The dopamine D2 receptor gene: a genetic risk factor in substance abuse

doi:10.1016/0376-8716(94)90154-6

Drug and Alcohol Dependence

Volume 34, Issue 3, February 1994, Pages 175-180

https://doi.org/10.1016/0376-8716(94)90154-6 Get rights and content

Abstract

Drug abuse has grown to epidemic proportions. Dopaminergic reward pathways have frequently been implicated in the etiology of drug addiction. To examine the possible role of genetic variants of the dopamine D₂ (DRD2) gene in susceptibility to drug abuse we determined the prevalence of the TaqI A1 variant of the DRD2 gene in 200 white patients hospitalized in the Addiction Treatment Unit of a Veterans Administration Hospital. While the prevalence of the D₂A1 allele was not significantly increased over controls, it did increase from 21% in subjects with alcohol abuse only to 32% in subjects with alcohol dependence only, consistent with other studies showing an association with the severity of alcoholism. By contrast, of 104 subjects with a discharge diagnosis of drug and alcohol abuse/dependence, 42.3% carried the D₂A1 allele versus 29.0% of the 763 white controls (representing all white controls published to date) (P = 0.006). Of those who spent more than $25/week on two or more substances, 56.9% carried the D₂A1 allele versus 28.2% of those abusing a single substance (P < 0.0005). Multiple logistic regression analysis showed a highly significant association between multiple substance abuse based on money spent and the presence of the D₂A1 allele (P = 0.0003) and age of onset of abuse (P < 0.0001). D₂A1 carriers exceeded D₂A2A2 subjects for a history of being expelled from school for fighting (P = 0.001), and of those ever jailed for violent crimes, 53.1% carried the D₂A1 allele versus 28.8% of those jailed for non-violent crimes (P = 0.011). This increased to 69.2% for those who were both jailed for violent crime and expelled from school. We conclude that possession of the D₂A1 allele is significantly associated with drug abuse/dependence and some aggressive behaviors.

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In contrast, various aspects of dopamine physiology, including dopamine synthesis, transporter activity and receptor expression, are generally downregulated in abstinent alcoholics (Heinz et al., 2005; Martinez et al., 2005) and experimental animals withdrawing from alcohol (Diana et al., 1993). Genetic polymorphisms in D2 receptor expression that lead to reduced expression increase the incidence of AUD (Comings et al., 1994). Although there is some conflicting evidence among experimental studies in animals, the majority conclude that dopaminergic physiology is involved in alcohol-related behaviors.
Traumatic brain injury (TBI) is closely interrelated with alcohol use disorders. This is mediated, in part, by the large number of individuals who are intoxicated at the time of their injuries. However, there is also evidence, both preclinically and epidemiologically that TBI, particularly when it occurs early in life can increase the incidence of alcohol use disorders later on. This is extremely important because drinking after TBI has been associated with much poorer long-term outcomes as compared to individuals who do not drink. However, for a number of reasons including potential confounders and a relatively long time between injury and onset of drinking it has been difficult to definitively assign causality. Here, we utilize a framework derived from the toxicology literature to determine whether a causal relationship between pediatric TBI and subsequent alcohol abuse is evident. In order for there to be a high likelihood of a causal relationship between an environmental factor and a health outcome, this framework indicates that an epidemiological relationship be present in humans and that analogous relationship has to exist in a preclinical model system and that the mechanism(s) of action that are identified in the model system must also be plausibly active in humans. In this review we discuss the epidemiological evidence for increased drinking in humans. Further, we discuss, the animal models for increased drinking after TBI and the potential mechanistic insights that have been derived from those animal models. We conclude, based on the framework described, that it is possible that pediatric TBI causes alcohol use disorders in humans.
Examining the link between reward and response inhibition in individuals with substance abuse tendencies
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Dopaminergic sensitization is therefore associated with a hyper-reactive reward response to drug cues which in turn enhances incentive salience on those cues. Furthermore, allelic variation in dopaminergic genes such as DRD2, DAT, and DRD4 have been associated with substance abuse problems (e.g., Blum et al., 1996; Comings et al., 1994; Kreek et al., 2005; Uhl et al., 1993). This evidence indicates that risk for developing substance abuse problems may have a common genetic basis that influences striatal dopaminergic function.
Substance use problems are often characterized by dysregulation in reward sensitivity and inhibitory control. In line with this representation, the goal of this investigation was to determine how substance abuse tendencies among university students affect incentivized response inhibition. Additionally, this study examined whether striatal dopamine moderates the impact of substance use on response inhibition performance.
The sample included ninety-eight university students. Participants completed this prospective experimental study at an on-campus laboratory. All participants completed substance abuse and disinhibition subscales of the Externalizing Spectrum Inventory-Brief Form. Using a within-subjects design, participants then performed the Stop Signal Task under both neutral (unrewarded) and reward conditions, in which correct response cancellations resulted in a monetary reward. Striatal tonic dopamine levels were operationalized using spontaneous eyeblink rate.
The outcome measures were Stop Signal Reaction Time (SSRT) performance in the unrewarded and rewarded phases of the task. A hierarchical linear regression analysis, controlling for trait disinhibition, age, gender, and cigarette smoking status, identified an interactive effect of substance use and striatal dopamine levels on incentivized SSRT. Substance abuse tendencies were associated with slower SSRT and thus poorer inhibitory control under reward conditions among individuals with low levels of striatal dopamine (F = 7.613, p = .007).
This work has implications for research examining advanced drug use trajectories. In situations in which rewards are at stake, drug users with low tonic dopamine may be more motivated to seek those rewards at the expense of regulating inhibitory control.
Application of Research Domain Criteria to childhood and adolescent impulsive and addictive disorders: Implications for treatment
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The Research Domain Criteria (RDoC) initiative provides a large-scale, dimensional framework for the integration of research findings across traditional diagnoses, with the long-term aim of improving existing psychiatric treatments. A neurodevelopmental perspective is essential to this endeavor. However, few papers synthesizing research findings across childhood and adolescent disorders exist. Here, we discuss how the RDoC framework may be applied to the study of childhood and adolescent impulsive and addictive disorders in order to improve neurodevelopmental understanding and to enhance treatment development. Given the large scope of RDoC, we focus on a single construct highly relevant to addictive and impulsive disorders – initial responsiveness to reward attainment. Findings from genetic, molecular, neuroimaging and other translational research methodologies are highlighted.
Reverse Translational Implications of Genome-Wide Association Studies for Addiction Genetics
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In recent years genome-wide association studies (GWAS) have transformed thinking about the genetics of addiction. Prior to the advent of these sorts of studies there were two primary problems in addiction genetics, which was based in large part on candidate gene studies: failure to replicate findings, and a priori expectation as the primary basis of hypotheses. GWAS overcame many of these problems, and has changed our view of the genetics of addiction. As discussed in this review, a substantial degree of replication began to emerge as these studies progressed, particularly as sample sizes increased, marker density increased, and we became more sensitive to issues of marker and genomic heterogeneity between different human populations. GWAS for addiction, like GWAS for most other common disorders, found that the genetic causes of such conditions were best explained by the contribution of a large number of allelic variants of small effect. Moreover, the genes identified by GWAS were quite different from those considered to be important for drug dependence based on candidate gene studies or studies of genetically modified mice, including a very large proportion of cell adhesion molecule genes. The current challenge for studies in genetically modified mice is to examine these genes, e.g., the reverse translational implications of the results of GWAS, thought to contribute to liability for drug dependence in humans.
A review of pharmacogenetic studies of substance-related disorders
2015, Drug and Alcohol Dependence
Substance-related disorders (SRDs) are a major cause of morbidity and mortality worldwide. Family, twin, and adoption studies have demonstrated the substantial heritability of SRDs. To determine the impact of genetic variation on risk for SRD and the response to treatment, researchers have conducted a number of secondary data analyses and quasi-experimental studies that target one or more candidate gene variants.
This review examines studies in which candidate polymorphisms were examined as mediator variables to identify pharmacogenetic effects on subjective responses to drug administration or cues or outcomes of medication trials for SRDs. Efforts to use a meta-analytic approach to quantify these effects are premature because the number of available studies using similar methods and outcomes is limited, so the present review is qualitative.
Findings from these studies provide preliminary evidence of clinically relevant pharmacogenetic effects. However, independent replication of these findings has been sparse.
Although this growing body of literature has produced conflicting results, improved statistical controls may help to clarify the findings. Additionally, the use of empirically derived sub-phenotypes (i.e., which serve to differentiate distinct groups of affected individuals) may also help to identify genetic mediators of pharmacologic response in relation to SRDs. The identification of genetic mediators can inform clinical care both by identifying risk factors for SRDs and predicting adverse events and therapeutic outcomes associated with specific pharmacotherapies.
Hypothesizing dopaminergic genetic antecedents in schizophrenia and substance seeking behavior
2014, Medical Hypotheses
Citation Excerpt :
Although other neuromodulators and neurotransmitters like glutamate, GABA, [61] serotonin [62] and enkephalin, [63] have a role in determining the rewarding and stimulating effects of drugs of addiction, dopamine may be essential for initiating and reinstating drug use after protracted abstinence [63,64–67]. Following the initial findings of a positive association of the Taq1 A1 of the DRD2 gene and severe alcoholism [24] there have been a plethora of studies both positive [26,28,30,33,57,65,67–91] and negative [92–105] [see reviews [25,58,78,95,105–126]]. A number of studies have found that the Taq1 A1 allele is associated with low dopamine D2 density in alcoholics [72,79,125,127].
The dopamine system has been implicated in both substance use disorder (SUD) and schizophrenia. A recent meta-analysis suggests that A1 allele of the DRD2 gene imposes genetic risk for SUD, especially alcoholism and has been implicated in Reward Deficiency Syndrome (RDS). We hypothesize that dopamine D2 receptor (DRD2) gene Taq1 A2 allele is associated with a subtype of non-SUD schizophrenics and as such may act as a putative protective agent against the development of addiction to alcohol or other drugs of abuse. Schizophrenics with SUD may be carriers of the DRD2 Taq1 A1 allele, and/or other RDS reward polymorphisms and have hypodopaminergic reward function. One plausible mechanism for alcohol seeking in schizophrenics with SUD, based on previous research, may be a deficiency of gamma type endorphins that has been linked to schizophrenic type psychosis. We also propose that alcohol seeking behavior in schizophrenics, may serve as a physiological self-healing process linked to the increased function of the gamma endorphins, thereby reducing abnormal dopaminergic activity at the nucleus accumbens (NAc). These hypotheses warrant further investigation and cautious interpretation. We, therefore, encourage research involving neuroimaging, genome wide association studies (GWAS), and epigenetic investigation into the relationship between neurogenetics and systems biology to unravel the role of dopamine in psychiatric illness and SUD.

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Review articleThe dopamine D2 receptor gene: a genetic risk factor in substance abuse

Abstract

Biol. Psychiatry

J. Psychiatr. Res.

Alcohol

Neurosci. Biobehav. Rev.

Drug Alcohol Depend.

Biol. Psychiatry

Ethanol and neuromodulator interactions. A cascade model of reward

Prog. Alcohol Res.

Allelic association of human dopamine D2 receptor gene in alcoholism

J. Am. Med. Assoc.

Population and pedigree studies reveal a lack of association between the dopamine D2 receptor gene and alcoholism

J. Am. Med. Assoc.

D2 dopamine receptor gene is associated but not linked with alcoholism

J. Am. Med. Assoc.

The dopamine D2 receptor locus as a modifying gene in neuropsychiatric disorders

J. Am. Med. Assoc.

The D2 dopamine receptor locus in heavy drinking and alcoholism: A study of 11 British families

Alcohol: Clin. Exp. Res.

Review article
The dopamine D₂ receptor gene: a genetic risk factor in substance abuse

Allelic association of human dopamine D₂ receptor gene in alcoholism

Population and pedigree studies reveal a lack of association between the dopamine D₂ receptor gene and alcoholism

D₂ dopamine receptor gene is associated but not linked with alcoholism

The dopamine D₂ receptor locus as a modifying gene in neuropsychiatric disorders

The D₂ dopamine receptor locus in heavy drinking and alcoholism: A study of 11 British families