabinoids inhibit the formation of new synapses between hippocampal neurons in culture. J Neurosci 21:RC146.Google Scholar
  118. Kimura M, Yamada H, Matsumoto N (2003) Tonically active neurons in the striatum encode motivational contexts of action. Brain Dev Suppl 1:S20–23.CrossRefGoogle Scholar
  119. Kimura M, Minamimoto T, Matsumoto N, Hori Y (2004) Monitoring and switching of cortico-basal ganglia loop functions by the thalamo-striatal system. Neurosci Res 48:355–360.PubMedCrossRefGoogle Scholar
  120. Knusel B, Winslow JW, Rosenthal A, Burton LE, Seid DP, Nikolics K, Hefti F (1991) Promotion of central cholinergic and dopaminergic neuron differentiation by brain-derived neurotrophic factor but not neurotrophin 3. Proc Natl Acad Sci USA 88:961–965.PubMedCrossRefGoogle Scholar
  121. Köfalvi A, Oliveira CR, Cunha RA (2006a) Lack of evidence for functional TRPV1 vanilloid receptors in rat hippocampal nerve terminals. Neurosci Lett 403:151–156.PubMedCrossRefGoogle Scholar
  122. Köfalvi A, Pereira MF, Rebola N, Rodrigues RJ, Oliveira CR, Cunha RA (2007) Anandamide and NADA bi-directionally modulate presynaptic Ca2+ levels and transmitter release in the hippocampus. Br J Pharmacol 151:551–563.PubMedCrossRefGoogle Scholar
  123. Köfalvi A, Rebola N, Rodrigues RJ, Pereira MF, Cunha RA (2006b) Evidence for CB1Rs, but lack of evidence for presynaptic functional CB2Rs and TRPV1Rs in the hippocampus. Annual International Cannabinoid Research Society Meeting, Tihany, Hungary.Google Scholar
  124. Köfalvi A, Rodrigues RJ, Ledent C, Mackie K, Vizi ES, Cunha RA, Sperlagh B (2005) Involvement of cannabinoid receptors in the regulation of neurotransmitter release in the rodent striatum: a combined immunochemical and pharmacological analysis. J Neurosci 25:2874–2884.PubMedCrossRefGoogle Scholar
  125. Kolb B, Gorny G, Limebeer CL, Parker LA (2006) Chronic treatment with Delta-9-tetrahydrocannabinol alters the structure of neurons in the nucleus accumbens shell and medial prefrontal cortex of rats. Synapse 60:429–436.PubMedCrossRefGoogle Scholar
  126. Kovasznay B, Fleischer J, Tanenberg-Karant M, Jandorf L, Miller AD, Bromet E (1997) Substance use disorder and the early course of illness in schizophrenia and affective psychosis. Schizophr Bull 23:195–201.PubMedGoogle Scholar
  127. Kraepelin E (1899) Psychiatrie, Dementia praecox. Ein Lehrbuch für Studierende und Aerzte. Leipzig: Barth.Google Scholar
  128. Kreitzer AC, Malenka RC (2007) Endocannabinoid-mediated rescue of striatal LTD and motor deficits in Parkinson’s disease models. Nature 445:643–647.PubMedCrossRefGoogle Scholar
  129. Kristensen K, Cadenhead KS (2007) Cannabis abuse and risk for psychosis in a prodromal sample. Psychiatry Res 151:151–154.PubMedCrossRefGoogle Scholar
  130. Lauckner JE, Hille B, Mackie K (2005) The cannabinoid agonist WIN55, 212–2 increases intracellular calcium via CB1 receptor coupling to Gq/11 G proteins. Proc Natl Acad Sci USA 102:19144–19149.PubMedCrossRefGoogle Scholar
  131. Leroy S, Griffon N, Bourdel MC, Olie JP, Poirier MF, Krebs MO (2001) Schizophrenia and the cannabinoid receptor type 1 (CB1): association study using a single-base polymorphism in coding exon 1. Am J Med Genet 105:749–752.PubMedCrossRefGoogle Scholar
  132. Levy FO, Holtgreve-Grez H, Tasken K, Solberg R, Ried T, Gudermann T (1994) Assignment of the gene encoding the 5-HT1E serotonin receptor (S31) (locus HTR1E) to human chromosome 6q14–q15. Genomics 22:637–640.PubMedCrossRefGoogle Scholar
  133. Leweke FM, Giuffrida A, Wurster U, Emrich HM, Piomelli D (1999) Elevated endogenous cannabinoids in schizophrenia. Neuroreport 10:1665–1669.PubMedCrossRefGoogle Scholar
  134. Lewis DA, Hashimoto T (2007) Deciphering the disease process of schizophrenia: the contribution of cortical GABA neurons. Int Rev Neurobiol 78:109–131.PubMedCrossRefGoogle Scholar
  135. Linszen DH, Dingemans PM, Lenior ME (1994) Cannabis abuse and the course of recent-onset schizophrenic disorders. Arch Gen Psychiatry 51:273–279.PubMedGoogle Scholar
  136. Lipska BK (2004) Using animal models to test a neurodevelopmental hypothesis of schizophrenia. J Psychiatry Neurosci 29:282–286.PubMedGoogle Scholar
  137. Long LE, Malone DT, Taylor DA (2006) Cannabidiol reverses MK-801-induced disruption of prepulse inhibition in mice. Neuropsychopharmacology 31:795–803.PubMedCrossRefGoogle Scholar
  138. Ludwig AM (1966) Altered states of consciousness. Arch Gen Psychiatry 15:225–234.PubMedGoogle Scholar
  139. Lupica CR, Riegel AC (2005) Endocannabinoid release from midbrain dopamine neurons: a potential substrate for cannabinoid receptor antagonist treatment of addiction. Neuropharmacology 48:1105–1116.PubMedCrossRefGoogle Scholar
  140. Luria AR (1973) The Working Brain: An Introduction to Neuropsychology. New York: Basic Books.Google Scholar
  141. MacDonald III AW, Chafee MV (2006) Translational and developmental perspective on N-methyl-D-aspartate synaptic deficits in schizophrenia. Dev Psychopathol 18:853–876.PubMedGoogle Scholar
  142. Macleod J, Davey Smith G, Hickman M (2006) Does cannabis use cause schizophrenia? Lancet 367:1055.PubMedCrossRefGoogle Scholar
  143. Maeda K, Sugino H, Hirose T, Kitagawa H, Nagai T, Mizoguchi H, Takuma K, Yamada K (2007) Clozapine prevents a decrease in neurogenesis in mice repeatedly treated with phencyclidine. J Pharmacol Sci 103:299–308.PubMedCrossRefGoogle Scholar
  144. Mäki P, Veijola J, Rantakallio P, Jokelainen J, Jones PB, Isohanni M (2004) Schizophrenia in the offspring of antenatally depressed mothers: a 31-year follow-up of the Northern Finland 1966 Birth Cohort. Schizophr Res 66:79–81.PubMedCrossRefGoogle Scholar
  145. Malaspina D, Dalack G, Leitman D, Corcoran C, Amador XF, Yale S, Glassman A, Gorman JM (2002) Low heart rate variability is not caused by typical neuroleptics in schizophrenia patients. CNS Spectr 7:53–57.PubMedGoogle Scholar
  146. Maldonado R, Valverde O, Berrendero F (2006) Involvement of the endocannabinoid system in drug addiction. Trends Neurosci 29:225–232.PubMedCrossRefGoogle Scholar
  147. Malone DT, Taylor DA (1999) Modulation by fluoxetine of striatal dopamine release following Delta9-tetrahydrocannabinol: a microdialysis study in conscious rats. Br J Pharmacol 128:21–26.PubMedCrossRefGoogle Scholar
  148. Mamounas LA, Blue ME, Siuciak JA, Altar CA (1995) Brain-derived neurotrophic factor promotes the survival and sprouting of serotonergic axons in rat brain. J Neurosci 15:7929–7939.PubMedGoogle Scholar
  149. Martinez-Gras I, Hoenicka J, Ponce G, Rodriguez-Jimenez R, Jimenez-Arriero MA, Perez-Hernandez E, Ampuero I, Ramos-Atance JA, Palomo T, Rubio G (2006) (AAT)n repeat in the cannabinoid receptor gene, CNR1: association with schizophrenia in a Spanish population. Eur Arch Psychiatry Clin Neurosci 256:437–441.PubMedCrossRefGoogle Scholar
  150. Massi P, Vaccani A, Parolaro D (2006) Cannabinoids, immune system and cytokine network. Curr Pharm Des 12:3135–3146.PubMedCrossRefGoogle Scholar
  151. Mathers DC, Ghodse AH (1992) Cannabis and psychotic illness. Br J Psychiatry 161:648–653.PubMedCrossRefGoogle Scholar
  152. Mato S, Chevaleyre V, Robbe D, Pazos A, Castillo PE, Manzoni OJ (2004) A single in-vivo exposure to delta 9THC blocks endocannabinoid-mediated synaptic plasticity. Nat Neurosci 7:585–586.PubMedCrossRefGoogle Scholar
  153. Mato S, Robbe D, Puente N, Grandes P, Manzoni OJ (2005) Presynaptic homeostatic plasticity rescues long-term depression after chronic Delta 9-tetrahydrocannabinol exposure. J Neurosci 25:11619–11627.PubMedCrossRefGoogle Scholar
  154. McGrath JJ (2006) Variations in the incidence of schizophrenia: data versus dogma. Schizophr Bull 32:195–197.PubMedCrossRefGoogle Scholar
  155. McGuire PK, Jones P, Harvey I, Bebbington P, Toone B, Lewis S, Murray RM (1994) Cannabis and acute psychosis. Schizophr Res 13:161–167.PubMedCrossRefGoogle Scholar
  156. McGuire PK, Jones P, Harvey I, Williams M, McGuffin P, Murray RM (1995) Morbid risk of schizophrenia for relatives of patients with cannabis-associated psychosis. Schizophr Res 15:277–281.PubMedCrossRefGoogle Scholar
  157. Mechri A, Saoud M, Khiari G, d’Amato T, Dalery J, Gaha L (2001) Glutaminergic hypothesis of schizophrenia: clinical research studies with ketamine. Encephale 27:53–59.PubMedGoogle Scholar
  158. Meck WH (1996) Neuropharmacology of timing and time perception. Cogn Brain Res 3:227–242.CrossRefGoogle Scholar
  159. Melges FT (1982) Time and the Inner Future–A Temporal Approach to Psychiatric Disorders. New York: Wiley.Google Scholar
  160. Melis M, Gessa GL, Diana M (2000) Different mechanisms for dopaminergic excitation induced by opiates and cannabinoids in the rat midbrain. Prog Neuropsychopharmacol Biol Psychiatry 24:993–1006.PubMedCrossRefGoogle Scholar
  161. Melis M, Perra S, Muntoni AL, Pillolla G, Lutz B, Marsicano G, Di Marzo V, Gessa GL, Pistis M (2004a) Prefrontal cortex stimulation induces 2-arachidonoyl-glycerol-mediated suppression of excitation in dopamine neurons. J Neurosci 24:10707–10715.PubMedCrossRefGoogle Scholar
  162. Melis M, Pistis M, Perra S, Muntoni AL, Pillolla G, Gessa GL (2004b) Endocannabinoids mediate presynaptic inhibition of glutamatergic transmission in rat ventral tegmental area dopamine neurons through activation of CB1 receptors. J Neurosci 24:53–62.PubMedCrossRefGoogle Scholar
  163. Meyer-Lindenberg A, Straub RE, Lipska BK, Verchinski BA, Goldberg T, Callicott JH, Egan MF, Huffaker SS, Mattay VS, Kolachana B, Kleinman JE, Weinberger DR (2007) Genetic evidence implicating DARPP-32 in human frontostriatal structure, function, and cognition. J Clin Invest 117:672–682.PubMedCrossRefGoogle Scholar
  164. Minamimoto T, Hori Y, Kimura M (2005) Complementary process to response bias in the centromedian nucleus of the thalamus. Science 308:1798–1801.PubMedCrossRefGoogle Scholar
  165. Mirnics K, Middleton FA, Stanwood GD, Lewis DA, Levitt P (2001) Disease-specific changes in regulator of G-protein signaling 4 (RGS4) expression in schizophrenia. Mol Psychiatry 6:293–301.PubMedCrossRefGoogle Scholar
  166. Misslin R (2003) The defense system of fear: behavior and neurocircuitry. Neurophysiol Clin 33:55–66.PubMedCrossRefGoogle Scholar
  167. Moreira FA, Guimarães FS (2005) Cannabidiol inhibits the hyperlocomotion induced by psychotomimetic drugs in mice. Eur J Pharmacol 512:199–205.PubMedCrossRefGoogle Scholar
  168. Mouri A, Noda Y, Noda A, Nakamura T, Tokura T, Yura Y, Nitta A, Furukawa H, Nabeshima T (2007) Involvement of a dysfunctional dopamine-D1/NMDA-NR1 and CaMKII pathway in the impairment of latent learning in a model of schizophrenia induced by phencyclidine. Mol Pharmacol doi:10.1124/mol.106.032961.Google Scholar
  169. Muller N, Riedel M, Gruber R, Ackenheil M, Schwarz MJ (2000) Immune system and schizophrenia. An integrative view. Ann NY Acad Sci 917:456–467.PubMedCrossRefGoogle Scholar
  170. Munson R, Ruchkin DS, Ritter W, Sutton S, Squires NK (1984) The relation of P3b to prior events and future behavior. Biol Psychol 19:1–29.PubMedCrossRefGoogle Scholar
  171. Narr KL, Bilder RM, Toga AW, Woods RP, Rex DE, Szeszko PR, Robinson D, Sevy S, Gunduz-Bruce H, Wang YP, DeLuca H, Thompson PM (2005a) Mapping cortical thickness and gray matter concentration in first episode schizophrenia. Cereb Cortex 15:708–719.PubMedCrossRefGoogle Scholar
  172. Narr KL, Cannon TD, Woods RP, Thompson PM, Kim S, Asunction D, van Erp TG, Poutanen VP, Huttunen M, Lonnqvist J, Standerksjold-Nordenstam CG, Kaprio J, Mazziotta JC, Toga AW (2002) Genetic contributions to altered callosal morphology in schizophrenia. J Neurosci 22:3720–3729.PubMedGoogle Scholar
  173. Narr KL, Thompson PM, Szeszko P, Robinson D, Jang S, Woods RP, Kim S, Hayashi KM, Asunction D, Toga AW, Bilder RM (2004) Regional specificity of hippocampal volume reductions in first-episode schizophrenia. Neuroimage 21:1563–1575.PubMedCrossRefGoogle Scholar
  174. Narr KL, Toga AW, Szeszko P, Thompson PM, Woods RP, Robinson D, Sevy S, Wang Y, Schrock K, Bilder RM (2005b) Cortical thinning in cingulate and occipital cortices in first episode schizophrenia. Biol Psychiatry 58:32–40.PubMedCrossRefGoogle Scholar
  175. Narushima M, Uchigashima M, Fukaya M, Matsui M, Manabe T, Hashimoto K, Watanabe M, Kano M (2007) Tonic enhancement of endocannabinoid-mediated retrograde suppression of inhibition by cholinergic interneuron activity in the striatum. J Neurosci 27:496–506.PubMedCrossRefGoogle Scholar
  176. Negrete JC (1989) Cannabis and schizophrenia. Br J Addict 84:349–351.PubMedCrossRefGoogle Scholar
  177. Newell KA, Deng C, Huang XF (2006) Increased cannabinoid receptor density in the posterior cingulate cortex in schizophrenia. Exp Brain Res 172:556–560.PubMedCrossRefGoogle Scholar
  178. Nieuwenhuys R, Voogd J, van Huijzen Ch (1988) The Human Central Nervous System. Berlin: Springer.Google Scholar
  179. Olincy A, Harris JG, Johnson LL, Pender V, Kongs S, Allensworth D, Ellis J, Zerbe GO, Leonard S, Stevens KE, Stevens JO, Martin L, Adler LE, Soti F, Kem WR, Freedman R (2006) Proof-of-concept trial of an alpha7 nicotinic agonist in schizophrenia. Arch Gen Psychiatry 63:630–638.PubMedCrossRefGoogle Scholar
  180. Olincy A, Johnson LL, Ross RG (2003) Differential effects of cigarette smoking on performance of a smooth pursuit and a saccadic eye movement task in schizophrenia. Psychiatry Res 117:223–236.PubMedCrossRefGoogle Scholar
  181. Olney JW, Farber NB (1995) Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry 52:998–1007.PubMedGoogle Scholar
  182. Ouimet CC, Langley-Guillion KC, Greengard P (1998) Quantitative immunochemistry of DARPP-32-expressing neurons in the rat caudatoputamen. Brain Res 808:8–12.PubMedCrossRefGoogle Scholar
  183. Oz M, Ravindran R, Zhang L, Morales M (2003) Endogenous cannabinoid, anandamide inhibits neuronal nicotinic acethylcholine receptor-mediated responses in Xenopus oocytes. J Pharmacol Exp Ther 306:1003–1010.PubMedCrossRefGoogle Scholar
  184. Oz M, Zhang L, Ravindran A, Morales M, Lupica CR (2004) Differential effects of endogenous and synthetic cannabinoids on alpha7-nicotinic acetylcholine receptor-mediated responses in Xenopus Oocytes. J Pharmacol Exp Ther 310:1152–1160.PubMedCrossRefGoogle Scholar
  185. Pearlman RJ, Aubrey KR, Vandenberg RJ (2003) Arachidonic acid and anandamide have opposite modulatory actions at the glycine transporter, GLYT1a. J Neurochem 84:592–601.PubMedCrossRefGoogle Scholar
  186. Pereira DB, Rebola N, Rodrigues RJ, Cunha RA, Carvalho AP, Duarte CB (2006) Trkb receptors modulation of glutamate release is limited to a subset of nerve terminals in the adult rat hippocampus. J Neurosci Res 83:832–844.PubMedCrossRefGoogle Scholar
  187. Pertwee RG (2006) Cannabinoid pharmacology: the first 66 years. Br J Pharmacol 147:S163–S171.PubMedCrossRefGoogle Scholar
  188. Pichat P, Bergis OE, Terranova JP, Urani A, Duarte C, Santucci V, Gueudet C, Voltz C, Steinberg R, Stemmelin J, Oury-Donat F, Avenet P, Griebel G, Scatton B (2007) SSR180711, a novel selective alpha7 nicotinic receptor partial agonist: (II) efficacy in experimental models predictive of activity against cognitive symptoms of schizophrenia. Neuropsychopharmacology 32:17–34.PubMedCrossRefGoogle Scholar
  189. Pistis M, Porcu G, Melis M, Diana M, Gessa GL (2001) Effects of cannabinoids on prefrontal neuronal responses to ventral tegmental area stimulation. Eur J Neurosci 14:96–102.PubMedCrossRefGoogle Scholar
  190. Ponce G, Hoenicka J, Rubio G, Ampuero I, Jimenez-Arriero MA, Rodriguez-Jimenez R, Palomo T, Ramos JA (2003) Association between cannabinoid receptor gene (CNR1) and childhood attention deficit/hyperactivity disorder in Spanish male alcoholic patients. Mol Psychiatry 8:466–467.PubMedCrossRefGoogle Scholar
  191. Power JM, Sah P (2007) Distribution of IP3-mediated calcium responses and their role in nuclear signaling in rat basolateral amygdala neurons. J Physiol 580:835–857.PubMedCrossRefGoogle Scholar
  192. Price DA, Owens WA, Gould GG, Frazer A, Roberts JL, Daws LC, Giuffrida A (2007a) CB1-independent inhibition of dopamine transporter activity by cannabinoids in mouse dorsal striatum. J Neurochem 101:389–396.PubMedCrossRefGoogle Scholar
  193. Price G, Cercignani M, Parker GJ, Altmann DR, Barnes TR, Barker GJ, Joyce EM, Ron MA (2007) Abnormal brain connectivity in first-episode psychosis: A diffusion MRI tractography study of the corpus callosum. Neuroimage 35:458–466.PubMedCrossRefGoogle Scholar
  194. Pryor SR (2000) Is platelet release of 2-arachidonoyl-glycerol a mediator of cognitive deficits? An endocannabinoid theory of schizophrenia and arousal. Med Hypotheses 55:494–501.PubMedCrossRefGoogle Scholar
  195. Ragozzino ME, Choi D (2004) Dynamic changes in acetylcholine output in the medial striatum during place reversal learning. Learn Mem 11:70–77.PubMedCrossRefGoogle Scholar
  196. Rashid AJ, So CH, Kong MM, Furtak T, El-Ghundi M, Cheng R, O’Dowd BF, George SR (2007) D1-D2 dopamine receptor heterooligomers with unique pharmacology are coupled to rapid activation of Gq/11 in the striatum. Proc Natl Acad Sci USA 104:654–659.PubMedCrossRefGoogle Scholar
  197. Risold PY (2004) The septal region. In: Paxinos G (ed.), The Rat Nervous System. Amsterdam: Elsevier, pp. 602–636.Google Scholar
  198. Rizzolatti G, Gallese V (2003) Mirror neurons. In: Nadel L (ed.), Encyclopedia of Cognitive Science. London: Nature PG, Vol. III, pp. 37–42.Google Scholar
  199. Ronesi J, Lovinger DM (2005) Induction of striatal long-term synaptic depression by moderate frequency activation of cortical afferents in rat. J Physiol 562:245–256.PubMedCrossRefGoogle Scholar
  200. Roopun AK, Middleton SJ, Cunningham MO, LeBeau FE, Bibbig A, Whittington MA, Traub RD (2006) A beta2-frequency (20–30 Hz) oscillation in nonsynaptic networks of somatosensory cortex. Proc Natl Acad Sci USA 103:15646–15650.PubMedCrossRefGoogle Scholar
  201. Samejima K, Ueda Y, Doya K, Kimura M (2005) Representation of action-specific reward values in the striatum. Science 310:1337–1340.PubMedCrossRefGoogle Scholar
  202. Sarter M, Bruno JP (2000) Cortical cholinergic inputs mediating arousal, attentional processing and dreaming: differential afferent regulation of the basal forebrain by telencephalic and brainstem afferents. Neuroscience 95:933–952.PubMedCrossRefGoogle Scholar
  203. Saulskaya NB (2000) Volume transmission in the striatum as constituting information processing In: Miller R, Ivanitsky AM, Balaban PM (eds.), Complex Brain Functions–Conceptual Advances in Russian Neuroscience. Singapore: OPA, pp. 1–19.Google Scholar
  204. Schneier FR, Siris SG (1987) A review of psychoactive substance use and abuse in schizophrenia. Patterns of drug choice. J Nerv Ment Dis 175:641–652.PubMedCrossRefGoogle Scholar
  205. Seeman P (1987) Dopamine receptors and the dopamine hypothesis of schizophrenia. Synapse 1:133–152.PubMedCrossRefGoogle Scholar
  206. Semple DM, McIntosh AM, Lawrie SM (2005) Cannabis as a risk factor for psychosis: systematic review. J Psychopharmacol 19:187–194.PubMedCrossRefGoogle Scholar
  207. Semple DM, Ramsden F, McIntosh AM. (2003) Reduced binocular depth inversion in regular cannabis users. Pharmacol Biochem Behav 75:789–793.PubMedCrossRefGoogle Scholar
  208. Shapovalova KB (2000) The striatal cholinergic system and instrumental behaviour. In: Miller R, Ivanitsky AM, Balaban PM (eds.), Complex Brain Functions–Conceptual Advances in Russian Neuroscience. Singapore: OPA, pp. 263–288.Google Scholar
  209. Sharp FR, Butman M, Koistinaho J, Aardalen K, Nakki R, Massa SM, Swanson RA, Sagar SM (1994) Phencyclidine induction of the hsp 70 stress gene in injured pyramidal neurons is mediated via multiple receptors and voltage gated calcium channels. Neuroscience 62:1079–1092.PubMedCrossRefGoogle Scholar
  210. Shearn CR, Fitzgibbons DJ (1972) Patterns of drug use in a population of youthful psychiatric patients. Am J Psychiatry 128:1381–1387.PubMedGoogle Scholar
  211. Shenton ME, Dickey CC, Frumin M, McCarley RW (2001) A review of MRI findings in schizophrenia. Schizophr Res 49:1–52.PubMedCrossRefGoogle Scholar
  212. Shergill SS, Samson G, Bays PM, Frith CD, Wolpert DM (2005) Evidence for sensory prediction deficits in schizophrenia. Am J Psychiatry 162:2384–2386.PubMedCrossRefGoogle Scholar
  213. Simmons JM, Richmond BJ (2007) Dynamic changes in representations of preceding and upcoming reward in monkey orbitofrontal cortex. Cereb Cortex doi:10.1093/cercor/bhm034.Google Scholar
  214. Simonyi A, Schachtman TR, Christoffersen GR (2005) The role of metabotropic glutamate receptor 5 in learning and memory processes. Drug News Perspect 18:353–361.PubMedCrossRefGoogle Scholar
  215. Skosnik PD, Krishnan GP, Aydt EE, Kuhlenshmidt HA, O’Donnell BF (2006) Psychophysiological evidence of altered neural synchronization in cannabis use: relationship to schizotypy. Am J Psychiatry 163:1798–1805.PubMedCrossRefGoogle Scholar
  216. Smesny S, Rosburg T, Baur K, Rudolph N, Sauer H (2007) Cannabinoids influence lipid-arachidonic acid pathways in schizophrenia. Neuropsychopharmacology 32:2067–2073.PubMedCrossRefGoogle Scholar
  217. Solowij N, Michie PT (2007) Cannabis and cognitive dysfunction: parallels with endophenotypes of schizophrenia? J Psychiatry Neurosci 32:30–52.PubMedGoogle Scholar
  218. Solowij N, Michie PT, Fox AM (1991) Effect of long-term cannabis use on selective attention: an event-related potential study. Pharmacol Biochem Behav 40:683–688.PubMedCrossRefGoogle Scholar
  219. Steffens M, Feuerstein TJ (2004) Receptor-independent depression of DA and 5-HT uptake by cannabinoids in rat neocortex–involvement of Na+/K+-ATPase. Neurochem Int 44:529–538.PubMedCrossRefGoogle Scholar
  220. Stein BE, Meredith MA (1993) The Merging of the Senses. Cambridge: MIT.Google Scholar
  221. Suh BC, Hille B (2007) Regulation of KCNQ channels by manipulation of phosphoinositides. J Physiol 582:911–916.PubMedCrossRefGoogle Scholar
  222. Sundram S, Copolov D, Dean B (2005) Clozapine decreases [3H]CP55940 binding to the cannabinoid 1 receptor in the rat nucleus accumbens. Naunyn Schmiedebergs Arch Pharmacol 371:428–433.PubMedCrossRefGoogle Scholar
  223. Surmeier DJ, Ding J, Day M, Wang Z, Shen W (2007) D1 and D2 dopamine-receptor modulation of striatal glutamatergic signaling in striatal medium spiny neurons. Trends Neurosci 30:228–235.PubMedCrossRefGoogle Scholar
  224. Swanson LW (2000) Cerebral hemisphere regulation of motivated behavior. Brain Res 886:113–164.PubMedCrossRefGoogle Scholar
  225. Szabo B, Siemes S, Wallmichrath I (2002) Inhibition of GABAergic neurotransmission in the ventral tegmental area by cannabinoids. Eur J Neurosci 15:2057–2061.PubMedCrossRefGoogle Scholar
  226. Szeszko PR, Robinson DG, Sevy S, Kumra S, Rupp CI, Betensky JD, Lencz T, Ashtari M, Kane JM, Malhotra AK, Gunduz-Bruce H, Napolitano B, Bilder RM (2007) Anterior cingulate grey-matter deficits and cannabis use in first-episode schizophrenia. Br J Psychiatry 190:230–236.PubMedCrossRefGoogle Scholar
  227. Talbot K, Arnold SA (2002) The parahippocampal region in schizophrenia. In: Witter M, Wouterlood F (eds.), The Parahippocampal Region–Organization and Role in Cognitive Function. Oxford: Oxford University Press, pp. 297–320.Google Scholar
  228. Tappe A, Kuner R (2006) Regulation of motor performance and striatal function by synaptic scaffolding proteins of the Homer1 family. Proc Natl Acad Sci USA 103:774–779.PubMedCrossRefGoogle Scholar
  229. Tendolkar I, Weis S, Guddat O, Fernandez G, Brockhaus-Dumke A, Specht K, Klosterkotter J, Reul J, Ruhrmann S (2004) Evidence for a dysfunctional retrosplenial cortex in patients with schizophrenia: a functional magnetic resonance imaging study with a semantic-perceptual contrast. Neurosci Lett 369:4–8.PubMedCrossRefGoogle Scholar
  230. Tsai SJ, Wang YC, Hong CJ (2000) Association study of a cannabinoid receptor gene (CNR1) polymorphism and schizophrenia. Psychiatr Genet 10:149–151.PubMedCrossRefGoogle Scholar
  231. Turner WM, Tsuang MT (1990) Impact of substance abuse on the course and outcome of schizophrenia. Schizophr Bull 16:87–95.PubMedGoogle Scholar
  232. Uchigashima M, Narushima M, Fukaya M, Katona I, Kano M, Watanabe M (2007) 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.PubMedCrossRefGoogle Scholar
  233. Ujike H, Morita Y (2004) New perspectives in the studies on endocannabinoid and cannabis: cannabinoid receptors and schizophrenia. J Pharmacol Sci 96:376–381.PubMedCrossRefGoogle Scholar
  234. Ujike H, Takaki M, Nakata K, Tanaka Y, Takeda T, Kodama M, Fujiwara Y, Sakai A, Kuroda S (2002) CNR1, central cannabinoid receptor gene, associated with susceptibility to hebephrenic schizophrenia. Mol Psychiatry 7:515–518.PubMedCrossRefGoogle Scholar
  235. 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 156:319–327.PubMedCrossRefGoogle Scholar
  236. Vignal JP, Maillard L, McGonigal A, Chauvel P (2007) The dreamy state: hallucinations of autobiographic memory evoked by temporal lobe stimulations and seizures. Brain 130:88–99.PubMedCrossRefGoogle Scholar
  237. Virchow R (1847) Standpoints in scientific medicine. In: Rather LJ (ed.), Diseases, Life and Man; Selected Essays by Rudolf Virchow. Stanford: Stanford University Press.Google Scholar
  238. Voruganti LN, Slomka P, Zabel P, Mattar A, Awad AG (2001) Cannabis induced dopamine release: an in-vivo SPECT study. Psychiatry Res 107:173–177.PubMedCrossRefGoogle Scholar
  239. Wang Y, Goldman-Rakic PS (2004) D2 receptor regulation of synaptic burst firing in prefrontal cortical pyramidal neurons. Proc Natl Acad Sci USA 101:5093–5098.PubMedCrossRefGoogle Scholar
  240. Weiser M, Knobler HY, Noy S, Kaplan Z (2002) Clinical characteristics of adolescents later hospitalized for schizophrenia. Am J Med Genet 114:949–955.PubMedCrossRefGoogle Scholar
  241. Weiser M, Noy S (2005) Interpreting the association between cannabis use and increased risk for schizophrenia. Dialogues Clin Neurosci 7:81–85.PubMedGoogle Scholar
  242. Wettschureck N, van der Stelt M, Tsubokawa H, Krestel H, Moers A, Petrosino S, Schutz G, Di Marzo V, Offermanns S (2006) Forebrain-specific inactivation of Gq/G11 family G proteins results in age-dependent epilepsy and impaired endocannabinoid formation. Mol Cell Biol 26:5888–5894.PubMedCrossRefGoogle Scholar
  243. Yamasue H, Iwanami A, Hirayasu Y, Yamada H, Abe O, Kuroki N, Fukuda R, Tsujii K, Aoki S, Ohtomo K, Kato N, Kasai K (2004) Localized volume reduction in prefrontal, temporolimbic, and paralimbic regions in schizophrenia: an MRI parcellation study. Psychiatry Res 131:195–207.PubMedCrossRefGoogle Scholar
  244. Yano M, Steiner H (2005) Methylphenidate (Ritalin) induces Homer 1a and zif 268 expression in specific corticostriatal circuits. Neuroscience 132:855–865.PubMedCrossRefGoogle Scholar
  245. Yeomans JS (1995) Role of tegmental cholinergic neurons in dopaminergic activation, antimuscarinic psychosis and schizophrenia. Neuropsychopharmacology 12:3–16.PubMedCrossRefGoogle Scholar
  246. Zammit S, Allebeck P, Andreasson S, Lundberg I, Lewis G (2002) Self reported cannabis use as a risk factor for schizophrenia in Swedish conscripts of 1969: historical cohort study. BMJ 325:1199.PubMedCrossRefGoogle Scholar
  247. 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 28:355–360.PubMedCrossRefGoogle Scholar
  248. Zhang PW, Isighuro H, Ohtsuki T, Hess J, Carillo F, Walther D, Onaivi ES, Arinami T, Uhl GR (2004) Human cannabinoid receptor 1:5¢ exons, candidate regulatory regions, polymorphisms, haplotypes and association with polysusbstance abuse. Mol Psychiatry 9:916–931.PubMedCrossRefGoogle Scholar
  249. Zuardi AW, Crippa JA, Hallak JE, Moreira FA, Guimaraes FS (2006) Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug. Braz J Med Biol Res 39:421–429.PubMedCrossRefGoogle Scholar
  250. Zuardi AW, Morais SL, Guimaraes FS, Mechoulam R (1995) Antipsychotic effect of cannabidiol. J Clin Psychiatry 56:485–486.PubMedGoogle Scholar

Copyright information

© Springer 2008

Authors and Affiliations

  • Attila Köfalvi
    • Markus Fritzsche
      • 1
    1. 1.Praxis für Innere MedizinAdliswilSwitzerland

    Personalised recommendations