Article

Reduced Dopamine Receptor Sensitivity as an Intermediate Phenotype in Alcohol Dependence and the Role of the COMT Val158Met and DRD2 Taq1A Genotypes

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Abstract

Alcohol dependence is a common neuropsychiatric disorder with high heritability. However, genetic association studies on alcohol dependence are often troubled by nonreplication. The use of intermediate phenotypes may help make clear the mode of action of various candidate genes and improve the reproducibility of genetic association studies. To test central dopamine receptor sensitivity as an intermediate phenotype for alcohol dependence, specifically evaluating the hypothesis that the dopaminergic genes COMT Val158Met and DRD2 Taq1A affect dopamine receptor sensitivity. Case-control pharmacogenetic challenge study. Patients with alcohol dependence admitted for detoxification were compared with healthy control subjects matched for age and level of education. Patients (n = 110) were a consecutive sample, whereas controls (n = 99) were recruited through advertisements in regional newspapers. A dopamine challenge test was subcutaneously administered using the dopamine agonist apomorphine hydrochloride (0.005 mg/kg). Outcome measures were plasma growth hormone levels and results of a continuous performance task. Central dopamine receptor sensitivity is reduced in alcohol dependence, and this is modulated by dopaminergic genes. Specifically, DRD2 Taq1A genotype affected dopamine receptor sensitivity as measured by plasma growth hormone levels, and COMT Val158Met genotype affected dopamine receptor sensitivity as measured by performance on a continuous performance task. In a logistic regression analysis, reduced dopamine receptor sensitivity on both measures predicted alcohol dependence, without an additive effect of the COMT Val158Met and DRD2 Taq1A genotypes. COMT Val158Met and DRD2 Taq1A may affect the intermediate phenotype of central dopamine receptor sensitivity. COMT Val158Met and DRD2 Taq1A may confer their risk of alcohol dependence through reduced dopamine receptor sensitivity in the prefrontal cortex and hindbrain, respectively.

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... The main characteristics of the included studies are listed in Table 1. A total of 20 studies [5,[8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] were included in this meta-analysis, including 18 case-control studies [5,8,[10][11][12][13][14][16][17][18][19][20][21][22][23][24][25][26] and 2 cohort studies [9,15]. The studies were published between 1999 and 2017. ...
... The main characteristics of the included studies are listed in Table 1. A total of 20 studies [5,[8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] were included in this meta-analysis, including 18 case-control studies [5,8,[10][11][12][13][14][16][17][18][19][20][21][22][23][24][25][26] and 2 cohort studies [9,15]. The studies were published between 1999 and 2017. ...
... Of the remaining 43 publications, 23 ineligible publications were excluded based on inclusion and exclusion criteria. Ultimately, 20 articles[5,[8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] remained for data combination. ...
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Background: The underlying mechanisms of alcohol use disorder (AUD) are regarded to be strongly associated with genetic factors. Although great efforts have been made to identify the association of rs4680 polymorphism in the catechol-o-methyltransferase gene and risk to AUD, the outcomes were still inconsistent. This study is aimed at exploring the association of rs4680 polymorphism and AUD by using a meta-analysis approach. Methods: Literature searching was undertaken across PubMed, Embase, Web of Science, Chinese National Knowledge Infrastructure (CNKI), and Wanfang databases. We set the search period before February 20, 2020. We used the Review Manager 5.3 (RevMan 5.3) software to estimate the effect sizes in five genetic models. Results: In total, eighteen case-control studies and two cohort studies were included in this study. The merged results of overall population indicated there was no significant association between rs4680 polymorphism and AUD: V vs. M, OR = 1.02, 95% CI 0.93-1.12, P = 0.70; VV vs. MM, OR = 0.99, 95% CI 0.79-1.23, P = 0.92; VM vs. MM, OR = 0.91, 95% CI 0.81-1.03, P = 0.15; VV+VM vs. MM, OR = 0.95, 95% CI 0.80-1.13, P = 0.65; VV vs. VM+MM, OR = 1.04, 95% CI 0.91-1.18, P = 0.57. Subgroup analysis by gender suggested rs4680 polymorphism was marginally associated with an elevated risk to AUD among males (VM vs. MM, OR = 0.81, 95% CI 0.67-0.98, P = 0.03). However, subgroup analysis by race and diagnosis did not support any significant association. Conclusions: The present study suggests that rs4680 polymorphism has no association with AUD in the overall population, but it has a weak association with AUD in males. Carriers of VM genotype in males appear to have an increased risk to AUD.
... Alcohol dependence considered to be a multifactorial disorder occurs due to various gene-gene and gene-environment interactions [1,5]. Numerous genetic association studies have been conducted to determine polymorphisms in genes of the dopamine pathway [2,[38][39][40][41][42][43][44][45][46][47][48][49][50][51]. ...
... Several studies have shown association of Val158 with impulsive behaviour and substance abuse [42,43]. Met158 has been reported to be associated with low activity of enzyme [29,44,45] and literature suggests Asian population in which risk appears to be associated with Met158 [11,29]. ...
... Alcohol dependence considered to be a multifactorial disorder occurs due to various gene-gene and gene-environment interactions [1,5]. Numerous genetic association studies have been conducted to determine polymorphisms in genes of the dopamine pathway [2,[38][39][40][41][42][43][44][45][46][47][48][49][50][51]. ...
... Several studies have shown association of Val158 with impulsive behaviour and substance abuse [42,43]. Met158 has been reported to be associated with low activity of enzyme [29,44,45] and literature suggests Asian population in which risk appears to be associated with Met158 [11,29]. ...
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Alcohol dependence (AD), associated with high mortality and morbidity is caused due to involvement of both environmental and genetic factors. Behavioral effects of alcohol including cognitive impairment, motor incoordination, tolerance and dependence are likely due to its effect on the multiple brain proteins including neurotransmitters. Dysfunction in these neurotransmitter systems may be at the level of enzymes involved in metabolic degradation, or receptors involved in neurotransmission like dopamine, Gamma-amino butyric acid (GABA), serotonin etc. Genetic polymorphisms in these neurotransmitter systems are implicated in conferring susceptibility to AD. Aim: To identify association of single nucleotide polymorphisms (SNPs) in COMT (rs4680 and rs2075507) and GABAA receptor genes (rs13172914 and rs211014) with AD. Method: A total of 100 AD patients diagnosed on the basis of DSM IV criteria from the outpatient clinic of the National Drug Dependence Treatment Centre (NDDTC) of All India Institute of Medical Sciences (AIIMS), and 100 healthy individuals from the general population were recruited. A detailed history including pattern of drug use and demographic details with pedigree information was noted. Genomic DNA from peripheral blood samples was processed for PCR amplification followed by restriction digestion to screen for the presence of polymorphisms. Genotype and allele frequencies were evaluated and correlated with alcohol use parameters including duration of alcohol use, age at onset of alcohol use, quantity of alcohol consumed (gms/day) and WHO ASSIST score and levels of liver function enzymes (SGPT and SGOT). Statistical analysis was performed using SPSS v21.0. Results: Genetic analysis of the study group revealed COMT rs4680 to be significantly associated with AD (p=0.03), while the other COMT SNP rs2075507 showed an association with increased levels of SGPT in the patients. GABAA receptor gene polymorphisms showed no association with AD. Conclusion: The study suggests a role of COMT gene polymorphism rs4680 in conferring susceptibility to AD.
... If additional genetic variants are identified, it appears feasible to predict to a useful degree an individual's therapeutic response or adverse effects with such drugs. For example, relative to rs1800497 major allele homozygotes, carriers of the minor allele (who tend to have lower D2 receptor expression, as reviewed above) showed lower sensitivity to the non selective dopaminergic agonist apomorphine [19]. Beyond the pharmacogenetic implications, our conceptualizations of neuropsychiatric disorders may also benefit. ...
... Low apomorphine sensi-"Complementary approaches in animal models and in vitro systems are also needed to understand the molecular, cellular and circuit-level mechanisms through which these genetic variants act. " future science group Genetic variation & the D2 dopamine receptor: implications for the treatment of neuropsychiatric disease Editorial tivity is found among many, but not all, individuals with alcoholism, suggesting that this pharmacological phenotype might be a genetically influenced characteristic of one type of alcohol addiction [19]. This example illustrates just one potential path through which a genetic variant might inform diagnosis and treatment. ...
... Previous data suggest that reduced dopaminergic tone in frontal brain regions contributes to both impulsivity (Kayser et al. 2012) and to problems with alcohol and drug abuse (Conner et al. 2010). Consistent with these findings, genetic variations in the dopamine-metabolizing enzyme catechol-O-methyltransferase (COMT), which represents an important pathway for degradation of cortical dopamine (Chen et al. 2004), have been linked to behavioral differences in drug and alcohol consumption and to impulsive decisionmaking (Boettiger et al. 2007;Schellekens et al. 2012). A single-nucleotide polymorphism (SNP) substitution from A to G in the COMT gene triggers a Met to Val substitution (Met158Val), which results in fourfold higher COMT activity and, via increased dopamine metabolism, a decrease in frontal dopamine tone (Schacht 2016). ...
... Past data indicate that reduced dopaminergic tone in frontal brain regions contributes to both impulsivity (Kayser et al. 2012) and to problems with alcohol and drug abuse (Conner et al. 2010). Variations in the dopaminemetabolizing enzyme catechol-O-methyltransferase (COMT) have been linked to behavioral differences in drug and alcohol consumption and to impulsive decision-making (Boettiger et al. 2007;Schellekens et al. 2012), and the administration of a single dose of tolcapone has previously been shown to attenuate impulsive choice in healthy control subjects (Kayser et al. 2012). While we demonstrated a main effect of tolcapone on alcohol consumption, we were unable to replicate the previously reported effect of a single dose of tolcapone on impulsive choice (Kayser et al. 2012). ...
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RationaleIndividuals suffering from alcohol use disorder (AUD) demonstrate difficulty with decision-making and impulsivity that may be associated with impaired frontal cortical function. Therapeutics that enhance frontal dopamine tone could decrease impulsivity and in turn reduce alcohol consumption in individuals with AUD.Objectives To determine if the catechol-O-methyltransferase (COMT) inhibitor tolcapone can attenuate alcohol consumption in individuals with AUD and whether this attenuation correlates with tolcapone-induced changes in laboratory-based decision-making tasks.Methods We used daily self-report and a novel group laboratory bar task to assess the effects of randomized double-blind crossover administration of tolcapone (100 mg TID for 5 days) on alcohol consumption and laboratory tasks assessing impulsivity in 55 non-treatment-seeking subjects with AUD.ResultsTolcapone significantly reduced self-reported alcohol consumption (t (54) = 2.05, p = 0.045). The effects of tolcapone on drinking significantly correlated with changes in impulsive decision-making, such that subjects with the greatest decrease in impulsive choice on tolcapone also reported the greatest decrease in alcohol consumption (r (45) = 0.40, p = 0.0053). We did not see effects of tolcapone on laboratory bar consumption. Adverse event (AE) reporting was low, with no significant difference in frequency or severity of AEs on tolcapone versus placebo.Conclusions These data demonstrate that COMT inhibitors such as tolcapone may be useful therapeutics for AUD.Trial registrationClinicalTrials.gov Identifier: NCT 02740582
... Neurochemical studies in animal models suggest that alcohol administration raises dopamine levels in nucleus accumbens and increases neurotransmission in dopaminergic neurons of the ventral tegmental area [38][39][40]. A decreased density in striatal dopamine receptors, observed in alcohol dependence, is supposed to decrease susceptibility to endogenous effectors of the reward circuits, pushing to alcohol abuse in order to compensate this lack of rewarding effect [41]. Among the components of the dopaminergic systems, the D2 dopamine receptor gene (Drd2) has been studied in depth in alcohol dependent subjects. ...
... However, a larger sample analysis by Foroud and colleagues [51] failed to replicate this association. A more recent work [41] confirms this lack of association between Comt p.Val158Met genotype and alcohol dependence, but suggests that this variation, affecting dopamine receptor sensitivity at the level of the pre frontal cortex, can increase vulnerability to the development of alcohol dependence. terms of molecular structure, pharmacology and signal transduction mechanism. ...
Article
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Alcohol misuse represents worldwide an important risk factor for death and disability. Excesses in alcohol consumption are widely diffused in different ethnicities and alcohol use is part of the lifestyle of both young and old people. The genetic basis of alcohol dependence concerning ethanol metabolism and the pathways of reward circuits are well known. The role of genetic variants in the neurobiology of addiction as well as in response to medication in alcoholism therapy still represent an intriguing argument that needs to be deeply analyzed and explained. The molecular approach to the study of these aspects could be difficult because of the large number of genes and variations involved. Our work is intended to offer an overview of genes and variants involved in alcohol addiction and pharmacogenetics. Our aim is to delineate a molecular approach strategy to look at alcohol dependence from a genetic and applicative point of view. The indications provided in this work should be of help for those who wish to undertake a molecular study of this multifactorial disease.
... The polymorphisms aggregated in these composites include single-nucleotide polymorphisms (SNPs) in COMT (rs4680/val158met) and ANKK1 (rs1800497/Taq1A, originally believed to be in the adjacent DRD2 promoter) and a 48 bp VNTR in DRD4. The COMT met allele has been associated with reduced COMT efficiency (Chen et al, 2004), likely increasing extrasynaptic DA accumulation, and with heightened DA receptor sensitivity among AUD individuals (Schellekens et al, 2012). The ANKK1 Taq1A A1 allele has been associated with dysregulated DA response among AUD individuals (Schellekens et al, 2012) and is in high linkage disequilibrium with the DRD2 rs1076560 T allele, which has been associated with reduced striatal expression of the short (primarily presynaptic) D 2 receptor isoform (Zhang et al, 2007), likely increasing extrasynaptic DA accumulation. ...
... The COMT met allele has been associated with reduced COMT efficiency (Chen et al, 2004), likely increasing extrasynaptic DA accumulation, and with heightened DA receptor sensitivity among AUD individuals (Schellekens et al, 2012). The ANKK1 Taq1A A1 allele has been associated with dysregulated DA response among AUD individuals (Schellekens et al, 2012) and is in high linkage disequilibrium with the DRD2 rs1076560 T allele, which has been associated with reduced striatal expression of the short (primarily presynaptic) D 2 receptor isoform (Zhang et al, 2007), likely increasing extrasynaptic DA accumulation. Finally, the DRD4 VNTR long allele has been associated with reduced DRD4 mRNA expression (Simpson et al, 2010), altered intracellular signaling after D 4 binding (Asghari et al, 1995), and, among heavy drinkers, greater alcohol craving after consumption of a priming drink (Hutchison et al, 2002), greater alcohol cue-elicited striatal activation (Filbey et al, 2008), and less cortical activation during response inhibition (Filbey et al, 2011). ...
Article
Dopamine (DA) signaling regulates many aspects of Alcohol Use Disorder (AUD). However, clinical studies of dopaminergic medications, including the DA partial agonist aripiprazole (APZ), have been inconsistent, suggesting the possibility of a pharmacogenetic interaction. This study examined whether variation in DA-related genes moderated APZ effects on reward-related AUD phenotypes. The interacting effects of APZ and a variable number tandem repeat (VNTR) polymorphism in DAT1/SLC6A3 (the gene encoding the DA transporter (DAT)) were tested. In addition, interactions between APZ and a genetic composite comprising the DAT1 VNTR and functional polymorphisms in catechol-O-methyltransferase (COMT), DRD2, and DRD4 were evaluated. Ninety-four non-treatment-seeking individuals with AUD were genotyped for these polymorphisms, randomized to APZ (titrated to 15 mg) or placebo for 8 days, and underwent an fMRI alcohol cue-reactivity task (day 7; n=81) and a bar lab paradigm (day 8). Primary outcomes were alcohol cue-elicited ventral striatal (VS) activation and the number of drinks consumed in the bar lab. DAT1 genotype significantly moderated medication effects, such that APZ, relative to placebo, reduced VS activation and bar-lab drinking only among carriers of the DAT1 9-repeat allele, previously associated with lower DAT expression and greater reward-related brain activation. The genetic composite further moderated medication effects, such that APZ reduced the primary outcomes more among individuals who carried a larger number of DAT1, COMT, DRD2, and DRD4 alleles associated with higher DA tone. Taken together, these data suggest that APZ may be a promising AUD treatment for individuals with a genetic predisposition to higher synaptic DA tone.
... DA is known to play a central role in the development of drug addiction, with animal studies suggesting that alcohol administration causes enhanced DAergic neurotransmission within the VTA and a consequent increase in DA levels in the NA [109][110][111]. In AUD, reduced DA receptor sensitivity is thought to decrease motivation for endogenous effectors of the reward circuitry, leading to enhanced compensatory alcohol consumption [112]. Of note, various genetic mutations and polymorphisms that play a role in DAergic neurotransmission have been suggested to contribute to increased vulnerability to alcohol addiction, including the DA receptor D2 Taq1A polymorphism [113][114][115], the DA transporter gene Slc6a3 polymorphism [113,116], and the missense mutation within the catechol-O-methyltransferase (Comt) gene [112,[117][118][119]. ...
... In AUD, reduced DA receptor sensitivity is thought to decrease motivation for endogenous effectors of the reward circuitry, leading to enhanced compensatory alcohol consumption [112]. Of note, various genetic mutations and polymorphisms that play a role in DAergic neurotransmission have been suggested to contribute to increased vulnerability to alcohol addiction, including the DA receptor D2 Taq1A polymorphism [113][114][115], the DA transporter gene Slc6a3 polymorphism [113,116], and the missense mutation within the catechol-O-methyltransferase (Comt) gene [112,[117][118][119]. However, further research is still required to completely elucidate the relationships among genetic factors, DAergic neurotransmission, and the development of AUD. ...
Article
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Alcohol use disorder (AUD) encompasses the dysregulation of multiple brain circuits involved in executive function leading to excessive consumption of alcohol, despite negative health and social consequences and feelings of withdrawal when access to alcohol is prevented. Ethanol exerts its toxicity through changes to multiple neurotransmitter systems, including serotonin, dopamine, gamma-aminobutyric acid, glutamate, acetylcholine, and opioid systems. These neurotransmitter imbalances result in dysregulation of brain circuits responsible for reward, motivation, decision making, affect, and the stress response. Despite serious health and psychosocial consequences, this disorder still remains one of the leading causes of death globally. Treatment options include both psychological and pharmacological interventions, which are aimed at reducing alcohol consumption and/or promoting abstinence while also addressing dysfunctional behaviours and impaired functioning. However, stigma and social barriers to accessing care continue to impact many individuals. AUD treatment should focus not only on restoring the physiological and neurological impairment directly caused by alcohol toxicity but also on addressing psychosocial factors associated with AUD that often prevent access to treatment. This review summarizes the impact of alcohol toxicity on brain neurocircuitry in the context of AUD and discusses pharmacological and non-pharmacological therapies currently available to treat this addiction disorder.
... In addition, the Met/Met genotype has been associated with greater impulsive and reward-seeking behavior (Lancaster et al. 2012; van den Bos et al. 2009Author Manuscript mesolimbic DA system, which is presumably modulated indirectly by COMT activity, appears to mediate motivation for reward (Berridge 2007). Although other past studies have reported conflicting results (Bierut et al. 2010; Foroud et al. 2007; Olfson and Bierut 2012; Schellekens et al. 2012), those studies attempted to relate COMT rs4680 to a diagnosis of alcohol dependence, whereas the current study used more sensitive categorical and dimensional measures of drinking problems. Thus, it is possible that the effect of the Met/Met genotype on drinking behavior is more easily detected in a nonclinical sample using more sensitive measures of alcohol abuse. ...
Article
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Disordered gambling and alcohol dependence are influenced by unique and shared genetic factors. Although the evidence is mixed, some research has linked catechol-O-methyltransferase (COMT) rs4680 (or COMT Val158Met) to the development of gambling or drinking problems; however, no molecular genetic study has jointly examined gambling and drinking problems. Furthermore, the majority of past studies examined gambling or drinking problems using a case–control design. The purpose of the current study was to examine associations of COMT rs4680 with dimensionally and categorically measured gambling and drinking problems in a nonclinical sample (139 Caucasian adults). The current study found that COMT rs4680 was related to both dimensionally and categorically measured gambling and drinking problems. It appears that the COMT Met/Met genotype may be a genetic risk factor that contributes to the development of both gambling and drinking problems.
... Compared to the COMT ValVal genotype, carriers of the COMT Met allele have higher catecholamine levels in the prefrontal cortex. Additionally, higher catecholamine availability causes higher vigilance by higher corticolimbic reactivity (Goddard et al., 2010;Schellekens et al., 2012). Several studies investigated the 'Worrier-Warrier' hypothesis (Goldman et al, 2005;, which states that COMT Met carriers (worriers) have enhanced cognitive performance but worse emotional processing, compared to the COMT ValVal genotype (warriors) (Enoch et al, 2003;Drabant et al., 2006;Williams et al., 2010). ...
... However, Schellekens et al. (2013) found that genotype may modulate an individual's sensitivity to adverse experiences in childhood and suggested that carriers of the low-activity Met allele, thus may have a higher risk of developing alcohol dependence than homozygous Val allele carriers. A recent and elegant study performed by the same group demonstrated that the COMT Val158Met and DRD2Taq1a genotypes affect the intermediate phenotype of central dopamine receptor sensitivity and, thus, the risk for alcohol dependence (Schellekens et al. 2012). COMT Met carriers with alcohol dependence were also found to perform better on neuropsychological assessments such as measures of executive skills (Durazzo et al. 2012). ...
Article
Aggression, violence and antisocial behavior are common in alcoholism, but their biological basis is poorly understood. Several studies and recent meta-analyses indicate that in schizophrenia the catecholamine-O-methyltransferase (COMT) Val158Met genotype may be associated with aggression, most often in methionine allele carriers. We tested this hypothesis in a sample of treatment-seeking alcohol-dependent in-patients (293 German patients and 499 controls, and additional 190 Polish patients as replication sample). As expected, patients with a history of violent or non-violent crime were more often male, had an earlier onset of alcoholism and more withdrawal seizures and delirium tremens, and were more likely to have a history of suicide attempts. COMT genotype was not associated with a history of violent or non-violent crime. More studies are needed on the neurobiological basis of aggression and violence in alcoholism.
... Para futuras investigaciones se recomienda incluir la interacción con otros genes ya que una de las limitaciones de este estudio fue la cantidad de mutaciones que se pudieron evaluar; en fenotipos complejos pueden estar interactuando múltiples genes. Un gen que podría ser incluido sería SLC6A4 que codifica una proteína de membrana llamada DAT lo cual podría revelar si la variante evaluada en conjunto con otros genes está involucrada en el hábito de fumar (Pombo 2014, Schellekens 2012, Watanabe 2011. ...
Article
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Smoking is a public health problem because consumption is growing and exhibits earlier ages of onset; in terms of the biological processes of smoking, several genes have been identified whose variants are related to this phenomenon. The aim of this study was to evaluate the relationship between rs6801272 and rs680244 polymorphisms in genes CYP2A6 and CHRNA5, respectively, with the consumption of tobacco. For this, a case study was conducted (smokers-ex smokers versus controls) matched by age and sex, as well as considering starting age and number of cigarettes per day. The monomorphic locus rs6801272 was found in the study population, presenting the T allele associated with normal metabolism of nicotine; and the rs6801272 locus was found to be polymorphic, but the relationship of this genetic variation with cigarette smoking (OR 3,2) or the capacity to abandon smoking (OR 5,3) was not established; it was not possible to establish a correlation between the genotype and the number of cigarettes per day (R2 = 0,001) or genotype and age of onset (R2 = 0,015). In conclusion, a relationship between the genetic variants studied and consumption, capacity of quitting, number of cigarettes per day and age of onset was not detected.
... Although the SNP was originally believed to map to DRD2, it is 10 kb downstream of the gene and results in a nonsynonymous substitution in the adjacent gene, ANKK1 (Neville et al., 2004). The polymorphism is associated with up to a 30% reduction in D2 receptor density, decreased dopamine receptor sensitivity, and elevated DAT density (Noble et al., 1991;Pohjalainen et al., 1998;Schellekens et al., 2012). Its association with alcohol dependence is under debate (for reviews, see Noble, 1998;Wang et al., 2013). ...
Article
Background Annually, the use and abuse of alcohol contributes to millions of deaths and billions of dollars in societal costs. To determine the impact of genetic variation on the susceptibility to the disorder and its response to treatment, studies have been conducted to assess the contribution of a variety of candidate genetic variants. These variants, which we review here, were chosen based upon their observed or hypothesized functional relevance to alcohol use disorder (AUD) risk or to the mechanism by which medications used to treat the disorder exert their effects.Methods This qualitative review examines studies in which candidate polymorphisms were tested as moderator variables to identify pharmacogenetic effects on either the subjective response to alcohol or the outcomes of pharmacotherapy.ResultsAlthough findings from these studies provide evidence of a number of clinically relevant pharmacogenetic effects, the literature is limited and there are conflicting findings that require resolution.Conclusions Pharmacogenetic studies of AUD treatment that use greater methodological rigor and better statistical controls, such as corrections for multiple testing, may help to resolve inconsistent findings. These procedures could also lead to the discovery of more robust and clinically meaningful moderator effects. As the field evolves through methodological standardization and the use of larger study samples, pharmacogenetic research has the potential to inform clinical care by enhancing therapeutic effects and personalizing treatments. These efforts may also provide insights into the mechanisms by which medications reduce heavy drinking or promote abstinence in patients with an AUD.
... Such an approach can be advantageous because the intermediate phenotypes are closer to PCOS pathogenesis in comparison to their combinatorial end point [37]. Also, intermediate phenotypes are genetically less complex and that their use can improve the validity of genetic association studies [38]. Moreover, more statistical power can be expected in analyzing the intermediate phenotypes which are continuously distributed. ...
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Abstract Polycystic ovarian syndrome is universally the most common endocrinopathy in women of reproductive age. It is characterized by composite clinical phenotypes reflecting the reproductive impact of ovarian dysfunction (androgen excess, oligo-/anovulation, polycystic ovary) and metabolic abnormalities (insulin resistance, obesity) with widely varying symptoms among the affected. Studies have shown a clear pattern of disparity in clinical manifestations of its component phenotypes across ethnic populations. Recent genetic association studies suggested differential genetic background that could contribute to the observed ethnic disparity. We summarize the current status in genetic studies of the disorder in different populations with a focus on ethnicity. Especially, we highlight and discuss the applications of recent developments in DNA sequencing, global transcriptional and epigenetic profiling that could help to unravel the molecular basis of the interethnic difference in the pathogenesis of the syndrome. It is hoped that identification and characterization of population-specific structural genetic and functional genomic patterns could help to not only deepen our understanding of the aetiology but also develop more efficient strategies for treatment and prevention of polycystic ovarian syndrome.
... It was associated with CD in AA (Lohoff et al., 2008) and cocaine-induced paranoia in EA and AA (Ittiwut et al., 2011). It has been suggested that environmental factors impact the detection of small effects of this variant on alcohol addiction vulnerability (Schellekens et al., 2012). COMT SNPs rs4680 and rs933271, indicated in this study, were predicted to have potential functionality based on a signature of positive selection in EA and AA (Ittiwut et al., 2011). ...
Article
Drugs of abuse activate the mesolimbic dopaminergic pathway. Genetic variations in the dopaminergic system may contribute to drug addiction. Several processes are shared between cocaine and heroin addictions but some neurobiological mechanisms may be specific. This study examined the association of 98 single nucleotide polymorphisms in 13 dopamine-related genes with heroin addiction (OD) and/or cocaine addiction (CD) in a sample of 801 African Americans (315 subjects with OD ± CD, 279 subjects with CD, and 207 controls). Single-marker analyses provided nominally significant evidence for associations of 24 SNPs) in DRD1, ANKK1/DRD2, DRD3, DRD5, DBH, DDC, COMT and CSNK1E. A DRD2 7-SNPs haplotype that includes SNPs rs1075650 and rs2283265, which were shown to alter D2S/D2L splicing, was indicated in both addictions. The Met allele of the functional COMT Val158Met was associated with protection from OD. None of the signals remained significant after correction for multiple testing. The study results are in accordance with the results of previous studies, including our report of association of DRD1 SNP rs5326 with OD. The findings suggest the presence of an overlap in genetic susceptibility for OD and CD, as well as shared and distinct susceptibility for OD in subjects of African and European descent. © 2015 John Wiley & Sons Ltd/University College London.
... The Taq1A polymorphism has been shown to be associated with altered dopamine transmission. Several studies have shown that the polymorphism is associated with an up to 30% reduction in D2 receptor density, decreased dopamine receptor sensitivity, and elevated dopamine transporter (DAT) density (Jönsson et al., 1999;Laine et al., 2001;Pohjalainen et al., 1998;Schellekens et al., 2012). Although less studied than the ANKK1 single nucleotide polymorphism (SNP), a non-synonymous DRD2 polymorphism (C957T polymorphism; rs6277) has been shown to be functional. ...
... The ankyrin repeat and kinase domain-containing 1 gene (ANKK1) Taq1A rs1800497 (C/T) polymorphism has been previously shown to be located in the dopamine D 2 receptor gene (DRD2) and to be associated with D 2receptor density, dopamine receptor sensitivity, and DAT density (Noble et al., 1991;Schellekens et al., 2012). The T allele is the minor frequency allele of rs1800497, which is also known as the A1 allele, and is closely associated with susceptibility to and severity of AD (Noble, 1998;Connor et al., 2007;Wang et al., 2013). ...
Article
Genetic factors contribute to more than 50% of the variation in the vulnerability to alcohol dependence (AD). Although significant advances have been made in medications for AD, these medications do not work for all people. Precise tailoring of medicinal strategies for individual alcoholic patients is needed to achieve optimal outcomes. This review updates the most promising information on genetic variants in AD, which may be useful for improving diagnostic, therapeutic, and monitoring strategies. We describe genetic candidates of various neurotransmitter and enzyme systems. In addition to biological and allelic associations with AD, genetic effects on AD-related phenotypes and treatment responses have also been described. Gene-gene and gene-environment interactions have been considered. Potential applications of genomewide and epigenetic approaches for identifying genetic biomarkers of AD have been discussed. Overall, the application of genetic findings in precision medicine for AD will likely involve an integrated approach that distinguishes effect sizes of specific genetic predictors with regard to sex, pharmacotherapy, ethnicity, and AD-related aspects and considers gene-gene and gene-environment interactions. Our work may pave the way toward more precise treatment for AD that could ultimately improve clinical management and interventions.
... After filtration, 61 studies (refer to Supplementary Table S1) were considered eligible for the present meta-analysis. Among these 61 studies, 36 analyzed the association between the TaqA1 polymorphism and AD in the European population (Amadeo et al. 1993;Amadeo et al. 2000;Anghelescu et al. 2001;Bau et al. 2000;Berggren et al. 2006;Bolos et al. 1990;Comings et al. 1991;Comings et al. 1994;Cook et al. 1992;Finckh et al. 1996;Foley et al. 2004;Freire et al. 2006;Geijer et al. 1994;Gelernter and Kranzler 1999;Gelernter et al. 1991;Goldman et al. 1992;Gorwood et al. 2000a;Gorwood et al. 2000b;Heinz et al. 1996;Hietala et al. 1997;Kasiakogia-Worlley et al. 2011;Konishi et al. 2004b;Kovanen et al. 2010;Kraschewski et al. 2009;Landgren et al. 2011;Lawford et al. 1997;Limosin et al. 2002;Ovchinnikov et al. 1999;Parsian et al. 1991;Pastorelli et al. 2001;Ponce et al. 2008;Samochowiec et al. 2008;Samochowiec et al. 2000;Sander et al. 1995;Sander et al. 1999;Schellekens et al. 2012); 18 analyzed the association between the TaqA1 polymorphism and AD in the Asian population (Arinami et al. 1993;Bhaskar et al. 2010;Chen et al. 1996;Chen et al. 1997;Huang et al. 2007;Ishiguro et al. 1998;Joe et al. 2008;Kono et al. 1997;Lee et al. 1997;Lu et al. 1996;Lu et al. 2010;Lu et al. 2001;Matsushita et al. 2001;Namkoong et al. 2008;Prasad et al. 2010;Shaikh et al. 2001;Wang et al. 2007;Wu et al. 2008); and seven analyzed the association between the TaqA1 polymorphism and AD in American Indians (Goldman et al. 1993;Goldman et al. 1997), a mix population Blum et al. 1990;Sakai et al. 2007), or other populations that were not stated (Neiswanger et al. 1995;Noble et al. 1994). ...
Article
Alcohol dependence (AD) is a common neuropsychiatric disorder with high heritability. A number of studies have analyzed the association between the Taq1A polymorphism (located in the gene cluster ANKK1/DRD2) and AD. In the present study, we conducted a large-scale meta-analysis to confirm the association between the Taq1A polymorphism and the risk for AD in over 18,000 subjects included in 61 case-control studies that were published up to August 2012. Our meta-analysis demonstrated both allelic and genotypic association between the Taq1A polymorphism and AD susceptibility [allelic: P(Z) = 1.1 × 10(-5), OR = 1.19; genotypic: P(Z) = 3.2 × 10(-5), OR = 1.24]. The association remained significant after adjustment for publication bias using the trim and fill method. Sensitivity analysis showed that the effect size of the Taq1A polymorphism on AD risk was moderate and not influenced by any individual study. The pooled odds ratio from published studies decreased with the year of publication, but stabilized after the year 2001. Subgroup analysis indicated that publication bias could be influenced by racial ancestry. In summary, this large-scale meta-analysis confirmed the association between the Taq1A polymorphism and AD. Future studies are required to investigate the functional significance of the ANKK1/DRD2 Taq1A polymorphism in AD.
... Temperament traits frequent in BD and AUD, e.g. sensation seeking behavior, might bridge these disorders across categorial boundaries [71,72].The genetic linkage may comprise, besides a polymorphism shared between AUD and BD of the aldehyde hydrogenase and alcohol dehydrogenase [73], candidate genes related to monoamine metabolism, e.g. a Ser23Cys (rs6318) polymorphism of the 5HT2C gene (in female bipolar patients) [74] and a VAL-158-MET polymorphism of the cathechol-o-methyltransferase (COMT) [75]. Findings from recent genome-wide association studies (GWAS), however, underline that the relationship between genetic variations and mental disorders is not straight forward; the genetic linkage of SUD and mental health disorders is rather highly pleiotropic and involves several components as shared neurodevelopmental pathways, neurotransmission, and intracellular signaling [76]. ...
Article
Introduction: Comorbidity of bipolar disorder (BD) and alcohol use disorder (AUD) is very frequent resulting in detrimental outcomes, including increased mortality. Diagnosis of AUD in BD and vice versa is often delayed as symptoms of one disorder mimic and obscure the other one. Evidence for pharmacotherapies for people with comorbid BD and AUD remains limited, and further proof-of-concept studies are urgently needed. Areas covered: This paper explores the currently available pharmacotherapies for AUD, BD and their usefulness for comorbid BD and AUD. It also covers to some degree the epidemiology, diagnosis, and potential common neurobiological traits of comorbid BD and AUD. Expert opinion: The authors conclude that more controlled studies are needed before evidence-based guidance can be drawn up for clinician's use. Since there are no relevant pharmacological interactions, approved medications for AUD can also be used safely in BD. For mood stabilization, lithium should be considered first in adherent persons with BD and comorbid AUD. Alternatives include valproate, lamotrigine and some atypical antipsychotics, with partial D2/D3 receptor agonism possibly being beneficial in AUD, too.
... Such an approach can be advantageous because the intermediate phenotypes are closer to PCOS pathogenesis in comparison to their combinatorial end point [37]. Also, intermediate phenotypes are genetically less complex and that their use can improve the validity of genetic association studies [38]. Moreover, more statistical power can be expected in analyzing the intermediate phenotypes which are continuously distributed. ...
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We perform a comprehensive heritability study on multiple phenotypes related to metabolic syndrome using Chinese twins to assess the genetic and environmental effects in determining the variation and covariation of the phenotypes in the Chinese population. The studied sample contains 654 twins collected in the Qingdao municipality. A total of 10 phenotypes covering anthropometric measurements, plasma glucose levels, lipids, blood pressures etc. were examined. Univariate and bivariate structural equation models were fitted for assessing the genetic and environmental contributions. The AE model combining additive genetic (A) and unique environmental (E) factors produced the best fit for all phenotypes except for triglyceride. Modest to high heritability estimates were obtained in univariate analysis ranging from 0.5 for total cholesterol to 0.78 for weight. The bivariate model estimated high genetic correlations between systolic and diastolic blood pressures, between total cholesterol and low density lipoprotein cholesterol, modest genetic correlations between BMI and blood pressures. No significant common environmental correlation was found between any pair of the phenotypes. Our results showed significant genetic contributions to the sub-phenotypes of metabolic syndrome. Although pleiotropic genetic control may exist for some physiologically similar phenotypes, our results do not support a common genetic mechanism among the phenotypes covered in our study.
... Insbesondere Temperamenteigenschaften, wie Sensation-Seeking ohne Rücksicht auf die Konsequenzen, scheint ein gemeinsames Persönlichkeitsmerkmal zu sein [27]; gemeinsame genetische Faktoren lassen sich vermuten [28]. Diskutiert werden unter anderem gemeinsame Polymorphismen der Aldehydhydrogenase und Alkoholdehydrogenase [29] sowie eine genetische Prädisposition in Form eines VAL-158-MET-Polymorphismus der Cathechol-O-Methyltransferase (COMT) [30], mit entsprechenden Auswirkungen auf den Metabolismus biogener Amine. Auch Familienstudien zeigen eine enge Verknüpfung zwischen Suchterkrankungen und bipolaren Störungen [31] mit generationsübergreifenden Auswirkungen. ...
Article
Sowohl bipolare Erkrankungen als auch schädlicher Substanzgebrauch beziehungsweise -abhängigkeit sind in der Bevölkerung weit verbreitet. Die Frage der Ätiologie und Kausalität ist dabei nicht abschließend geklärt. Eventuell fördert ein gemeinsamer genetischer Faktor beide Erkrankungen.
... A118G carriers experience attenuated pain sensitivity that may alter analgesic responses to alcohol [141]. The A118G or val158met polymorphism of the catechol-O-methyl-transferase (COMT) gene could be a possible link between alcohol's analgesia and reinforcement activities [165,166]. The val158met carrier exhibit higher COMT levels, lower DA ergic neurotransmission, elevated activation of the MORs [167,168], and suppressed MOR NT response to pain [169]. ...
Article
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Millions of people around the world drink alcoholic beverages to cope with the stress of modern lifestyle. Although moderate alcohol drinking may have some relaxing and euphoric effects, uncontrolled drinking exacerbates the problems associated with alcohol abuse that are exploding in quantity and intensity in the United States and around the world. Recently, mixing of alcohol with other drugs of abuse (such as opioids, cocaine, methamphetamine, nicotine, cannabis, and γ-hydroxybutyric acid) and medications has become an emerging trend, exacerbating the public health concerns. Mixing of alcohol with other drugs may additively or synergistically augment the seriousness of the adverse effects such as the withdrawal symptoms, cardiovascular disorders, liver damage, reproductive abnormalities, and behavioral abnormalities. Despite the seriousness of the situation, possible mechanisms underlying the interactions is not yet understood. This has been one of the key hindrances in developing effective treatments. Therefore, the aim of this article is to review the consequences of alcohol’s interaction with other drugs and decipher the underlying mechanisms.
... Among these 62 studies, 1,6,12,[15][16][17][18] 24 analyzed the association between the rs1800497 T allele and AUD in Europe, 29,31,33,35,36,40,42,46,47,[49][50][51][52]54,56,59,65,66,68,[71][72][73][74]77 17 studies were from Asia, 30,34,37,38,41,43,44,53,55,61,63,64,67,69,70,75,76 15 were from North America, 1,6,12,15-18,25-28,32,39,58,62 3 were from South America, 48,56,78 2 were from Australia, 42,57 and 1 was from Central America. 79 ...
Article
Importance The association between the D2 dopamine receptor gene (DRD2) Taq1A locus (rs1800497) and alcohol use disorder (AUD) is enduring but the subject of long-standing controversy; meta-analysis of studies across 3 decades shows an association between rs1800497 and AUD, but genome-wide analyses have detected no role for rs1800497 in any phenotype. No evidence has emerged that rs1800497, which is located in ANKK1, perturbs the expression or function of DRD2. Objective To resolve contradictions in previous studies by identifying hidden confounders and assaying for functional effects of rs1800497 and other loci in the DRD2 region. Data Sources PubMed (882 studies), Embase (1056 studies), and Web of Science (501 studies) databases were searched through August 2018. Three clinical populations—Finnish, Native American, and African American participants—were genotyped for 208 to 277 informative single-nucleotide polymorphisms (SNPs) across the DRD2 region to test the associations of SNPs in this region with AUD. Study Selection Eligible studies had diagnosis of AUD made by accepted criteria, reliable genotyping methods, sufficient genotype data to calculate odds ratios and 95% CIs, and availability of control allele frequencies or genotype frequencies. Data Extraction and Synthesis After meta-analysis of 62 studies, metaregression was performed to detect between-study heterogeneity and to explore the effects of moderators, including deviations of cases and controls from allele frequencies in large population databases (ExAC and 1000 Genomes). Linkage to AUD and the effect on gene expression of rs1800497 were evaluated in the context of other SNPs in the DRD2 region. Data analysis was performed from August 2018 to March 2019. This study follows the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline. Main Outcomes and Measures The effects of rs1800497 and other SNPs in the DRD2 region on gene expression were measured in human postmortem brain samples via differential allelic expression and evaluated in other tissues via publicly available expression quantitative locus data. Results A total of 62 studies of DRD2 and AUD with 16 294 participants were meta-analyzed. The rs1800497 SNP was associated with AUD (odds ratio, 1.23; 95% CI, 1.14-1.31; P < .001). However, the association was attributable to spuriously low allele frequencies in controls in positive studies, which also accounted for some between-study heterogeneity (I² = 43%; 95% CI, 23%-58%; Q61 = 107.20). Differential allelic expression of human postmortem brain and analysis of expression quantitative loci in public data revealed that a cis-acting locus or loci perturb the DRD2 transcript level; however, rs1800497 does not and is not in strong disequilibrium with such a locus. Across the DRD2 region, other SNPs are more strongly associated with AUD than rs1800497, although no DRD2 SNP was significantly associated in these 3 clinical samples. Conclusions and Relevance In this meta-analysis, the significant association of DRD2 with AUD was reassessed. The DRD2 association was attributable to anomalously low control allele frequencies, not function, in positive studies. For genetic studies, statistical replication is not verification.
... Moreover, it is unclear whether alterations of D2/3 receptors are an adaptation process due to the dopamine excess in harmful alcohol consumption or if the availability of D2/3 receptors may be a genetic predisposing factor for AUD. Many genetic and epigenetic influences on the dopamine D2 receptor expression are known to play a role in addiction [53][54][55][56]. Thus, higher D2/3 receptors in individuals at HR in this study may be the result of an adaptation or may be a genetically predisposed factor. ...
Article
Introduction: Reduced striatal dopamine D2/3 receptor availability in alcohol use disorder (AUD) has been demonstrated in recent clinical studies and meta-analyses. However, only a limited number of studies investigated extrastriatal D2/3 availability in AUD or in at-risk populations. In line with a dimensional understanding of addiction, extrastriatal dopaminergic neuroadaptations have been suggested to be relevant from a pathobiological perspective. Methods: We investigated D2/3 receptor availability via 18F-fallypride positron emission tomography applying a region of interest (ROI) approach. We selected ROIs for the prefrontal cortex (PFC) and the anterior cingulate cortex (ACC). Our sample included 19 healthy controls (low risk [LR]), 19 individuals at high risk (HR) to develop addiction, and 20 recently detoxified AUD patients. Results: We found significantly higher D2/3 receptor availability of HR compared to AUD in the left and right rostral ACC (rACC), as well as in the left ventrolateral PFC (vlPFC). We did not observe a significant difference between AUD and LR. After corrections for multiple comparisons none of the ROIs reached significance throughout the group comparison. The D2/3 receptor availability in the left rACC was inversely correlated with symptom severity assessed with the Alcohol Dependency Scale. Discussion: To our knowledge, the present work is the first study investigating extrastriatal D2/3 receptor availabilities in individuals at HR and patients with AUD. The observation that D2/3 receptor availabilities are highest in HR might suggest that their pathobiology differs from subjects with AUD. Future studies are necessary to clarify the intraindividual course of this biomarker over different disease stages and its possible role as a risk or protective factor.
... Out of remaining 29 articles, we also excluded thirteen articles (duplicate articles, meta-analysis and only case studied). After applying inclusion/exclusion criteria, total 16 articles ( Figure 1) were suitable for the present meta-analysis (Ishiguro et al.,1999;Tiihonen et al., 1999;Hallikainen et al., 2000;Nakamura et al.,2001;Kohnke et al.,2003;Kweon et al.,2005;Enoch et al., 2006;Sery et al.,2006;Voicey et al.,2011;Wang et al.,2011;Altintoprak et al.,2012;Franke et al., 2012;Schellekens et al.,2012 ;Soyka et al.,2013;Malhotra et al.,2016;Carra et al., 2017) (Table 1). One author (Hallikainen et al., 2000) has studied cases from two population (Turku and Kuopio) and also one case group of type I alcoholics, so we included a these three case groups separate in the meta-analysis. ...
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Catechol-O-methyl transferase (COMT) enzyme catalyzes the metabolism of dopamine and other catechols in the brain. Several articles investigated catechol-O-methyltransferase (COMT) Val158Met polymorphism as risk factor for alcohol dependence (AD) but the results were inconclusive. The aim of present meta-analysis was to evaluate the association of Val158Met (COMT) polymorphism with AD. Authors performed keyword search of the four electronic databases- Pubmed, Google Scholar, Springer Link and Science Direct databases up to December 31,2019 . Total eighteen studies that investigated the association of Val158Met polymorphism with AD were retrieved. The pooled results from the meta-analysis (2,278 AD cases and 3717 healthy controls) did not show association with AD using all five genetic models (allele contrast model: OR = 1.02, 95% CI= 0.90-1.14, p= 0.03; homozygote model: OR = 1.06, 95% CI= 0.81-1.38, p= 0.69; dominant model: OR = 0.99, 95% CI= 0.85-1.14, p= 0.87; co-dominant model: OR = 0.97, 95% CI= 0.86-1.11, p= 0.71; recessive model: OR = 1.05;95% CI= 0.85-1.29, p=0.61). Results of subgroup analysis showed that Val158Met is not risk for AD in Asian and Caucasian population. In conclusion, COMT Val158Met is not a risk factor for alcohol dependence.
Article
The present study aimed to evaluate the association of alcohol dependence and alcohol dependence-related phenotypes with platelet monoamine oxidase type B (MAO-B) activity, Val108/158Met of catechol-o-methyltransferase (COMT), variable number of tandem repeats (VNTR) in the third exon of dopamine receptor D4 (DRD4) gene, VNTR in the 3'-untranslated region of dopamine transporter (DAT) gene, -1021C/T of dopamine beta-hydroxylase (DBH) and MAO-B intron 13 polymorphisms. The study included 1270 Caucasian men and women of Croatian origin: 690 patients with alcohol dependence and 580 healthy controls. Patients with alcohol dependence were subdivided according to the presence or absence of withdrawal symptoms, aggressive behavior, severity of alcohol dependence, delirium tremens, comorbid depression, suicidal behavior, lifetime suicide attempt and early/late onset of alcohol abuse. The results, corrected for multiple testing, revealed increased platelet MAO-B activity in patients with alcohol dependence, subdivided into those with or without alcohol-related liver diseases, compared to control subjects (P<0.001). In addition, we found an increased frequency of the COMT Met/Met genotype among suicidal (P=0.002) and patients who attempted suicide (P<0.001) and an increased frequency of COMT Val/Val genotype in patients with an early onset of alcohol dependence (P=0.004). This study provides data from a sample of ethnically homogenous unrelated Caucasian subjects for future meta-analyses and suggests that the increased platelet MAO-B activity might be used as independent peripheral indicator of alcohol dependence, while COMT Val108/158Met polymorphism is associated with increased suicidality and early onset of alcohol dependence.
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Alcohol use disorder (AUD) is a complex condition or conditions and there is no single cause of its development, which often varies dramatically over time and in different circumstances and even cultures, but genetic research helps us recognize that there is an important DNA component shaping individual risk. Utilizing both techniques, genome-wide association studies and candidate gene investigations, should help researchers and practitioners more effectively gage individual risk for AUD and problem-drinking. Over time, they could also help us develop targeted treatments—treatments tailored for individuals and for specific genetic risk factors they may have as we proposed herein with GARS testing coupled to precision prodopamine regulation. AUDs are likely to be complicated by cooccurring conditions, life experiences, trauma, early drinking, and associations with other traits. We must keep in mind that based on a plethora of solid scientific data, a neurochemical commonality exists between alcoholism and opioid dependence. Opioid use disorder appears to be linked to multiple traits, including psychiatric conditions, neuroticism, depression, and substance use. Genetic studies of substance use disorders and psychiatric illnesses are advancing rapidly and may have heuristic value especially in terms of early identification of one’s risk for all reward deficiency syndrome behaviors. In these troubled times with both viral and opioid pandemics, we need to move from bench to bedside by gearing up for development of genetic testing to identify risk as well as DNA-guided therapeutics.
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The etiology of substance use disorders is related to changes in neuronal systems involved in reward anticipation, negative affect, and withdrawal, as well as to alterations in inhibition and executive control. Genetic and epigenetic variation associated with individual differences in these mechanisms may be important for predicting the effectiveness of current treatments and informing future pharmacogenomic investigations. Genetic research efforts have increasingly involved the use of approaches that leverage neurobiological phenotypes to link changes at the molecular level (e.g., genetic and epigenetic variation) to changes in intermediate neuroimaging phenotypes, and ultimately to clinical outcomes. The current review summarizes recent efforts that utilize neuroimaging and genetic approaches in the context of a three-stage model of addiction. In addition, this review explores how these approaches have been used to study the progression from impulsive, recreational substance use to the compulsive, addicted state. Finally, this review describes future ways that research may incorporate these approaches to examine important stage-specific mechanisms of addiction.
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Having entered the genomics era with confidence in the future of medicine, including psychiatry, identifying the role of DNA and polymorphic associations with brain reward circuitry has led to a new understanding of all addictive behaviors. It is noteworthy that this strategy may provide treatment for the millions who are the victims of "Reward Deficiency Syndrome" (RDS) a genetic disorder of brain reward circuitry. This article will focus on drugs and food being mutuality addictive, and the role of dopamine genetics and function in addictions, including the interaction of the dopamine transporter, and sodium food. We will briefly review our concept that concerns the genetic antecedents of multiple-addictions (RDS). Studies have also shown that evaluating a panel of established reward genes and polymorphisms enables the stratification of genetic risk to RDS. The panel is called the "Genetic Addiction Risk Score (GARS)", and is a tool for the diagnosis of a genetic predisposition for RDS. The use of this test, as pointed out by others, would benefit the medical community by identifying at risk individuals at a very early age. We encourage, in depth work in both animal and human models of addiction. We encourage further exploration of the neurogenetic correlates of the commonalities between food and drug addiction and endorse forward thinking hypotheses like "The Salted Food Addiction Hypothesis".
Chapter
We have entered the genomics era with hope for the future of medicine including psychiatry. Understanding the role of DNA and polymorphic associations with brain reward circuitry has led to a new understanding of all addictive behaviors. We present here a brief review of the role of both neurogenetics and nutrigenomics as cornerstones that link more accurate genetic diagnosis and dopamine D2 agonist therapy to induce dopaminergic activation. Based on numerous experiments we are indeed proposing a novel approach. We challenge the entire recovery field to use these tools, the result of years of scientific research into the nature of addiction, and to incorporate them into treatment programs for patients attending inpatient/outpatient addiction clinics, such as the Genetic Addiction Risk Score (GARS)™ for appropriate RDS diagnosis, Comprehensive Analysis of Reported Drugs (CARD)™ to determine both compliance and abstinence during treatment, natural D2 agonistic therapy (NAAT-KB220™), and, eventually, mRNA (patent pending) to determine pre- and post-candidate gene expressions in reward deficiency syndrome (RDS). We are, therefore, proposing a paradigm shift we have called “Reward Deficiency Solutions System (RDSS)™.”
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Alcoholism and cirrhosis, which are two of the most serious health problems worldwide, have a broad spectrum of clinical outcomes. Both diseases are influenced by genetic susceptibility and cultural traits that differ globally but are specific for each population. In contrast to other regions around the world, Mexicans present the highest drinking score and a high mortality rate for alcoholic liver disease with an intermediate category level of per capita alcohol consumption. Mexico has a unique history of alcohol consumption that is linked to profound anthropological and social aspects. The Mexican population has an admixture genome inherited from different races, Caucasian, Amerindian and African, with a heterogeneous distribution within the country. Thus, genes related to alcohol addiction, such as dopamine receptor D2 in the brain, or liver alcohol-metabolizing enzymes, such as alcohol dehydrogenase class I polypeptide B, cytochrome P450 2E1 and aldehyde dehydrogenase class 2, may vary from one individual to another. Furthermore, they may be inherited as risk or non-risk haplogroups that confer susceptibility or resistance either to alcohol addiction or abusive alcohol consumption and possibly liver disease. Thus, in this era of genomics, personalized medicine will benefit patients if it is directed according to individual or population-based data. Additional association studies will be required to establish novel strategies for the prevention, care and treatment of liver disease in Mexico and worldwide.
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(1) Background: Alcohol use disorder (AUD) is associated with poor medical, psychological, and psychosocial outcomes and approximately 60% of individuals with AUD relapse six months after treatment. Craving is a core aspect of AUD and associated with high risk of relapse. One promising avenue to improve outcomes may be in understanding the relationship between COMT genotype, craving, and treatment outcomes. (2) Methods: To this end, we assessed craving, recent drinking history, and impulsivity in 70 individuals with AUD undergoing a standard course of treatment at a regional Veteran Affairs (VA) medical center. Saliva samples were collected to determine COMT genotype. In this prospective observational study, participants were followed for six months to determine who went on to relapse after treatment. (3) Results: Results revealed a significant interaction between craving and catechol-O-methyltransferse (COMT) genotype in predicting relapse. Post hoc exploratory analyses indicated that Met/Met homozygotes reported the highest levels of craving, and craving was associated with recent drinking history. Among Val/Val homozygotes, who had higher rates of relapse, craving was associated with impulsivity. (4) Conclusions: These associations highlight that specific profiles of psychological and biological factors may be important in understanding which individuals are at highest risk of relapse following treatment. Future studies that build on these findings are warranted.
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Catechol-O-methyl transferase (COMT) enzyme catalyzes the metabolism of dopamine and other catechols in the brain. Several articles investigated catechol-O-methyltransferase (COMT) Val158Met polymorphism as risk factor for alcohol dependence (AD) but the results were inconclusive. The aim of present meta-analysis was to evaluate the association of Val158Met (COMT) polymorphism with AD. Authors performed keyword search of the 4 electronic databases—Pubmed, Google Scholar, Springer Link and Science Direct databases up to December 31, 2019. Total eighteen studies that investigated the association of Val158Met polymorphism with AD were retrieved. The pooled results from the meta-analysis (2278 AD cases and 3717 healthy controls) did not show association with AD using all 5 genetic models (allele contrast model: OR = 1.02, 95% CI = 0.90–1.14, p = 0.03; homozygote model: OR = 1.06, 95% CI = 0.81–1.38, p = 0.69; dominant model: OR = 0.99, 95% CI = 0.85–1.14, p = 0.87; co-dominant model: OR = 0.97, 95% CI = 0.86–1.11, p = 0.71; recessive model: OR = 1.05;95% CI = 0.85–1.29, p = 0.61). Results of subgroup analysis showed that Val158Met is not risk for AD in Asian and Caucasian population. In conclusion, COMT Val158Met is not a risk factor for alcohol dependence.
Chapter
Co-abuse of alcohol (drinks containing ethanol) with drugs of abuse (DOA) or medications is a serious health problem the society faces today. Although mechanisms underlying the interaction of alcohol with DOA or medication are not fully understood, abnormalities in the pharmacokinetics and pharmacodynamics of both alcohol and DOA or medications have been implicated. The factors determining this interaction depends on the physicochemical properties of the medicines, the doses of drugs and alcohol, the mode of administration, and the health status of the patients. Acute ethanol exposure (i) inhibits the cytochrome p450-mediated drug metabolism, thus enhancing the drug’s effects, (ii) attenuates excitatory neurotransmitters, and (iii) activates inhibitory neurotransmitters. Conversely, chronic ethanol exposure caused opposite effects. Therefore, an understanding of the alcohol-DOA/medicine interaction may be important for improving general human and animal health.
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dül eksikliği sendromu (ÖES), beynin ödüllendirme süreçlerinde meydana gelen kimyasal dengesizlikler sonucunda birçok davranışsal bozuklukların ortaya çıktığı bir tablo olarak tanımlanmıştır. Beyindeki ödül sistemi 1950'lerde tesadüfen Olds tarafından keşfedilmiştir. Beyindeki ödül sisteminin temelini limbik sistem oluşturmaktadır. ÖES'nin bazal gangliyonlar, başta NAC olmak üzere mezolimbik beyin bölgeleri, prefrontal korteks, hipotalamus ve amigadala gibi limbik sistemin önemli parçalarını da kapsayan geniş bir beyin alanında meydana gelen çeşitli bozukluklarla ilişkili olduğu artık bilinmektedir. Limbik sistem, temel duyguları ve davranışları kontrol etmekte ve haz algısına temel oluşturmaktadır. Ayrıca hafıza ve öğrenme, cinsel davranış, motivasyon ve beslenme gibi önemli davranışları da kontrol etmektedir. Dopamin başta olmak üzere birçok nörotransmitterin ÖES patogenezinde rol aldığı belirtilmektedir. ÖES'nin alkol bağımlılığı, madde kötüye kullanımı, sigara kullanımı, kompulsif aşırı yeme, obezite, dikkat eksikliği hiperaktivite bozukluğu, Tourette bozukluğu, kontrolsüz internet kullanımı ve patolojik kumar oynama gibi bozukluklar ile ilişkisi ve nörobiyolojik ortak yolları da çalışmalarla gösterilmiştir. Bu makalede, ÖES ile ilgili bilgilerin ve çalışmaların literatür eşliğinde tartışılması amaçlandı. Anahtar Kelimeler: Ödül eksikliği sendromu, ödül yolağı, bağımlılık. Bağıntı beyanı: Yazarlar bu makale ile ilgili olarak herhangi bir çıkar çatışması bildirmemişlerdir. Reward deficiency syndrome (RDS) has been described as a statement resulted in many behavioral disorders due to chemical imbalances in the brain's reward system. This system has been incidentally discovered by Olds in 1950. Limbic system is the basis of that system. It is now known that RDS is associated with a variety of disorders occur in a wide area of the brain covering the important parts of the limbic-system as basal ganglia, including the mesolimbic regions of the brain; particularly NAC, the prefrontal cortex, hypothalamus and amygdala. The limbic system, the basis for the perception of pleasure, controls basic emotions and behaviors. İt is stated that many neurotransmitters, especially dopamine play a role in the pathogenesis of RDS. Furthermore, it also controls important behaviors including memory and learning, sexual behavior, motivation and nutrition. It is reported that RDS has neurobiological common paths and relation with alcohol addiction, substance abuse, smoking, compulsive overeating, obesity, attention deficit and hyperactivity, Tourette's disorder, uncontrolled internet usage and pathological gambling. RDS-related information and studies discussed in the literature were evaluated in this article. Key Words: Reward deficiency syndrome, reward cascade, dependence Declaration of interest: The authors reported no conflict of interest related to this article.
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Catechol-O-methyltransferase (COMT) plays an important role in dopamine degradation, which is associated with the pathophysiology of Alzheimer's disease (AD) and alcoholism. A functional COMT polymorphism, Val158Met (rs4680 G > A), affects the onset of AD and is associated with alcohol dependence through dopamine receptor sensitivity in the prefrontal cortex. The aim of this case-control study (398 cases and 149 controls) was to investigate whether Val158Met polymorphism influences the onset of AD stratified according to alcohol consumption and apolipoprotein E (APOE) status. We also used single photon-emission computed tomography (SPECT) to analyse 26 patients with AD with the polymorphism. As a function of APOE status, the genotypic frequencies of rs4680 in patients with AD did not differ from those in controls. We detected a significant association between high alcohol consumption in patients with AD (HAC-AD group) and the polymorphism in genotypic and allelic frequencies. Logistic regression analyses demonstrated that the presence of the APOE genotype with rs4680 increased the risk for HAC-AD synergistically. Hyperperfusion in the right sub-lobar insula of patients with the G/G genotype was found compared with that of patients with the G/A genotype. SPECT studies showed a relationship between the polymorphism and compensatory reactions for dysfunctions of dopaminergic neurotransmission in AD pathophysiology. Although genetic association between the polymorphism and the onset of AD in a Japanese population were not observed, the polymorphism affected the risk for HAC-AD. Copyright © 2014 John Wiley & Sons, Ltd. Copyright © 2014 John Wiley & Sons, Ltd.
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Aim The Lithuanian population has outstanding rates of alcohol consumption and alcohol related mortality. Alteration of brain dopaminergic system play a role in the risk for addiction disorders. We evaluated the association of one single nucleotide polymorphism rs1800497 in the Ankyrin Repeat and Kinase Domain Containing 1 – Dopamine Receptor D2 complex (ANKK1-DRD2) and a catechol-o-methyltransferase (COMT) rs4680 single nucleotide polymorphism with the risk for alcohol use disorder and impulsiveness in Lithuanian population. Both genetic polymorphisms are known to alter brain dopaminergic activity, thus we also investigated the possible interaction effect of these polymorphisms. Methods The study included 329 participants recruited from the local community. Hazardous alcohol use was evaluated using the Alcohol Use Disorder Identification Test (AUDIT). Impulsiveness was measured using the Barratt Impulsiveness Scale – 11 (BIS-11). Between group differences of AUDIT and BIS-11 scores were examined stratified by genetic polymorphisms and their combinations. The independent effect of each polymorphism and their interaction for hazardous alcohol use were evaluated using adjusted logistic regression analyses. Results The ANKK1-DRD2 rs1800497 polymorphism was associated with total AUDIT score, but not with the hazardous use of alcohol, as indicated by the AUDIT test cut-off of 8. The COMT rs4680 GG genotype was associated with the hazardous use of alcohol (adjusted OR = 2.094, p=0.029), but this association was not statistically significant after adjustment for multiple comparisons. Presence of both COMT rs4680 and ANKK1-DRD2 rs1800497 GGxCT/TT polymorphisms was associated with significantly increased risk for hazardous use of alcohol (adjusted OR = 5.016, p=0.005). The COMT rs4680 and ANKK1-DRD2 rs1800497 genetic polymorphisms, and their combination were not associated with impulsiveness. Conclusions Our study demonstrated that the interaction of COMT rs4680 and ANKK1-DRD2 rs1800497 genetic polymorphisms is associated with a hazardous use of alcohol.
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Alcohol use disorder (AUD) is the most common substance use disorder worldwide. Although dopamine‐related findings were often observed in AUD, associated neurobiological mechanisms are still poorly understood. Therefore, in the present study, we investigate D2/3 receptor availability in healthy participants, participants at high risk (HR) to develop addiction (not diagnosed with AUD), and AUD patients in a detoxified stage, applying ¹⁸F‐fallypride positron emission tomography (¹⁸F‐PET). Specifically, D2/3 receptor availability was investigated in (1) 19 low‐risk (LR) controls, (2) 19 HR participants, and (3) 20 AUD patients after alcohol detoxification. Quality and severity of addiction were assessed with clinical questionnaires and (neuro)psychological tests. PET data were corrected for age of participants and smoking status. In the dorsal striatum, we observed significant reductions of D2/3 receptor availability in AUD patients compared with LR participants. Further, receptor availability in HR participants was observed to be intermediate between LR and AUD groups (linearly decreasing). Still, in direct comparison, no group difference was observed between LR and HR groups or between HR and AUD groups. Further, the score of the Alcohol Dependence Scale (ADS) was inversely correlated with D2/3 receptor availability in the combined sample. Thus, in line with a dimensional approach, striatal D2/3 receptor availability showed a linear decrease from LR participants to HR participants to AUD patients, which was paralleled by clinical measures. Our study shows that a core neurobiological feature in AUD seems to be detectable in an early, subclinical state, allowing more individualized alcohol prevention programs in the future.
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This article focuses on the shared molecular and neurogenetics of food and drug addiction tied to the understanding of reward deficiency syndrome. Reward deficiency syndrome describes a hypodopaminergic trait/state that provides a rationale for commonality in approaches for treating long-term reduced dopamine function across the reward brain regions. The identification of the role of DNA polymorphic associations with reward circuitry has resulted in new understanding of all addictive behaviors. Copyright © 2015 Elsevier Inc. All rights reserved.
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This chapter gives a short overview on the comorbidity and clinical correlates of substance use in affective and anxiety disorders, as well as in schizophrenia. The emphasis is on pharmacotherapies available for the treatment of comorbid disorders. While no specific drugs have been developed for comorbid substance use disorders, psychotropic drugs such as antidepressants or antipsychotics have been tested in dual disorder patients, as well as anticraving compounds. Most studies have included few patients. Very few randomized controlled trials are available in the dual disorder research field. Thus, the empirical basis for evidence-based recommendations is rather limited. The possible benefits of available medications so far are discussed.
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A high percentage of patients with schizophrenia or bipolar disorder suffer from co morbid substance use disorder complicating both diagnosis and treatment. To avoid inferior long-term outcomes the therapist needs to recognize the underlying mental disorder early in course and to take it into consideration for the treatment plan. Knowledge of pharmacological treatment options for both disorders are mandatory. In patients with schizophrenia and co morbid substance use atypical antipsychotics show similar advantages over typical antipsychotics as in uncomplicated schizophrenia. Furthermore, they might have a positive impact on addiction. The same is true for atypical antipsychotics in bipolar disorder with co occurring substance use; moreover, valproic acid might be an option with some degree of additional effects on substance use. On the whole, however, the evidence for all pharmacotherapies in this patient group can be considered as quite limited. An individualized, symptom and long term course oriented treatment making use of all options is demanded.
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Alcohol use disorders (AUDs) are highly comorbid with human immunodeficiency virus (HIV) infection, occurring at nearly twice the rate in HIV positive individuals as in the general population. Individuals with HIV who consume alcohol show worse long-term prognoses and may be at elevated risk for the development of HIV-associated neurocognitive disorders. The direction of this relationship is unclear, and likely multifactorial. Chronic alcohol exposure and HIV infection independently promote cognitive dysfunction and further may interact to exacerbate neurocognitive deficits through effects on common targets, including corticostriatal glutamate and dopamine neurotransmission. Additionally, drug and alcohol use is likely to reduce treatment adherence, potentially resulting in accelerated disease progression and subsequent neurocognitive impairment. The development of neurocognitive impairments may further reduce cognitive control over behavior, resulting in escalating alcohol use. This review will examine the complex relationship between HIV infection and alcohol use, highlighting impacts on dopamine and glutamate systems by which alcohol use and HIV act independently and in tandem to alter corticostriatal circuit structure and function to dysregulate cognitive function.
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Anhedonia, the inability to feel or experience pleasure, is a major problem for recovering addicts. Anhedonia can persist long after all traces of the offending drug are gone, and it can cause suicidal thinking and behaviors. We believe that anhedonia is not a distinct disorder but is a symptom of hypodopaminergic traits (genetic), epigenetic states, or a combination of the two. The 2011 endorsement of the American Society of Addiction Medicine’s new definition of addiction as a brain disorder has caught up with the science. Addiction involves an extended neuro-circuitry of the brain, and anhedonia is a condition that involves some of those same regions, including dopaminergic pathways in the mesocorticolimbic system. Andedonia, commonly reported by addicts in detox centers or early abstinence, may be directly tied to the drug-induced dopaminergic changes. It has been our position for decades that brain dopaminergic deficiencies result in reward- circuitry impairments, ultimately leading to Reward Deficiency Syndrome (RDS). The prefrontal cortex and cingulate gyrus contribute to drug relapse, and the nucleus accumbens (NAc) is a locus for craving behavior. While dopaminergic activity is very complex and may evoke differential physiological processes as it relates to pain and pleasure mechanisms (e.g., “liking” and “wanting”), anhedonic behavior has at its root a hypodopaminergic phenotype. In this chapter we discuss polymorphisms of reward genes in terms of inducing this hypodopaminergic phenotype (interaction of both genes and environment) and attempt to show their impact on the induction of anhedonia as a symptom of drug-induced withdrawal. Understanding of putative neurogenetic antecedents to RDS behaviors may provide a gene map for accessing the risk of an individual in developing anhedonia, especially following long-term drug abuse. We encourage the scientific community to carry on required studies to test this hypothesis. It is our belief that one mode of treatment to attenuate anhedonia is to provide natural activation of dopaminergic receptors (D2/D3) at the brain sites for craving and relapse in order to increase dopamine sensitivity.
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Alcohol dependence (alcoholism) is a complex disorder attributed to the interaction of genetic and environmental factors that form a collage of "disease" predisposition, which is not identical for every alcohol-dependent individual. There is considerable evidence to demonstrate that genetic predisposition accounts for roughly half the risk in the development of alcohol dependence. Both family and population studies have identified a number of genomic regions with suggestive links to alcoholism, yet there have been relatively few definitive findings with regard to genetic determinants of alcoholism. This ambiguity can be attributed to a multitude of complications of studying complex mental disorders, such as clinical heterogeneity, polygenic determinants, reduced penetrance, and epistatic effects. Complex mental disorders are clinical manifestations described by combinations of various signs and symptoms. One approach to overcoming the ambiguity in studying the association between genetic risk factors and disease is to dissect the complex, heterogeneous disorder by using intermediate phenotypes--or endophenotypes--to generate more homogeneous diagnostic groupings than an all-encompassing definition, such as the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)-derived term "alcohol dependence" or the commonly used term "alcoholism." The advantage of using endophenotypes is that the number of influential factors that contribute to these characteristics should be fewer and more easily identified than the number of factors affecting the heterogeneous entity of alcohol dependence (alcoholism). A variety of alcohol-related characteristics have been investigated in epidemiological, clinical, and basic research as potential endophenotypes of alcohol dependence. These include phenotypes related to alcohol metabolism, physiological and endocrine measures, neural imaging, electrophysiology, personality, drinking behavior, and responses to alcohol and alcohol-derived cues. This review summarizes the current literature, focused on human data, of promising endophenotypes for dissecting alcoholism.
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Monamines subserve many critical roles in the brain, and monoaminergic drugs such as amphetamine have a long history in the treatment of neuropsychiatric disorders and also as a substance of abuse. The clinical effects of amphetamine are quite variable, from positive effects on mood and cognition in some individuals, to negative responses in others, perhaps related to individual variations in monaminergic function and monoamine system genes. We explored the effect of a functional polymorphism (val(158)-met) in the catechol O-methyltransferase gene, which has been shown to modulate prefrontal dopamine in animals and prefrontal cortical function in humans, on the modulatory actions of amphetamine on the prefrontal cortex. Amphetamine enhanced the efficiency of prefrontal cortex function assayed with functional MRI during a working memory task in subjects with the high enzyme activity val/val genotype, who presumably have relatively less prefrontal synaptic dopamine, at all levels of task difficulty. In contrast, in subjects with the low activity met/met genotype who tend to have superior baseline prefrontal function, the drug had no effect on cortical efficiency at low-to-moderate working memory load and caused deterioration at high working memory load. These data illustrate an application of functional neuroimaging in pharmacogenomics and extend basic evidence of an inverted-"U" functional-response curve to increasing dopamine signaling in the prefrontal cortex. Further, individuals with the met/met catechol O-methyltransferase genotype appear to be at increased risk for an adverse response to amphetamine.
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The present study was performed to test the hypotheses that allelic variants at the human dopamine D2 receptor gene locus (DRD2) confer susceptibility to alcoholism or are associated with clinical subtypes of alcoholism. We investigated anA^G substitution polymorphism in the 3'-untranslated region of exon 8 (E8) of DRD2 with allele frequencies of/G=0.295 - 0.329. No significant association of the DRD2 genotype or allele frequencies with alcoholism was found in an association study including 283 alcoholics and 146 non-alcoholic controls. However, the frequent homozygous E8 A/A genotype with fAA=0.47 - 0.48 was associated with increased anxiety and depression scores in alcoholics during the follow up after clinical detoxification treatment. In addition, E8 A/A was associated with increased suicide attempts and showed a tendency towards more severe withdrawal symptoms, early relapse and reduced responsiveness to the dopaminergic agonist apomorphine. Regression analysis revealed the DRD2 E8 genotype as the only significant factor determining withdrawal severity in female alcoholics. The findings suggest an influence of the DRD2 genotype on the neuropharmacological effects of chronic alcohol exposure and the clinical course of alcoholism. (C) Lippincott-Raven Publishers.
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Addictive drugs, including ethanol, increase the brain's dopaminergic transmission, and catechol-o-methyltransferase (COMT) enzyme has a crucial role in dopamine inactivation. A common functional polymorphism in the COMT gene results in a three- to four-fold variation in enzyme activity. In a previous study, we found an association between type 1 (with late-onset but without prominent antisocial behavior) alcoholism and the low activity allele of the COMT gene. In this work we analyzed whether the COMT polymorphism has any effect on the development of type 2 (with early-onset and habitual impulsive violent behavior) alcoholism. The COMT genotype was determined in 62 impulsive violent recidivist offenders with early-onset (type 2) alcoholism, 123 late-onset nonviolent (type 1) alcoholics, and 267 race and gender-matched controls. The allele and genotype frequencies of these groups were compared with each other and also with previously published data from 3,140 Finnish blood donors. The type 2 alcoholics did not differ from either the blood donors or the controls. The low activity (L) allele frequency was higher among type 1 alcoholics (χ2 = 4.98, P = 0.026) when compared with type 2 cases. The odds ratio for type 1 alcoholism as compared with type 2 alcoholism for those subjects with the LL genotype versus the HH genotype was 3.0 (95% confidence interval 1.1–8.4, P = 0.017). The results suggest that COMT genotype has no major role in the development of early-onset alcoholism with severe antisocial behavior. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:348–352, 2000. © 2000 Wiley-Liss, Inc.
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Neuroimaging studies have suggested the involvement of ventrolateral, dorsolateral, and frontopolar prefrontal cortex (PFC) regions in both working (WM) and long-term memory (LTM). The current study used functional magnetic resonance imaging (fMRI) to directly compare whether these PFC regions show selective activation associated with one memory domain. In a within-subjects design, subjects performed the n-back WM task (two-back condition) as well as LTM encoding (intentional memorization) and retrieval (yes–no recognition) tasks. Additionally, each task was performed with two different types of stimulus materials (familiar words, unfamiliar faces) in order to determine the influence of material-type vs task-type. A bilateral region of dorsolateral PFC (DL-PFC; BA 46/9) was found to be selectively activated during the two-back condition, consistent with a hypothesized role for this region in active maintenance and/or manipulation of information in WM. Left frontopolar PFC (FP-PFC) was also found to be selectively engaged during the two-back. Although FP-PFC activity has been previously associated with retrieval from LTM, no frontopolar regions were found to be selectively engaged by retrieval. Finally, lateralized ventrolateral PFC (VL-PFC) regions were found to be selectively engaged by material-type, but uninfluenced by task-type. These results highlight the importance of examining PFC activity across multiple memory domains, both for functionally differentiating PFC regions (e.g., task-selectivity vs material-selectivity in DL-PFC and VL-PFC) and for testing the applicability of memory domain-specific theories (e.g., FP-PFC in LTM retrieval).
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Although the prominent role of genetics in psychiatric diseases has been established in various family, twin and adoption studies over the last decades, the identification of concrete contributing genes has been demanding. The reasons for this are manifold, including inconsistencies in psychiatric classification systems, complexity and heterogeneity of psychiatric disorders, epistatic effects and intervening environmental factors. In recent years interest has focused increasingly on the concept of endophenotypes. Genetic analyses have concentrated on discrete phenotypes supposedly linked to a particular psychiatric disorder by common neurobiological pathways, instead of studying the complex disease itself. Several endophenotypes have been established for psychiatric diseases including electrophysiological abnormalities and alterations in structural and functional brain imaging. Although results seem to be getting more consistent and reliable, several concerns have also emerged with the experience gained on the topic. This review will give an overview of the prospects and limitations related to endophenotypes in psychiatric diseases. We will also summarize essential prerequisites for successful endophenotypes in the future as well as applications for psychiatric diseases which have been envisioned.
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Evidence of marked variability in response among people exposed to the same environmental risk implies that individual differences in genetic susceptibility might be at work. The study of such Gene-by-Environment (GxE) interactions has gained momentum. In this article, the authors review research about one of the most extensive areas of inquiry: variation in the promoter region of the serotonin transporter gene (SLC6A4; also known as 5-HTT) and its contribution to stress sensitivity. Research in this area has both advanced basic science and generated broader lessons for studying complex diseases and traits. The authors evaluate four lines of evidence about the 5-HTT stress-sensitivity hypothesis: 1) observational studies about the serotonin transporter linked polymorphic region (5-HTTLPR), stress sensitivity, and depression in humans; 2) experimental neuroscience studies about the 5-HTTLPR and biological phenotypes relevant to the human stress response; 3) studies of 5-HTT variation and stress sensitivity in nonhuman primates; and 4) studies of stress sensitivity and genetically engineered 5-HTT mutations in rodents. The authors then dispel some misconceptions and offer recommendations for GxE research. The authors discuss how GxE interaction hypotheses can be tested with large and small samples, how GxE research can be carried out before as well as after replicated gene discovery, the uses of GxE research as a tool for gene discovery, the importance of construct validation in evaluating GxE research, and the contribution of GxE research to the public understanding of genetic science.
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Animal studies point to a role of estrogen in explaining gender differences in striatal dopaminergic functioning, but evidence from human studies is still lacking. Given that dopamine is crucial for controlling and organizing goal-directed behavior, estrogen may have a specific impact on cognitive control functions, such as the inhibition of prepotent responses. We compared the efficiency of inhibitory control (as measured by the stop-signal task) in young women across the three phases of their menstrual cycle (salivary estradiol and progesterone concentrations were assessed) and in young men. Women were less efficient in inhibiting prepotent responses in their follicular phase, which is associated with higher estradiol levels and with higher dopamine turnover rates, than in their luteal or menstruation phase. Likewise, women showed less efficient inhibitory control than men in their follicular phase but not in their luteal or menstruation phase. Our results are consistent with models assuming that the over-supply of striatal dopamine in the follicular phase weakens inhibitory pathways, thus leading to enhanced competition between responses. We conclude that gender differences in response inhibition are variable and state dependent but not structural.
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D(2) receptor function can be assessed by growth hormone (GH) response to apomorphine. Several association studies between dopamine receptor polymorphisms and results of the apomorphine challenge test with normal and alcohol-dependent subjects yielded inconsistent results. In this pilot study, we tested polymorphisms from the DRD2 region for GH response to apomorphine challenge in more detail. Apomorphine challenge tests measuring GH responses on 5 time points were performed on day 1 of alcohol detoxification in 43 patients with alcohol dependence; patients were genotyped for 11 polymorphisms including DRD2, ANKK1, NCAM1 and TTC12. Associations (p<0.05) were found for ANKK1 (rs11604671, rs1800497) and DRD2 (rs6276, rs1076560), which are located on adjacent chromosomal positions. Consistent with PET studies suggesting a reduced D(2) receptor availability in patients carrying the ANKK1 rs1800497 T polymorphism (formerly known as DRD2 TaqI A1) we found a reduced GH response to apomorphine in those subjects. This has been the first study showing significant associations between apomorphine-induced GH response and SNPs in DRD2 and ANKK1 in alcohol-dependent patients. In this respect, our preliminary results are in line with other reports which suggested that DRD2 and ANKK1 polymorphisms influence D(2) receptor availability and signal transduction in the dopaminergic pathways. Small sample size in our study limits the generalizability of our results.
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Heritability estimates for alcoholism range from 50% to 60%, pointing out the importance of genetic and environmental factors in its etiology. This review highlights recent advances in translational work investigating genetic influences on alcoholism. We focus on genetic research involving corticotropin-releasing factor, glutamatergic, and opioidergic systems. Variation in the CRF1 receptor gene has been shown to moderate stress-induced alcohol drinking (gene-environment interaction) in animals, and this finding was recently extended to humans. Also, the hyperglutamatergic state, first observed during withdrawal from chronic alcohol exposure in animal models, is associated with aversive and dysphoric states in alcoholics. Pharmacogenetic studies of naltrexone efficacy are in the clinical stages, and recent studies confirmed a differential response dependent on the mu-opioid receptor genotype. Such advances will be essential for the effective treatment of alcoholism in the future.
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An extensive body of literature provides evidence for both sexual dimorphism and menstrual cycle effects in drug abuse patterns and behavioral responses. However, the cellular mechanisms underlying sexually dimorphic responses to and hormonal effects on cocaine use remain unclear. We hypothesized that endogenous hormonal fluctuations during the estrous cycle of rats modulate cocaine's effects on dopamine- and PKA-mediated intracellular responses. To test this hypothesis, intact female rats at different stages of their cycle received a single injection of saline or cocaine (20 mg/kg) and were sacrificed after 15 or 60 min. The nucleus accumbens (NAc) and caudate putamen (CPu) were dissected and analyzed via Western blot for total and phosphorylated (p-thr34) dopamine- and 3'-5'-cyclic AMP-regulated phosphoprotein with molecular weight 32 kDa (DARPP-32), PP1, PP2B (CNA1 and CNB1 subunits), PKA, CREB, cFOS, and Delta-FosB. Our results show that saline-treated rats had estrous cycle-related differences in protein levels of pCREB, DARPP-32, p-thr34-DARPP-32, PP1, and CNA1. Saline-treated female rats in the estrus stage had higher levels of pCREB in the NAc, but cocaine-treatment lowered pCREB levels. The estrous cycle also significantly affected the magnitude of change for p-thr34-DARPP-32 protein levels in both the NAc and CPu. Sixty minutes of cocaine administration increased p-thr34-DARPP-32 levels in the NAc of rats during estrus and proestrus and in the CPu of rats in diestrus. Furthermore, cocaine-induced changes in PP1 protein levels in the NAc were also affected by the stage of the cycle; 60 min of cocaine administration increased PP1 levels in the NAc of rats during diestrus, whereas PP-1 levels decreased in rats during estrus. Taken together, these novel findings suggest that hormonal fluctuations during the estrous cycle may contribute to the previously reported sex differences in the PKA pathway and in behavioral responses to cocaine.
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Drug dependence is a chronic, relapsing disorder in which compulsive drug-seeking and drug-taking behaviours persist despite serious negative consequences. Addictive substances, such as opioids, ethanol, psychostimulants and nicotine, induce pleasant states or relieve distress, effects that contribute to their recreational use. Dopamine is critically involved in drug addiction processes. However, the role of the various dopaminergic receptor subtypes has been difficult to delineate. Here, we will review the information collected implicating the receptors of the D1 family (DRD1 and DRD5) and of the D2 family (DRD2, DRD3 and DRD4) in drug addiction. We will summarize the distribution of these receptors in the brain, the preclinical experiments carried out with pharmacological and transgenic approaches and the genetic studies carried out linking genetic variants of these receptors to drug addiction phenotypes. A meta-analysis of the studies carried out evaluating DRD2 and alcohol dependence is also provided, which indicates a significant association. Overall, this review indicates that different aspects of the addiction phenotype are critically influenced by dopaminergic receptors and that variants of those genes seem to influence some addiction phenotypes in humans.
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The Addiction Severity Index (ASI) is 12 years old and has been revised to include a new section on family history of alcohol, drug, and psychiatric problems. New items were added in existing sections to assess route of drug administration; additional illegal activities; emotional, physical, and sexual abuse; quality of the recovery environment; and history of close personal relationships. No changes were made in the composite scoring to maintain comparability with previous editions. This article discusses the clinical and research uses of the ASI over the past 12 years, emphasizing some special circumstances that affect its administration. The article then describes the rationale for and description of the changes made in the ASI. The final section provides "normative data" on the composite scores and severity ratings for samples of opiate, alcohol, and cocaine abusers as well as drug abusing inmates, pregnant women, homeless men, and psychiatrically ill substance abusers.
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Postsynaptic dopamine (DA) receptor sensitivity was assessed during abstinence in 15 male patients with alcohol dependence. The DA receptor sensitivity was evaluated using growth hormone (GH) responses to the DA receptor agonist apomorphine (0.18-0.24 mg intravenously). The patients were cared for in an alcoholism treatment unit for the 2 months prior to the investigation. They were carefully controlled for sobriety during this period. Thirteen healthy men were used as controls. The maximum GH responses to apomorphine were significantly reduced in patients compared with those in the control group. The patients had a significantly higher proportion of blunted GH responses. The findings suggest reduced postsynaptic DA, possibly D2, receptor sensitivity in abstinent alcoholics. The question whether this abnormal DA receptor status is genetically determined or acquired after long-term alcohol consumption remains to be addressed.
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A simple extraction system for the selective and quantitative isolation of apomorphine from human plasma is described. Apomorphine and N-n-propylnorapomorphine were isolated by complex formation between a borate group and the diol group of the apomorphines in an alkaline medium, this in combination with ion-pair formation. The reproducibility and linearity of this extraction method combined with high-performance liquid chromatography with electrochemical detection is excellent. The absolute mean recovery of apomorphine was 100%, the recovery of N-n-propylnorapomorphine was 98%. The detection limit of apomorphine in human plasma in the described system is approximately 0.5 ng/ml.
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Sixty-five psychotic probands were divided into three groups (low, intermediate, and high) on the basis of the GH response to the dopamine receptor agonist apomorphine. Two hundred and sixty-five first-degree relatives of the probands were diagnosed according to SADS-DSM-III methods, and the relatives of the three groups of probands were compared so as to detect familial differences in the incidence of DSM-III Axis I disorders, schizotypal personality disorder, and antisocial personality. Although the morbid risk of schizophrenic spectrum disorder was only 3.1% in the relatives of the high GH probands, the morbid risk for disorders of the schizophrenic spectrum was 17.0% and 10.7% in the relatives of the intermediate and low GH probands, respectively. These data provide preliminary evidence that there may be a psychotic subtype that is characterized by supersensitivity of the dopamine system that is familially, and perhaps genetically, distinct from the bulk of the schizophrenias.