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.

  • Original Article
  • Published:

Depression in Parkinson's disease is related to a genetic polymorphism of the cannabinoid receptor gene (CNR1)

The Pharmacogenomics Journal volume 5, pages 135–141 (2005)Cite this article

Abstract

Depression is a common symptom in Parkinson's disease (PD) and it is present in up to 40% of the patients. The cause of depression in PD is thought to be related to disturbance of monoamine neurotransmission. The endogenous cannabinoid system mediates different brain processes that play a role in the control of behaviour and emotions. Cannabinoid function may be altered in neuropsychiatry diseases, directly or through interactions with monoamine, GABA and glutamate systems. For this reason, we have investigated whether there is a genetic risk factor for depression in PD linked to the polymorphisms of CB1 receptor gene. Depression was more frequent in patients with PD than in controls with osteoarthritis. The presence of depression did not correlate with the stage of the disease but it was more frequent in patients with pure akinetic syndrome than in those with tremoric or mixed type PD. The CB1 receptor gene polymorphism (AAT)n is considered to modify the transcription of the gene and, therefore, it may have functional relevance. We analysed the length of the polymorphic triplet (AAT)n of the gene that encodes CB1 (CNR1) receptor in 89 subjects (48 PD patients and 41 controls). In patients with PD, the presence of two long alleles, with more than 16 repeated AAT trinucleotides in the CNR1 gene, was associated with a reduced prevalence of depression (Fisher's exact test: P=0.003). This association did not reach significant differences in the control group, but the number of control individuals with depression was too small to allow for statistical analysis. Since the alleles with long expansions may have functional impact in cannabinoid neurotransmission, our data suggest that the pharmacological manipulation of cannabinoid neurotransmission could open a new therapeutic approach for the treatment of depression in PD and possibly in other conditions.

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

Similar content being viewed by others

References

  1. Tanner CM, Goldman SM . Epidemiology of Parkinson's disease. Neurol Clin 1996; 14: 317–335.

    Article  CAS  Google Scholar 

  2. Gibb WRG, Lees AJ . Pathological clues to the cause of Parkinson's disease. In: Marsden CD, Fahn S (eds). Movement Disorders, vol. 3. Butterworth-Heinemann: Oxford, 1994, pp 146–166.

    Google Scholar 

  3. Chia LG, Cheng LJ, Chuo LJ, Cheng FC, Cu JS . Studies of dementia, depression, electrophysiology and cerebrospinal fluid monoamine metabolites in patients with Parkinson's disease. J Neurol Sci 1995; 133: 73–78.

    Article  CAS  Google Scholar 

  4. Cummings LF . Depression and Parkinson's disease: a review. Am J Psychiatric 1992; 149: 443–454.

    Article  CAS  Google Scholar 

  5. Tandberg E, Larsen JP, Arsland D, Cummings JL . The occurrence of depression in Parkinson's disease. A community-based study. Arch Neurol 1996; 53: 175–179.

    Article  CAS  Google Scholar 

  6. McDonald WM, Richard IH, DeLong MR . Prevalence, etiology, and treatment of depression in Parkinson's disease. Biol Psychiatry 2003; 54: 363–375.

    Article  Google Scholar 

  7. Serrano-Dueñas M . A comparison between low doses of amitriptyline and low doses of fluoxetin used in the control of depression in patients suffering from Parkinson's disease. Rev Neurol 2002; 35: 1010–1014.

    PubMed  Google Scholar 

  8. Kostic VS, Filipovic SR, Lecic D, Momcilovic D, Sokic D, Sternic N . Effect of age at onset on frequency of depression in Parkinson's disease. J Neurol Neurosurg Psychiatry 1994; 57: 1265–1267.

    Article  CAS  Google Scholar 

  9. Mayeux R, Stern Y, Rosen J, Leventhal J . Depression intellectual impairment and Parkinson's disease. Neurology 1981; 31: 645–650.

    Article  CAS  Google Scholar 

  10. Mayeux R . Behavioral manifestations of movement disorders. Neurol Clin 1984; 2: 527–540.

    Article  CAS  Google Scholar 

  11. Huber SJ, Paulson GW, Shuttleworth EC . Relationship of motor symptoms, intellectual impairment, and depression in Parkinson's disease. J Neurol Neurosurg Psychiatry 1998; 51: 855–858.

    Article  Google Scholar 

  12. Liu C-Y, Wang S-J, Fuh J-L, Liu CH, Yang YY, Liu HC . The correlation of depression with functional activity in Parkinson's disease. J Neurol 1997; 244: 493–498.

    Article  CAS  Google Scholar 

  13. Gil Saladié D, Delgado González M . y cols. La depresión de la enfermedad de Parkinson y su relación con las manifestaciones cognitivas y motoras. Neurología 1992; 7: 176–179.

    PubMed  Google Scholar 

  14. Hammond-Tooke G, Pollock M . Depression, dementia, and Parkinson's disease. In: Hoseph AB, Young RR (eds). Movement Disorders in Neurology and Neuropsychiatry, 2 edn. Blackwell Science: Massachusetts, 1999, pp 195–204.

    Google Scholar 

  15. Meltzer HY, Lowy MT . The serotonin hypothesis of depression. In: Meltzer HY (eds). Psychopharmacology: The Third Generation of Progress. Raven Press: New York, 1987, pp 513–526.

    Google Scholar 

  16. Howlett AC, Bidaut-Rusell M, Devane WA, Melvin LS, Johnson MR, Herkenham M . The cannabinoid receptor: biochemical, anatomical and behavioural characterization. Trends Neurosci 1990; 13: 420–423.

    Article  CAS  Google Scholar 

  17. Tsout K, Brown S, Sañudo-Peña MC, Mackie K, Walker JM . Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system. Neuroscience 1998; 83: 393–411.

    Article  Google Scholar 

  18. Hoehe MR, Caenazzo L, Martinez MM, Hsieh WT, Modi WS, Gershon ES et al. Genetic and physical mapping of the human cannabinoid receptor gene chromosome 6q14–q15. New Biol 1991; 3: 880–885.

    CAS  PubMed  Google Scholar 

  19. 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 

  20. Hermann H, Marsicano G, Lutz B . Coexpression of the cannabinoid receptor type 1 with dopamine and serotonin receptors in distinct neuronal subpopulations of the adult mouse forebrain. Neuroscience 2002; 109: 451–460.

    Article  CAS  Google Scholar 

  21. Sieradzan KA, Fox SH, Hill M, Disck JP, Crossman AR, Brotchie JM et al. Cannabinoids reduce levodopa-induced dyskinesia in Parkinson's disease: a pilot study. Neurology 2001; 57: 2108–2111.

    Article  CAS  Google Scholar 

  22. Sañudo-Peña MC, Tsoy K, Walker JM . Motor action of cannabinoids in the basal ganglia output nuclei. Life Sci 1999; 65: 713.

    Article  Google Scholar 

  23. Lastres-Becker I, Cebeira M, de Cevallos M, Zeng B-Y, Jenner P, Ramos JA . Fernández–Ruiz increased cannabinoid CB1 receptor binding and activation of GPT-binding proteins in the basal ganglia of patients with Parkinson's disease and MPTP-treated marmosets. Eur J Neurosci 2001; 14: 1827–1832.

    Article  CAS  Google Scholar 

  24. Rottanburg D, Robins AH, Ben-Arie O, Teggin A, Elk R . Cannabis associated psychosis with hipomanic features. Lancet 1982; 2: 1364–1366.

    Article  CAS  Google Scholar 

  25. Devane AA, Dysarz FA, Johnson MR, Melvin LS, Howlett AC . Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol 1988; 34: 605–613.

    CAS  Google Scholar 

  26. 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 

  27. Banerjee SP, Synder SH, Mechulam R . Cannabinoids: L influence on neurotransmitter uptake in rat brain synaphosomes. J Pharmacol Exp Ther 1975; 194: 74–81.

    CAS  PubMed  Google Scholar 

  28. Musty RE, Kaback L . Relationships between motivation and depression in chronic marijuana users. Life Sci 1995; 56: 2151–2158.

    Article  CAS  Google Scholar 

  29. Mato S, Rodriguez-Puertas R, González-Maeso J, Meana J, Sallés J, Pazos A . Receptores centrales para cannabinoides en cerebro humano postmortem: estudio radiométrico en la depresión mayor. 1a Reunión nacional sobre investigación en cannabinoides, Madrid, 2000.

  30. Robbe D, Kopf M, Remaury A, Bockaert J, Manzoni OJ . Endogenous cannabinoids mediate long-term synaptic depression in the nucleus accumbens. Proc Natl Acad Sci USA 2002; 99: 8384–8388.

    Article  CAS  Google Scholar 

  31. Wainwright NWJ, Surtees PG . Childhood adversity, gender and depression over the life-course. J Affect Disorders 2002; 72: 33–44.

    Article  CAS  Google Scholar 

  32. Martin M, Ledent C, Parmentir M, Maldonado R, Valverde O . Involvement of CB1 cannabinoid receptors in emotional behaviour. Psychopharmacology 2002; 159: 379–387.

    Article  CAS  Google Scholar 

  33. Dawson E . Identification of a polymorphic triplet repeat marker for the brain cannabinoid receptor gene: use in linkage and association studies. Psychiat Genet 1995; 5: S50.

    Article  Google Scholar 

  34. Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A et al. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science 1997; 276: 2045–2047.

    Article  CAS  Google Scholar 

  35. Mizuno Y, Hattori N, Mori H, Suzuki T, Tanaka K . Parkin and Parkinson's disease. Curr Opin Neurol 2001; 14: 477–482.

    Article  CAS  Google Scholar 

  36. Vaughan JR, Davis MB, Wood NW . Genetics of Parkinsonism: a review. Ann Hum Genet 2001; 65: 111–126.

    Article  CAS  Google Scholar 

  37. Tan EK, Khajavi M, Thornby JL, Nagamitsu S, Jankovic J, Ashizawa T . Variability and validity of polymorphism association studies in Parkinson's disease. Neurology 2000; 55: 533–538.

    Article  CAS  Google Scholar 

  38. Schroth GP, Chou PJ, Ho PS . Mapping Z-DNA in the human genome. Computer-aided mapping reveals a nonrandom distribution of potential Z-DNA-forming sequences in human genes. J Biol Chem 1992; 267: 11846–11855.

    CAS  PubMed  Google Scholar 

  39. Comings DE . Polygenic inheritance and minisatellites. Psychiat Genet 1996; 6: 157–158.

    Article  Google Scholar 

  40. Tsai SJ, Wang YC, Hong CJ . Association study between cannabonoid receptor gene (CNR1) and pathogenesis and psychotic symptoms of mood disorders. Am J Med Genet 2001; 105: 219–221.

    Article  CAS  Google Scholar 

  41. Comings DE, Muhleman D, Gade R, Jonson P, Verde R, Saucier G et al. Cannabinoid receptor gene (CNR1): association with IV drug abuse. Mol Psychiatry 1997; 2: 161–168.

    Article  CAS  Google Scholar 

  42. Lutz G, Schmidt T, Samochowiec J, Finckh U, Fiser-Piosik E, Horodinicki J et al. Association of a CB1 cannabinoid receptor gene (CNR1) polymorphism with severe alcohol dependence. Drug Alcohol Depen 2002; 65: 221–224.

    Article  Google Scholar 

  43. 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 

  44. Heller D, Schneider U, Seifert J, Cimander KF, Stuhrmann M . The cannabinoid receptor gene (CNR1) is not affected in German i.v. drugs users. Addict Biol 2001; 6: 183–187.

    Article  CAS  Google Scholar 

  45. 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 

  46. Hungund BL, Vinod KY, Kassir SA, Basavarajappa BS, Yalamanchili R, Cooper TB et al. Upregulation of CB1 receptors and agonist-stimulated [35S] GTPgammaS binding in the prefrontal cortex of depressed suicide victims. Mol Psychiatry 2004; 9: 184–190.

    Article  CAS  Google Scholar 

  47. Melamed E . Neurobehavioral abnormalities in Parkinson's disease. In: Watt RL, Koller WC (eds). Movement Disorders. Neurologic Principles and Practice. McGraw-Hill: New York, 1997, pp 257–261.

    Google Scholar 

  48. Errea-Abad JM, Ara-Callizo JR, Aibar-Remón C . Drug-induced Parkinsonism. Clinical aspects compared with Parkinson disease. Rev Neurol 1998; 27: 35–39.

    CAS  PubMed  Google Scholar 

  49. Mayberg HS, Solomon DH . Depression in Parkinson's disease: a biochemical and organic viewpoint. Adv Neurol 1995; 65: 49–60.

    CAS  PubMed  Google Scholar 

  50. Hantz P, Caradoc-Davis G, Caradoc-Davis T, Weatherall M, Dixon G . Depression in Parkinson's disease. Am J Psychiatry 1994; 151: 1010–1014.

    Article  CAS  Google Scholar 

  51. Santamaría J, Tolosa E, Valles A . A Parkinson's disease with depression: a possible subgroup of idiopathic Parkinsonism. Neurology 1986; 36: 1130–1133.

    Article  Google Scholar 

  52. Starkstein SE, Petracca G, Chemerinski E, Teson A, Sabe L, Merello M et al. Depression in classic versus akinetic-rigid Parkinson's disease. Mov Disord 1998; 13: 29–33.

    Article  CAS  Google Scholar 

  53. Mayeux R, Stern Y, Rosen J, Leventhal J . Depression, intellectual impairment and Parkinson's disease. Neurology 1991; 31: 645–650.

    Article  Google Scholar 

  54. Ponce G, Hoenicka J, Rubio G, Ampuero I, Jiménez-Arriero MA, Rodríguez-Jimenez R et al. Association between the cannabinoid receptor gene (CNR1) and childhood attention-deficit/hyperactivity disorder in Spanish male alcoholic, patients. Mol Psychiatry 2003; 8: 466–467.

    Article  CAS  Google Scholar 

  55. Macritchie KA, Young AH . Emerging targets for the treatment of depressive disorder. Expert Opin Ther targets 2001; 5: 601–612.

    Article  CAS  Google Scholar 

  56. Gelb DJ, Oliver E, Gliman S . Diagnostic criteria for Parkinson Disease. Arch Neurol 1999; 56: 33–39.

    Article  CAS  Google Scholar 

  57. Hoehn MM, Yahr MD . Parkinsonism: onset, progression and mortality. Neurology 1967; 17: 427–442.

    Article  CAS  Google Scholar 

  58. Fahn S, Elton RL . Members of the UPDRS Development Committee: Unified Parkinson's Disease Rating Scale. In: Fahn S, Marsden CD, Calne DB, Goldstein M (eds). Recent Developments in Parkinson's Disease, vol. 2. Macmillan Healthcare information: Florham Park, NJ, 1987, pp 153–163, 293–304.

    Google Scholar 

  59. Hamilton M . A rating scale for depression. J Neurol Neurosurg Psychiatry 1960; 23: 56–62.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work has been possible owing to a research grant from Fondo de Investigaciones Sanitarias year 2000, number 00/0785, to D Blas Morales and support from Centro Investigaciones sobre Enfermedades Neurologicas and to Dr Justo García de Yébenes, years 2003 and 2004. Israel Ampuero was a research fellow of Fondo de Investigaciones.

Author information

Authors and Affiliations

  1. Movement Diseases Unit, University Hospital of San Cecilio, Granada, Spain

    F J Barrero & B Morales

  2. Banco de Tejidos para Investigaciones Neurológicas, Facultad de Medicina, Universidad Complutense de Madrid, Spain

    I Ampuero, J Hoenicka & J García Yébenes

  3. Department of Physiology, Faculty of Medicine, University of Granada, Spain

    F Vives

  4. Department of Biostatistics, Faculty of Medicine, University of Granada, Spain

    J de Dios Luna del Castillo

  5. Department of Neurology, Foundation Jiménez Díaz, Madrid, Spain

    J García Yébenes

Authors
  1. F J Barrero
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. I Ampuero
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. B Morales
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. F Vives
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J de Dios Luna del Castillo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J Hoenicka
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J García Yébenes
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to B Morales.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Barrero, F., Ampuero, I., Morales, B. et al. Depression in Parkinson's disease is related to a genetic polymorphism of the cannabinoid receptor gene (CNR1). Pharmacogenomics J 5, 135–141 (2005). https://doi.org/10.1038/sj.tpj.6500301

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.tpj.6500301

Keywords

This article is cited by

Search

Advanced search

Quick links