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The Molecular Genetics of Pathological Gambling

Published online by Cambridge University Press:  07 November 2014

David E. Comings
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Abstract

As gambling becomes available to more and more individuals in this country, the problem of compulsive or pathological gambling (PG) will also increase. As with other forms of addiction, both environmental and genetic factors are involved in PG. Identification of the genes that play a role in increasing a person's risk for PG will lead to a better understanding of the disorder and to more rational and effective treatment. Although studies of the molecular genetics of PG are just beginning, a number of interesting observations have been made and are reviewed in this article. As with other addictive behaviors, abnormalities in dopaminergic reward pathways a likely to be involved. Consistent with this, we have observed a significant association between PG and the D1, D2, D3, and D4 dopamine receptor genes. The fact that each these genes has an effect is consistent with a polygenic inheritance of a susceptibility to PG The involvement of multiple dopamine genes consistent with the “reward deficiency syndrome,” which suggests that addictive impulsive disorders are due, at least in part, to genetic abnormalities of the dopamine reward pathways. On the basis of this hypothesis, we describe other genes also likely to play a role in a person's susceptibility to PG.

Type
Feature Articles
Information
CNS Spectrums , Volume 3 , Issue 6: Pathological Gambling , June 1998 , pp. 20 - 37
Copyright
Copyright © Cambridge University Press 1998

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References

REFERENCES

1.American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.Google Scholar
2.Volberg, RA. The prevalence and demographics of pathological gamblers: implications for public health. Am J Public Health. 1994;84:237–241.CrossRefGoogle ScholarPubMed
3.Beckham, J. Gamble: weary bettors pay the ultimate toll for habit. Los Angeles Times. June 22, 1997; A14–A15.Google Scholar
4.Rosenthal, RJ. Pathological gambling. Psychiatric Annals. 1992;22:72–78.CrossRefGoogle Scholar
5.Lesieur, HR, Blume, SB, Zoppa, RM. Alcoholism, drug abuse and gambling. Alcohol Clin Exp Res. 1984; 10:33–38.Google Scholar
6.Levinson, PK, Gerstein, DR, Maloff, DR. Commonalities in Substance Abuse and Habitual Behaviors. Lexington, Ky: Lexington Books; 1983.Google Scholar
7.Ramirez, LF, McCormick, RA, Russo, AM, et al.Patterns of substance abuse in pathological gamblers undergoing treatment. Addict Behav. 1984;8:425–428.Google Scholar
8.Lesieur, HR, Heineman, M. Pathological gambling among youthful multiple substance abusers in a therapeutic community. Br J Addict. 1988;83:765–771.Google Scholar
9.Carlton, PL, Manowitz, P, McBride, H, Nora, R, Swartzburg, M, Goldstein, L. Attention deficit disorder and pathological gambling. J Clin Psychiatry. 1987;48:487–488.Google ScholarPubMed
10.Rugle, L. Neuropsychological Assessment of Attention Deficit Disorder in Pathological Gamblers [dissertation]. Kent, Ohio: Kent State University; 1990.Google Scholar
11.Rugle, L, Melamed, L. Neuropsychological assessment of attention problems in pathological gamblers. J Nerv Ment Dis. 1993;181:107–112.Google Scholar
12.Carlton, PL, Goldstein, L. Physiological determinants of pathological gambling. In: Galski, T, ed. Handbook on Pathological Gambling. Springfield, Ill: Charles C. Thomas Publisher; 1987.Google Scholar
13.Blaszcynski, A, McConaghy, N, Frankova, A. Crime, antisocial personality and pathological gambling. Gambling Behav. 1989;5:137–152.CrossRefGoogle Scholar
14.Rosenthal, RJ. The pathological gambler's system of self-deception. Gambling Behav. 1986;2:108–120.Google Scholar
15.Glenn, A. The narcissistic personality as it relates to pathological gamblers. Presented at: 7th International Conference on Gambling and Risktaking; 1987; Reno, Nev.Google Scholar
16.Russo, AM. The Relationship Between Pathological Gambling and Narcissism [master's thesis]. Athens, Ohio: Ohio University; 1987.Google Scholar
17.McCormick, RA, Russo, AM, Ramirez, LF, Taber, JI. Affective disorders among pathological gamblers seeking treatment. Am J Psychiatry. 1984;141:215–218.Google Scholar
18.Linden, RD, Pope, HG, Jonas, SM. Pathological gambling and major affective disorder: preliminary findings. J Clin Psychiatry. 1986;47:201–203.Google Scholar
19.Comings, DE. Polygenetic inheritance of psychiatric disorders. In: Blum, K, Noble, EP, Sparks, RS, Sheridan, PJ, eds. Handbook of Psychiatric Genetics. Boca Raton, Fla: CRC Press; 1996:235.Google Scholar
20.Comings, DE. Polygenic inheritance and micro/-minisatellites. Mol Psychiatry. 1998;3:21–31.Google Scholar
21.Comings, DE. Why different rules are required for investigating polygenic inheritance: lessons from studies of the DRD2 gene in addictive behaviors. Alcohol Clin Exp Res. In press.Google Scholar
22.American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 3rd ed, rev. Washington, DC: American Psychiatric Association; 1987.Google Scholar
23.Comings, DE. Tourette Syndrome and Human Behavior. Duarte, Calif: Hope Press; 1990.Google Scholar
24.Hudson, JI, Pope, HG Jr.Affective spectrum disorder: does antidepressant response indentify a family of disorders with a common pathophysiology? Am J Psychiatry. 1990;147:552–564.Google Scholar
25.McElroy, SL, Hudson, JI, Pope, HG Jr, Keck, PE, Aizley, HG. The DSM-III-R impulse control disorders not elsewhere classified: clinical characteristics and relationship to other psychiatric disorders. Am J Psychiatry. 1992;149:318–327.Google Scholar
26.Comings, DE, Comings, BG. Comorbid behavioral disorders. In: Kurlan, R, ed. Handbook of Tourette's Syndrome and Related Tic and Behavioral Disorders. New York, NY: Marcel Dekker; 1993:111.Google Scholar
27.Sacks, O. Awakenings. 4th ed. New York, NY: EP Dutton; 1983.Google Scholar
28.Blum, K, Noble, EP, Sheridan, PJ, et al.Allelic association of human dopamine D2 receptor gene in alcoholism. JAMA. 1990;263:2055–2059.CrossRefGoogle ScholarPubMed
29.Grandy, DK, Litt, M, Allen, L, et al.The human dopamine D2 receptor gene is located on chromosome 11 at q22-q23 and identifies a TaqI RFLP. Am J Hum Genet. 1989;45:778–785.Google Scholar
30.Noble, EP. The D2 dopamine receptor gene: a review of association studies in alcoholism. Behav Genet. 1993;23:119–129.Google Scholar
31.Blum, K, Sheridan, PJ, Wood, RC, Braverman, ER, Chen, T, Comings, DE. Dopamine D2 receptor gene variants: association and linkage studies in impulsive-addictive-compulsive behavior. Pharmacogenetics. 1995;5:121–141.CrossRefGoogle Scholar
32.Comings, DE, Comings, BG, Muhleman, D, et al.The dopamine D2 receptor locus as a modifying gene in neuropsychiatric disorders. JAMA. 1991;266:1793–1800.Google Scholar
33.Pakstis, AJ, Heutink, P, Pauls, DL, et al.Progress in the search for genetic linkage with Tourette syndrome: an exclusion map covering more than 50% of the autosomal genome. Am J Hum Genet. 1991;48(2):281–294.Google ScholarPubMed
34.Comings, DE, Wu, H, Chiu, C, Ring, RH, Dietz, G, Muhleman, D. Polygenic inheritance of Tourette's syndrome, stuttering, attention deficit hyperactivity, conduct, and oppositional defiant disorder: the additive and subtractive effect of the three dopaminergic genes—DRD2, D beta H and DAT1. Am J Med Genet. 1996;67:264–288.3.0.CO;2-N>CrossRefGoogle Scholar
35.Comings, DE. The role of genetic factors in conduct disorder based on studies of Tourette's syndrome and ADHD probands and their relatives. J Dev Behav Pediatr. 1995:16:142–157.CrossRefGoogle ScholarPubMed
36.Comings, DE. Search for the Tourette's Syndrome and Human Behavior Genes. Duarte, Calif: Hope Press; 1996.Google Scholar
37.Blum, K, Cull, JG, Braverman, ER, Comings, DE. Reward deficiency syndrome. Am Scientist. 1996;84:132–145.Google Scholar
38.Comings, DE, Rosenthal, RJ, Lesieur, HR, et al.A study of the dopamine D2 receptor gene in pathological gambling. Pharmacogenetics. 1996;6:223–234.Google Scholar
39.Self, DW, Barnhart, WJ, Lehrman, DA, Nestler, EJ. Opposite modulation of cocaine-seeking behavior by D1- and D2-like dopamine receptor agonists. Science. 1996:271:1586–1589.Google Scholar
40.Comings, DE, Gade, R, Wu, S, et al.Studies of the potential role of the dopamine D1 receptor gene in addictive behaviors. Mol Psychiatry. 1997:2:44–56.CrossRefGoogle ScholarPubMed
41.Cichon, S, Nöthen, MM, Erdman, J, Propping, P. Detection of four polymorphic sites in the human dopamine D1 receptor gene (DRD1). Hum Mol Genet. 1994;3:209.Google Scholar
42.Crocq, M-A. Mant, R, Asherson, P. et al.Association between schizophrenia and homozygosity at the dopamine D3 receptor gene. J Med Genet. 1992;29:858–860.Google Scholar
43.Asherson, P, Mant, R, Holmans, P, et al.Linkage, association and mutational analysis of the dopamine D3 receptor gene in schizophrenia. Mol Psychiatry. 1996:1:125–132.Google Scholar
44.Comings, DE, Muhleman, D, Dietz, G, Dino, M, Legro, R, Gade, R. Association between Tourette's syndrome and homozygosity at the dopamine-D3 receptor gene. Lancet. 1993;341:906.Google Scholar
45.Comings, DE, Muhleman, D, Dietz, G, Dino, M, Legro, R, Gade, R. Tourette's syndrome and homozygosity for the dopamine D3 receptor gene - reply [editorial]. Lancet. 1993:341:1483–1484.Google Scholar
46.Van Tol, HHM, Wu, CM, Guan, H-C, et al.Multiple dopamine D4 receptor variants in human population. Nature. 1992;358:149–152.Google Scholar
47.Benjamin, J, Paterson, C, Greenberg, B, Murphy, DL, Hamer, D. Dopamine D4 receptor gene association with normal personality traits. Psychiatr Genet. 1995;5:S36.Google Scholar
48.Novick, O, Ebstein, R, Umansky, R, Priel, B, Osher, Y, Belmaker, RH. D4 receptor polymorphism associated with personality variation in normals. Psychiatr Genet. 1995;5:S36.Google Scholar
49.Malhotra, AK, Virkkunen, M, Rooney, W, Eggert, M, Linnoila, M, Goldman, D. The association between the dopamine D4 receptor (DRD4) 16 amino acid repeat polymorphisms and novelty seeking. Mol Psychiatry. 1996:1:388–391.Google Scholar
50.Grice, DE, Leckman, JF, Pauls, DL, et al.Linkage disequilibrium of an allele at the dopamine D4 receptor locus with Tourette's syndrome by TDT. Am J Hum Genet. 1996;59:644–652.Google Scholar
51.Lahoste, GJ, Swanson, JM, Wigal, SB, et al.Dopamine D4 receptor gene polymorphism is associated with attention deficit hyperactivity disorder. Mol Psychiatry. 1996;1:121–124.Google Scholar
52.Kotler, M, Cohen, H, Segman, R, et al.Excess dopamine D4 receptor (DRD4) exon III seven repeat allele in opioid dependent subjects. Mol Psychiatry. 1997:2:251–254.CrossRefGoogle ScholarPubMed
53.Banki, CM, Arato, M, Papp, Z, Kurz, M. Biochemical markers in suicidal patients. Investigations with cerebrospinal fluid amine metabolites and neuroendrocrine tests. J Affect Disord. 1984;6:341–350.CrossRefGoogle Scholar
54.Branchey, L, Branchey, M, Shaw, S, Lieber, CS. Depression, suicide, and aggression in alcoholics and their relationship to plasma amino acids. Psychiatry Res. 1984;12:219–226.Google Scholar
55.Brown, GL, Ebert, MF, Goyer, PH, et al.Aggression, suicide and serotonin relationships to CSF amine metabolism. Am J Psychiatry. 1982;139:741–746.Google Scholar
56.Brown, S-L, van Praag, HM. The Role of Serotonin in Psychiatric Disorders. New York, NY: Brunner/Mazel; 1990.Google Scholar
57.Comings, DE, Muhleman, D, Dietz, G, Sherman, M, Forest, G. Sequence of human tryptophan 2,3-dioxygenase: presence of a glucocorticoid response-like element composed of a GTT repeat and an intronic CCCCT repeat. Genomics. 1995;29:390–396.Google Scholar
58.Comings, DE, Muhleman, D, Gade, R, et al.Exon and intron mutations in the human tryptophan 2,3-dioxygenase gene and their potential association with Tourette's syndrome, substance abuse and other psychiatric disorders. Pharmacogenetics. 1996;6:307–318.Google Scholar
59.Wiberg, A, Gottfries, CG, Oreland, L. Low platelet monoamine oxidase activity in human alcoholics. Med Biol. 1977;55:181–186.Google Scholar
60.Gottfries, CG, Oreland, L, Wiberg, A, Winblad, B. Lowered monoamine oxidase activity in brains from alcoholic suicides. J Neurochem. 1975:25:667–673.Google Scholar
61.Devor, EJ, Cloninger, CR, Hoffman, PL, Tabakoff, B. Association of monoamine oxidase (MAO) activity with alcoholism and alcoholic subtypes. Am J Med Genet. 1994;48:209–213.CrossRefGoogle Scholar
62.Vonknorring, AL, Hallmann, J, Vonknorring, L, Oreland, L. Platelet monoamine oxidase activity in type-1 and type-2 alcoholism. Alcohol Alcohol. 1991;26:409–416.Google Scholar
63.Sherif, F, Marcusson, J, Oreland, L. Brain gamma-aminobutyrate transaminase and monoamine oxidase activities in suicide victims. Eur Arch Psychiatry Clin Neurosci. 1991:241:139–144.CrossRefGoogle ScholarPubMed
64.Pandey, GN, Sharma, RP, Janicak, PG, Davis, JM. Monamine oxidase and cortisol response in depression and schizophrenia. Psychiatry Res. 1992;44:1–8.Google Scholar
65.Pandey, GN, Dorus, E, Shaughnessy, R, Gaviria, M, Val, E, Davis, JM. Reduced platelet MAO activity and vulnerability to psychiatric disorders. Psychiatry Res. 1980;2:315–321.Google Scholar
66.Buchsbaum, MS, Coursey, RD, Murphy, DL. The biochemical high-risk paradigm: behavioral and familial correlates of low platelet monoamine oxidase activity. Science. 1976;194:339–341.Google Scholar
67.Buchsbaum, MS, Haier, RJ, Murphy, DL. Suicide attempts, platelet monamine oxidase and the average evoked response. Acta Psychiatr Scand. 1977;56:69–79.Google Scholar
68.Meltzer, HY, Arora, RC. Platelet markers of suicidality. Ann NY Acad Sci. 1986;487:271–280.CrossRefGoogle ScholarPubMed
69.Skekim, WO, Davis, LG, Bylund, DB, Brunngraber, E, Fikes, L, Lanham, J. Platelet MAO in children with attention deficit disorder and hyperactivity: a pilot study. Am J Psychiatry. 1982;139:936–938.Google Scholar
70.Schooler, C, Zahn, TP, Murphy, DL, Buchsbaum, MS. Psychological correlates of monoamine oxidase acivity in normals. J Nerv Ment Dis. 1978; 166:177–186.Google Scholar
71.Shekim, WO, Bylund, DB, Frankel, F, et al.Platelet MAO activity and personality variations in normals. Psychiatry Res. 1989;27:81–88.CrossRefGoogle ScholarPubMed
72.Vonknorring, L, Oreland, L, Winblad, B. Pesonality traits related to monoamine oxidase activity in platelets. Psychiatry Res. 1984;12:11–26.CrossRefGoogle Scholar
73.Mann, JJ, Stanley, M. Postmortem monoamine oxidase enzyme kinetics in the frontal cortex of suicide victims and controls. Acta Psychiatr Scand. 1984;69:135–139.Google Scholar
74.Propping, P, Rey, ER, Friedl, W, Beckmann, H. Platelet monoamine oxidase in healthy subjects: the “biochemical high-risk paradigm” revisited. Arch Psychiatr Nervenkr. 1981;230:209–219.Google Scholar
75.Tabakoff, B, Hoffman, PL, Lee, JM, Saito, T, Willard, B, Leon-Jones, FD. Differences in platelet enzyme activity between alcoholics and nonalcoholics. N Engl J Med. 1988:318:134–139.Google Scholar
76.Blanco, C, Orensanz-Muñoz, L, Blanco-Kerez, C, Saizruiz, J. Pathological gambling and platelet MAO activity: a psychobiological study. Am J Psychiatry. 1966;153:119–121.Google Scholar
77.DiChiara, G, Imperato, A. Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci USA. 1988;85:5274–5278.Google Scholar
78.Routtenberg, A. The reward system of the brain. Sci Am. 1978;239:154–165.CrossRefGoogle ScholarPubMed
79.Wise, RA, Rompre, PP. Brain dopamine and reward. Ann Rev Psychol. 1989;40:191–225.Google Scholar
80.Kuhar, MJ, Ritz, MC, Boja, JW. The dopamine hypothesis of the reinforcing properties of cocaine. Trends Neurosci. 1991;14:299–302.CrossRefGoogle ScholarPubMed
81.Koob, GF. Drug of abuse: anatomy, pharmacology and function of reward pathways. Trends Pharmacol Sci. 1992;13:177–184.Google Scholar