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How do genetic variations in the dopamine D-2 receptor relate to alcohol dependence?

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  • The dopamine system in involved the rewarding effects of drugs of abuse including alcohol, and dopamine-2 receptor antagonists reduce rewarding effects.Healthy individuals with the Taq1A allele of the dopamine D-2 receptor have reduced D-2 receptor number measured post mortem in the striatum and bypositron emission tomography(PET) imaging, also a group that included both alcoholics and healthy individuals with the Taq1A allele had reduced dopamine receptor binding in the caudate nucleus measured post mortem.Alcoholics have reduced availability of dopamine D-2 receptors measured by PET, and nonalcoholic individuals from alcoholic families have increased availability of dopamine D-2 receptors.Military veterans with PTSD who drank more alcohol had a higher frequency of the 1Aallele and adolescentsons of alcoholics with the 1A allele have tried alcohol more frequently and smoke more.Taken together these findings suggest that genetic variations that reduce dopamine D2 function increase the risk of alcohol dependence, however similar findings have not been seen in all studies and Taq1A is thought to reflect changes in other genes in the area such asANKK1, which has also been related to alcoholism.

  • There is a reduced dopamine D2 receptor number in the striatum of healthy individuals with the A1 allele.

    The Risk Allele of the Dopamine D2 Receptor (DRD2A1) Is Associated with Reduced Dopamine D2 Receptor Binding in the Striatum of Individuals without Neurologic or Psychiatric Illness
    The Risk Allele of the Dopamine D2 Receptor (DRD2A1) Is Associated with Reduced

    Brain tissue at autopsy was obtained from 17 male and 27 female Caucasians mean age 76 yrs. D2 receptor binding was measured by autoradiography using the specific D2 receptor ligand 3H, raclopride.(Constructed from data in Thompson, J. et al. Pharmacogenetics, 7: 479 - 484, 1997) ©2010 NBEP

  • The A1 allele of the D2 dopamine receptor is associated with reduced D2 receptor availability.

    Healthy Individuals with the A1 Allele of the D2 Dopamine Receptor Gene Have Reduced D2 Receptor Availability
    Healthy Individuals with the A1 Allele of the D2 Dopamine Receptor Gene Have Red

    In 2 studies (A and B) positron emission tomography with labeled raclopride was used to measure D2 receptor availability in healthy Caucasian volunteers with different alleles of the dopamine receptor gene. Individuals with one or two of theTaq1A1alleles had lower dopamine receptor availability than individuals with twoTaqA2A2alleles, which are more common.(Constructed from data in Study A: Pohjalainen, T. et al. Mol Psych, 3: 256, 1998; and Study B: Jonsson, E.G. et al. Mol Psych, 4: 290, 1999)©2006NBEP

  • There is a reduced dopamine receptor number in the caudate nucleus of a mixed group of alcoholic and nonalcoholic individuals with the A1 allele.

    Individuals with the A1 Allele of the Dopamine Receptor Gene have Reduced Dopamine Receptor Binding in the Caudate Nucleus
    Individuals with the A1 Allele of the Dopamine Receptor Gene have Reduced Dopami

    The brains from 33 alcoholic and 33 nonalcoholic individuals had the presence of the Taq1 A1 allele measured in cortex and dopamine receptor binding measured with labeled spiperone in the caudate nucleus. The number of dopamine receptors as estimated by Bmax adjusted for Log kd and age was lower in the 29 individuals with the A1 allele compared to the 37 without the A1 allele. 76% of the A1 alleles came from alcoholics while only 30% of the non-A1 alleles came from alcoholics (p < .001) but Bmax did not significantly differ between alcoholics and nonalcoholics. (Constructed from data in Noble, E.P. et al. Arch Gen Psych, 48: 648, 1991) ©2006 NBEP

  • There is decreased availability of dopamine D2 receptors in alcoholics.

    Alcoholics Have Decreased Availability of Dopamine D2 Receptors
    Alcoholics Have Decreased Availability of Dopamine D2 Receptors

    Positron emission tomography was used with labeled raclopride to measure D2 receptor availability in 10 alcoholics and 17 nonalcoholics and labeled methylphenidate to measure dopamine transporters in 5 alcoholics and 16 nonalcoholics. Alcoholics had decreased D2 receptor availability but had similar dopamine transporter values compared to nonalcoholics. The ratio of dopamine receptor availability to transporter availability was significantly higher in nonalcoholics (p < .005).(Constructed from data in Volkow, N.D. et al. Alcoholism: Clinical and Experimental Research, 20: 1594, 1996)©2006 NBEP

  • In families with alcoholism the nonalcoholic individuals have increased availability of dopamine D2 receptors, which suggests that is protective for the development of alcoholism

    Nonalcoholic Individuals from Alcoholic Families Have Increased Availability of Dopamine D2 Receptors
    Nonalcoholic Individuals from Alcoholic Families Have Increased Availability of

    15 nonalcoholic individuals (mean age 24) with an alcoholic father and at least 2 other alcoholic 1stor 2nddegree relatives were compared to 16 nonalcoholic individuals (mean age 26) with no family history of alcoholism. Positron emission tomography was used with labeled raclopride to measure D2 receptor availability and labeled fludeoxyglucose to measure brain glucose. In the family history positive subjects but not in the family history negative controls, increased D2 availability was associated with increased glucose metabolism in anterior cingulate, orbital frontaland frontal cortical areas. The data suggests that high levels of D2 receptor protect against alcoholism, possibly by regulating cortical pathways involved in controlling behavioral responses and emotions. (Constructed from data in Volkow, N.D. et al. Arch Gen Psych, 63: 999, 2006) ©2006 NBEP

  • The A1 allele of the dopamine D2 receptor is associated with heavy alcohol drinking in veterans with PTSD.

    There Is an Increased Frequency of the Dopamine D2 Taql A1 Allele in Military Veterans with Heavy Alcohol Drinking and Post-Traumatic Stress Disorder (PTSD)
    There Is an Increased Frequency of the Dopamine D2 Taql A1 Allele in Military Ve

    Patients and controls were Australian Caucasians of European descent. No control reported smoking in the past,or family history of alcoholism or illicit drug use. 37% of PTSD patients reported smoking and 42% reported a 1stdegree family history of alcoholism, none reported illicit drug use. One 12 oz can of beer with 5% alcohol gives 13.4 g alcohol and 3 cans beer = 40 g alcohol/day. (Constructed from data in Young, R.M. et al. Alcohol and Alcoholism, 37: 451, 2002) ©2006 NBEP

  • The A1 allele of the D2 dopamine receptor increases risk of substance use in the sons of alcoholics.

    The A1 Allele of the D2 Dopamine Receptor Gene (DRD2) Increases Risk for Alcohol Use and Substance Use in Adolescent Sons of Alcoholics
    The A1 Allele of the D2 Dopamine Receptor Gene (DRD2) Increases Risk for Alcohol

    Of 48 boys with at least 1 alcohol dependent parent, 24 had the A1+ allele (A1, A1 or A1, A2 genotype) and 24 had the A1- allele (A2, A2 genotype). The two groups did not differ in age (mean = 16.2, SD = 1.6 yrs) or number of parents that were active or recovering alcoholics. Compared to the sons of alcoholics with the A1- allele, the sons with the A1+ allele gave a history of increased % that had tried alcohol, and increased number of times intoxicated in the past 6 months, increased number of substances tried, more total substance use, a younger age of first high on marijuana and a higher % with a tobacco habit. (Constructed from data in Connor, B.T. et al. Drug and Alcohol Dependence, 79: 379 - 387, 2005) ©2006NBEP