Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Lilly-Molecular Psychiatry Award Honorable Mention
  • Published:

Lilly Molecular Psychiatry Award, Honorary Mention

Human cannabinoid receptor 1: 5′ exons, candidate regulatory regions, polymorphisms, haplotypes and association with polysubstance abuse

Molecular Psychiatry volume 9, pages 916–931 (2004)Cite this article

Abstract

A number of lines of evidence make the gene that encodes the G-protein-coupled CB1/Cnr1 receptor a strong candidate to harbor variants that might contribute to individual differences in human addiction vulnerability. The CB1/Cnr1 receptor is the major brain site at which cannabinoid marijuana constituents are psychoactive as well as the principal brain receptor for endogenous anandamide ligands. It is densely expressed in brain circuits likely to be important for both the reward and mnemonic processes important for addiction. Altered drug effects in CB1/Cnr1 knockout mice and initial association studies also make variants at the CB1/Cnr1 locus candidates for roles in human vulnerabilities to addictions. However, many features of this gene's structure, regulation and variation remain poorly defined. This poor definition has limited the ability of previous association studies to adequately sample variation at this locus. We now report improved definition of the human CB1/Cnr1 locus and its variants. Novel exons 1–3, splice variant and candidate promoter region sequences add to the richness of the CB1/Cnr1 locus. Candidate promoter region sequences confer reporter gene expression in cells that express CB1/Cnr1. Common polymorphisms reveal patterns of linkage disequilibrium in European- and in African-American individuals. A 5′ CB1/Cnr1 ‘TAG’ haplotype displays significant allelic frequency differences between substance abusers and controls in European-American, African-American and Japanese samples. Post-mortem brain samples of heterozygous individuals contain less mRNA transcribed from the TAG alleles than from other CB1/Cnr1 haplotypes. CB1/ Cnr1 genomic variation thus appears to play roles in human addiction vulnerability.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

References

  1. Herkenham M, Lynn AB, Little MD, Johnson MR, Melvin LS, de Costa BR et al. Cannabinoid receptor localization in brain. Proc Natl Acad Sci USA 1990; 87: 1932–1936.

    Article  CAS  Google Scholar 

  2. Herkenham M, Lynn AB, Johnson MR, Melvin LS, de Costa BR, Rice KC . Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study. J Neurosci 1991; 11: 563–583.

    Article  CAS  Google Scholar 

  3. Matsuda LA, Bonner TI, Lolait SJ . Localization of cannabinoid receptor mRNA in rat brain. J Comp Neurol 1993; 327: 535–550.

    Article  CAS  Google Scholar 

  4. Tsou K, Brown S, Sanudo-Pena MC, Mackie K, Walker JM . Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system. Neuroscience 1998; 83: 393–411.

    Article  CAS  Google Scholar 

  5. Ledent C, Valverde O, Cossu G, Petitet F, Aubert JF, Beslot F et al. Unresponsiveness to cannabinoids, reduced addictive effects of opiates in CB1 receptor knockout mice. Science 1999; 283: 401–404.

    Article  CAS  Google Scholar 

  6. Mascia MS, Obinu MC, Ledent C, Parmentier M, Bohme GA, Imperato A 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–R2.

    Article  CAS  Google Scholar 

  7. Berrendero F, Castane A, Ledent C, Parmentier M, Maldonado R, Valverde O . Increase of morphine withdrawal in mice lacking A2a receptors and no changes in CB1/A2a double knockout mice. Eur J Neurosci 2003; 17: 315–324.

    Article  Google Scholar 

  8. 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: 857–867.

    Article  CAS  Google Scholar 

  9. Arnone M, Maruani J, Chaperon F, Thiebot MH, Poncelet M, Soubrie P et al. Selective inhibition of sucrose and ethanol intake by SR 141716, an antagonist of central cannabinoid (CB1) receptors. Psychopharmacology (Berl) 1997; 132: 104–106.

    Article  CAS  Google Scholar 

  10. Murray JB . Marijuana's effects on human cognitive functions, psychomotor functions, and personality. J Gen Psychol 1986; 113: 23–55.

    Article  CAS  Google Scholar 

  11. Arndt S, Tyrrell G, Flaum M, Andreasen NC . Comorbidity of substance abuse and schizophrenia: the role of pre-morbid adjustment. Psychol Med 1992; 22: 379–388.

    Article  CAS  Google Scholar 

  12. Batel P . Addiction and schizophrenia. Eur Psychiatry 2000; 15: 115–122.

    Article  CAS  Google Scholar 

  13. Ujike H, Takaki M, Nakata K, Tanaka Y, Takeda T, Kodama M et al. CNR1, central cannabinoid receptor gene, associated with susceptibility to hebephrenic schizophrenia. Mol Psychiatry 2002; 7: 515–518.

    Article  CAS  Google Scholar 

  14. Tsai SJ, Wang YC, Hong CJ . Association study of a cannabinoid receptor gene (CNR1) polymorphism and schizophrenia. Psychiatr Genet 2000; 10: 149–151.

    Article  CAS  Google Scholar 

  15. Dawson E, Powell JF, Sham PC, Nothen M, Crocq MA, Propping P et al. An association study of a neurotrophin-3 (NT-3) gene polymorphism with schizophrenia. Acta Psychiatr Scand 1995; 92: 425–428.

    Article  CAS  Google Scholar 

  16. Cao Q, Martinez M, Zhang J, Sanders AR, Badner JA, Cravchik A et al. Suggestive evidence for a schizophrenia susceptibility locus on chromosome 6q and a confirmation in an independent series of pedigrees. Genomics 1997; 43: 1–8.

    Article  CAS  Google Scholar 

  17. Levinson DF, Holmans P, Straub RE, Owen MJ, Wildenauer DB, Gejman PV et al. Multicenter linkage study of schizophrenia candidate regions on chromosomes 5q, 6q, 10p, and 13q: schizophrenia linkage collaborative group III. Am J Hum Genet 2000; 67: 652–663.

    Article  CAS  Google Scholar 

  18. Martinez M, Goldin LR, Cao Q, Zhang J, Sanders AR, Nancarrow DJ et al. Follow-up study on a susceptibility locus for schizophrenia on chromosome 6q. Am J Med Genet 1999; 88: 337–343.

    Article  CAS  Google Scholar 

  19. Shire D, Carillon C, Kaghad M, Calandra B, Rinaldi-Carmona M, Le Fur G et al. An amino-terminal variant of the central cannabinoid receptor resulting from alternative splicing. J Biol Chem 1995; 270: 3726–3731.

    Article  CAS  Google Scholar 

  20. Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI . Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 1990; 346: 561–564.

    Article  CAS  Google Scholar 

  21. Gerard C, Mollereau C, Vassart G, Parmentier M . Nucleotide sequence of a human cannabinoid receptor cDNA. Nucleic Acids Res 1990; 18: 7142.

    Article  CAS  Google Scholar 

  22. Gerard CM, Mollereau C, Vassart G, Parmentier M . Molecular cloning of a human cannabinoid receptor which is also expressed in testis. Biochem J 1991; 279: 129–134.

    Article  CAS  Google Scholar 

  23. Gadzicki D, Muller-Vahl K, Stuhrmann M . A frequent polymorphism in the coding exon of the human cannabinoid receptor (CNR1) gene. Mol Cell Probes 1999; 13: 321–323.

    Article  CAS  Google Scholar 

  24. Comings DE, Gonzalez N, Wu S, Gade R, Muhleman D, Saucier G et al. Studies of the 48 bp repeat polymorphism of the DRD4 gene in impulsive, compulsive, addictive behaviors: Tourette syndrome, ADHD, pathological gambling, and substance abuse. Am J Med Genet 1999; 88: 358–368.

    Article  CAS  Google Scholar 

  25. Schmidt LG, Samochowiec J, Finckh U, Fiszer-Piosik E, Horodnicki J, Wendel B et al. Association of a CB1 cannabinoid receptor gene (CNR1) polymorphism with severe alcohol dependence. Drug Alcohol Depend 2002; 65: 221–224.

    Article  CAS  Google Scholar 

  26. Leroy S, Griffon N, Bourdel MC, Olie JP, Poirier MF, Krebs MO . Schizophrenia and the cannabinoid receptor type 1 (CB1): association study using a single-base polymorphism in coding exon 1. Am J Med Genet 2001; 105: 749–752.

    Article  CAS  Google Scholar 

  27. Johnson JP, Muhleman D, MacMurray J, Gade R, Verde R, Ask M et al. Association between the cannabinoid receptor gene (CNR1) and the P300 event-related potential. Mol Psychiatry 1997; 2: 169–171.

    Article  CAS  Google Scholar 

  28. Hungund BL, Basavarajappa BS . Distinct differences in the cannabinoid receptor binding in the brain of C57BL/6 and DBA/2 mice, selected for their differences in voluntary ethanol consumption. J Neurosci Res 2000; 60: 122–128.

    Article  CAS  Google Scholar 

  29. Li T, Liu X, Zhu ZH, Zhao J, Hu X, Ball DM et al. No association between (AAT)n repeats in the cannabinoid receptor gene (CNR1) and heroin abuse in a Chinese population. Mol Psychiatry 2000; 5: 128–130.

    Article  Google Scholar 

  30. Uhl GR, Liu QR, Walther D, Hess J, Naiman D . Polysubstance abuse-vulnerability genes: genome scans for association, using 1,004 subjects and 1,494 single-nucleotide polymorphisms. Am J Hum Genet 2001; 69: 1290–1300.

    Article  CAS  Google Scholar 

  31. Ho BY, Zhao J . Determination of the cannabinoid receptors in mouse x rat hybridoma NG108-15 cells and rat GH4C1 cells. Neurosci Lett 212: 123–126.

  32. Wang JB, Imai Y, Eppler CM, Gregor P, Spivak CE, Uhl GR . mu opiate receptor: cDNA cloning and expression. Proc Natl Acad Sci USA 1993; 90: 10230–10234.

    Article  CAS  Google Scholar 

  33. Van Tol HH, Bunzow JR, Guan HC, Sunahara RK, Seeman P, Niznik HB et al. Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine. Nature 1991; 350: 610–614.

    Article  CAS  Google Scholar 

  34. He X, Zhang Y, Yan Y, Li Y, Koide SS . Identification of GABABR2 in rat testis and sperm. J Reprod Dev 2003; 49: 397–402.

    Article  CAS  Google Scholar 

  35. Fan D, Grooms SY, Araneda RC, Johnson AB, Dobrenis K, Kessler JA et al. AMPA receptor protein expression and function in astrocytes cultured from hippocampus. J Neurosci Res 1999; 57: 557–571.

    Article  CAS  Google Scholar 

  36. Guptan P, Dhingra A, Panicker MM . Multiple transcripts encode the 5-HT1F receptor in rodent brain. Neuroreport 1997; 8: 3317–3321.

    Article  CAS  Google Scholar 

  37. Zhou D, Song ZH . CB1 cannabinoid receptor-mediated neurite remodeling in mouse neuroblastoma N1E-115 cells. J Neurosci Res 2001; 65: 346–353.

    Article  CAS  Google Scholar 

  38. Takahashi Y . Gene expression in cells of the central nervous system. Prog Neurobiol 1992; 38: 523–569.

    Article  CAS  Google Scholar 

  39. Dodson RE, Shapiro DJ . Regulation of pathways of mRNA destabilization and stabilization. Prog Nucleic Acid Res Mol Biol 2002; 72: 129–164.

    Article  CAS  Google Scholar 

  40. Hambraeus G, von Wachenfeldt C, Hederstedt L . Genome-wide survey of mRNA half-lives in Bacillus subtilis identifies extremely stable mRNAs. Mol Genet Genomics 2003; 269: 706–714.

    Article  CAS  Google Scholar 

  41. Schneider RJ, Mohr I . Translation initiation and viral tricks. Trends Biochem Sci 2003; 28: 130–136.

    Article  CAS  Google Scholar 

  42. Hoehe MR, Rinn T, Flachmeier C, Heere P, Kunert HJ et al. Comparative sequencing of the human CB1 cannabinoid receptor gene coding exon: no structural mutations in individuals exhibiting extreme responses to cannabis. Psychiatr Genet 2000; 10: 173–177.

    Article  CAS  Google Scholar 

  43. Covault J, Gelernter J, Kranzler H . Association study of cannabinoid receptor gene (CNR1) alleles and drug dependence. Mol Psychiatry 2001; 6: 501–502.

    Article  CAS  Google Scholar 

  44. Marsicano G, Wotjak CT, Azad SC, Bisogno T, Rammes G, Cascio MG et al. The endogenous cannabinoid system controls extinction of aversive memories. Nature 2002; 418: 530–534.

    Article  CAS  Google Scholar 

  45. Fergusson DM, Horwood LJ . Does cannabis use encourage other forms of illicit drug use? Addiction 2000; 95: 505–520.

    Article  CAS  Google Scholar 

  46. Wagner FA, Anthony JC . Into the world of illegal drug use: exposure opportunity and other mechanisms linking the use of alcohol, tobacco, marijuana, and cocaine. Am J Epidemiol 2002; 155: 918–925.

    Article  Google Scholar 

  47. Muschamp JW, Siviy SM . Behavioral sensitization to amphetamine follows chronic administration of the CB1 agonist WIN 55,212-2 in Lewis rats. Pharmacol Biochem Behav 2002; 73: 835–842.

    Article  CAS  Google Scholar 

  48. Vinklerova J, Novakova J, Sulcova A . Inhibition of methamphetamine self-administration in rats by cannabinoid receptor antagonist AM 251. J Psychopharmacol 2002; 16: 139–143.

    Article  CAS  Google Scholar 

  49. Masserano JM, Karoum F, Wyatt RJ . SR 141716A, a CB1 cannabinoid receptor antagonist, potentiates the locomotor stimulant effects of amphetamine and apomorphine. Behav Pharmacol 1999; 10: 429–432.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We acknowledge financial support from NIDA IRP, NIH, DHSS and the Ministries of Health, Labor and Welfare and of Education, Culture, Sports, Science and Technology of Japan. Some of this data was generated through the use of the Celera Discovery System and Celera's associated database.

Author information

Author notes

  1. P-W Zhang and H Ishiguro: The authors contributed equally to this work and should be regarded as joint first authors.

Authors and Affiliations

  1. Molecular Neurobiology Branch, NIDA-IRP, NIH, DHSS, Baltimore, MD, USA

    P-W Zhang, H Ishiguro, J Hess, F Carillo, D Walther, E S Onaivi & G R Uhl

  2. Department of Human Genetics, Institute of Basic Medicine, University of Tsukuba, Ibaraki, Japan

    T Ohtsuki & T Arinami

  3. Department of Biology, William Patterson University, Wayne, NJ, USA

    E S Onaivi

Authors
  1. P-W Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H Ishiguro
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T Ohtsuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J Hess
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. F Carillo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. D Walther
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. E S Onaivi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. T Arinami
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. G R Uhl
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to G R Uhl.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, PW., Ishiguro, H., Ohtsuki, T. et al. Human cannabinoid receptor 1: 5′ exons, candidate regulatory regions, polymorphisms, haplotypes and association with polysubstance abuse. Mol Psychiatry 9, 916–931 (2004). https://doi.org/10.1038/sj.mp.4001560

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.mp.4001560

Keywords

This article is cited by

Search

Advanced search

Quick links