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Dopamine DRD2/ANKK1 Taq1A and DAT1 VNTR polymorphisms are associated with a cognitive flexibility profile in pathological gamblers
Abstract
Like drug addiction, pathological gambling (PG) has been associated with impairments in executive functions and alterations in dopaminergic functioning; however, the role of dopamine (DA) in the executive profile of PG remains unclear. The aim of this study was to identify whether the DRD2/ANKK1 Taq1A-rs1800497 and the DAT1-40 bp VNTR polymorphisms are associated with cognitive flexibility (measured by Wisconsin Card Sorting Test (WCST) and Trail Making Test (TMT)) and inhibition response (measured by Stroop Color and Word Test (SCWT)), in a clinical sample of 69 PG patients. Our results showed an association between DA functioning and cognitive flexibility performance. The Taq1A A1+ (A1A2/A1A1) genotype was associated with poorer TMT performance (p < 0.05), while DAT1 9-repeat homozygotes displayed better WCST performance (p < 0.05) than either 10-repeat homozygotes or heterozygotes. We did not find any association between the DRD2 or DAT1 polymorphisms and the inhibition response. These results suggested that pathological gamblers with genetic predispositions toward lower availability of DA and D2 receptor density are at a higher risk of cognitive flexibility difficulties. Future studies should aim to shed more light on the genetic mechanisms underlying the executive profile in PG.
... Age-related loss of dopamine markers may have multiple and unique loci at the molecular level. For example, the rs1800497 SNP of the dopamine D2 receptor gene (DRD2-rs1800497) was found to associate with mental flexibility but not with the ability to inhibit prepotent responses [29]. The 5-hydroxytryptamine transmitter (also called the serotonin transmitter) has been frequently shown to associate with working memory, inhibition and mental flexibility [30]. ...
... Our study further revealed that scores of two established shifting measures were consistently associated with two DRD2 SNPs, which is in line with previous research showing that the DRD2 TaqIA -rs1800497 is associated with mental flexibility but not with the ability to inhibit prepotent responses [29]. This result is also consistent with a twin study showing that there are significant additional genetic influences on shifting [5]. ...
... In addition, flexible performance is sensitive to the dopamine D2 receptor density determined by genetic factors [52]. Consistent with previous research that the DRD2-rs1800497 with dominant genotypes decreases dopamine synthesis capacity enabling one to perform worse on shifting measures [29], our results demonstrate that those with dominant genotypes exhibit worse shifting performance. ...
This study aimed to examine the organization of executive functions (EFs), specifically working memory updating, prepotent response inhibition, and mental-set shifting in old age, with a particular focus on determining whether the shifting function was behaviorally and genetically separated from the other functions. A total of 248 healthy older Chinese individuals participated, and multiple measures of executive functions were collected. Additionally, measures of fluid intelligence were included to explore the varying relationships between the three executive functions and this higher-order cognitive ability. Furthermore, genetic data were gathered and analyzed to investigate the associations between EFs and six candidate single-nucleotide polymorphisms (SNPs) mapped to dopaminergic, serotonergic, or glutamatergic genes. The results indicated that both the three-factor model and the two-factor model, which combined updating and inhibition, demonstrated a good fit. Furthermore, shifting was found to be behaviorally separated from the other two functions. Moreover, the correlation between shifting and fluid intelligence was smaller compared to the correlations between updating and inhibition with fluid intelligence. Moreover, the DRD2 SNPs showed significant associations with shifting, rather than with updating and inhibition. These findings provide evidence that shifting is distinct and separate from updating and inhibition, highlighting the diversity of EFs among older adults.
... A possible pathophysiological trajectory of D2 impact could be found in the association between dopamine functioning and executive functions. The Taq1A A1+ (A1A2/A1A1) genotype was associated with poorer cognitive flexibility (Trail Making Test performance) in sixty-nine GD subjects (Fagundo et al., 2014). In a study with probabilistic reversal learning task, DRD2/ANKK Taq1A genotype showed no significant effects on cognitive flexibility performance of GD vs cocaine users and healthy control subjects (Verdejo-Garcia et al., 2015). ...
... In all studies but one (Lobo et al., 2007), DAT1 contribution has been proposed as a possible candidate for the overall GD risk (Comings et al., 2001). As compared to 10-repeat homozygotes or heterozygotes, GD subjects with DAT1 9-repeat homozygotes displayed better Wisconsin Card Sorting Test performances, thus suggesting a lower genetic predisposition for difficulties in cognitive flexibility (Fagundo et al., 2014). Polymorphisms in SLC6A3 or SLC18A2 genes were significantly associated with delay discounting, as well as with gambling severity (only SLC6A3; Gray and Mackillop, 2014). ...
... Human studies investigating the alteration of dopamine transmission in GD used genetic and neuroimaging techniques. The majority of the nineteen genetic studies found a significant role for the DRD2 polymorphism, mainly related to DRD2TaqA1 (Comings et al., 1996(Comings et al., , 1997Comings et al., 2001;Fagundo et al., 2014;Hillemacher et al., 2016;Ibáñez et al., 2001;Verdejo-Garcia et al., 2015), with a possible pathophysiological action of epigenetic processes (Hillemacher et al., 2015). Moreover, six articles explored DRD3 role in GD, revealing a role in the occurrence of the disorder (Lobo et al., 2015), as well as in gambling-related cognitive processes (i.e. ...
Dopamine has a crucial and well-documented role in the development and maintenance of Gambling Disorder (GD). This systematic review adopts a translational approach aimed at providing a comprehensive synthesis of current clinical and preclinical knowledge on dopaminergic function in GD at a neurobiological level. To this end, we present and discuss converging dopaminergic alterations and phenotypes. Preclinical and clinical review protocols were registered on the PROSPERO database (CRD42019124404, CRD42019124405). The literature search was conducted in accordance with PRISMA guidelines using three databases (PubMed, Web of Science, Scopus). We identified 67 preclinical studies using pharmacological and non-pharmacological manipulations of the gambling-like phenotype and 33 human studies investigating either genetic polymorphisms or functional brain imaging data. Dopamine transporter and D2, D3, D4 receptor alterations showed strongest translational concordance. Though no postsynaptic dopaminergic alterations were observed, several studies point at dysfunctions in presynaptic dopamine trafficking in GD, suggestive of hyperdopaminergic states. Developing meaningful translational models is essential to working towards the development of an integrated conceptual framework for GD and neurobiologically-based treatment interventions.
... The SLC6A3 VNTR modulates the dopamine transporter (DAT1) expression, as the 9-repeat allele decreases DAT-binding capacities and increases dopamine availability (Heinz et al., 2000;VannNess et al., 2005). This variant seems to support decision-making processes under risky situations, reward seeking behavior, and cognitive flexibility (Dreher et al., 2009;Zhong et al., 2009;Mata et al., 2012;Fagundo et al., 2014). rs4680 affects the enzymatic activity of COMT, as the G/A base change leads to a Val/Met amino acidic change and to a less efficient degradation of dopamine (Chen et al., 2004). ...
... Imaging studies showed that, compared to A2/A2 carriers, the A1-carriers have a significant reduction in the number of DRD2-binding sites in the caudate nucleus (Noble et al., 1991;Ritchie and Noble, 2003) and in the striatum (Pohjalainen et al., 1998) and a decreased dopaminergic activity (Noble et al., 1991(Noble et al., , 1997. This deficiency in dopaminergic system due to the A1-allele has been associated with substance dependency and abuse (Blum et al., 1996;Vereczkei et al., 2013), with lower performance in executive functions (Fossella et al., 2006;Klein et al., 2007), and with poor cognitive flexibility and decision-making abilities (Fagundo et al., 2014;Marinos et al., 2014). ...
... To this aim, single variant genotypes were combined in multilocus genetic profiles, which are the representatives of the overall effect of different combinations of these alleles both on dopaminergic neurotransmission and on cognitive processes and behavioral traits associated with moral choices. Interestingly, by applying the multilocus analysis, a gender effect was observed in females carrying genetic profiles that result in a more efficient dopamine signaling due to increased prefrontal dopamine availability (Heinz et al., 2000; al., 2004), enhanced expression of DRD2 and DRD4 (Pohjalainen et al., 1998;Okuyama et al., 1999;Ritchie and Noble, 2003), or augmentation of cognitive processes (Egan et al., 2001;Bertolino et al., 2006;Gilsbach et al., 2012;Fagundo et al., 2014). These females showed a higher acceptability than females with genetic profiles that impair the dopamine signaling (Figures 1B, 2B). ...
Moral behavior has been a key topic of debate for philosophy and psychology for a long time. In recent years, thanks to the development of novel methodologies in cognitive sciences, the question of how we make moral choices has expanded to the study of neurobiological correlates that subtend the mental processes involved in moral behavior. For instance, in vivo brain imaging studies have shown that distinct patterns of brain neural activity, associated with emotional response and cognitive processes, are involved in moral judgment. Moreover, while it is well-known that responses to the same moral dilemmas differ across individuals, to what extent this variability may be rooted in genetics still remains to be understood. As dopamine is a key modulator of neural processes underlying executive functions, we questioned whether genetic polymorphisms associated with decision-making and dopaminergic neurotransmission modulation would contribute to the observed variability in moral judgment. To this aim, we genotyped five genetic variants of the dopaminergic pathway [rs1800955 in the dopamine receptor D4 (DRD4) gene, DRD4 48 bp variable number of tandem repeat (VNTR), solute carrier family 6 member 3 (SLC6A3) 40 bp VNTR, rs4680 in the catechol-O-methyl transferase (COMT) gene, and rs1800497 in the ankyrin repeat and kinase domain containing 1 (ANKK1) gene] in 200 subjects, who were requested to answer 56 moral dilemmas. As these variants are all located in genes belonging to the dopaminergic pathway, they were combined in multilocus genetic profiles for the association analysis. While no individual variant showed any significant effects on moral dilemma responses, the multilocus genetic profile analysis revealed a significant gender-specific influence on human moral acceptability. Specifically, those genotype combinations that improve dopaminergic signaling selectively increased moral acceptability in females, by making their responses to moral dilemmas more similar to those provided by males. As females usually give more emotionally-based answers and engage the “emotional brain” more than males, our results, though preliminary and therefore in need of replication in independent samples, suggest that this increase in dopamine availability enhances the cognitive and reduces the emotional components of moral decision-making in females, thus favoring a more rationally-driven decision process.
... The ANKK1 gene has a Taq1A (rs1800497) single nucleotide polymorphism (SNP), which has been studied most widely for it is associated with neuro functions (Masiak et al., 2020;Ramos-Lopez et al., 2019). ANKK1 Taq1A polymorphism could affect DRD2 density and auto-receptor mediated DA synthesis inhibition in brain (Beaver et al., 2010), and influence cognition (Fagundo et al., 2014;Failla et al., 2015). ...
... However, researches on the association of DAT1 VNTR and DAT expression showed inconsistent results, some studies found that the 9-repeat allele is associated with higher DAT1 gene expression (Jelaš et al., 2018), some other studies found excessive levels of the DAT protein in homozygotes (10/10) subjects (Brookes et al., 2007), while some studies found no functional differences among DAT1 VNTR polymorphism groups (Martinez et al., 2001). Studies found that DAT1 VNTR polymorphism is associated with cognitive flexibility and intelligence (Fagundo et al., 2014;Qian et al., 2010). ...
Background
Excessive fluoride exposure is related to adverse health outcomes, but whether dopamine (DA) relative genes are involved in the health effect of low-moderate fluoride exposure on children’s intelligence remain unclear.
Objectives
We conducted a cross-sectional study to explore the role of DA relative genes in the health effect of low-moderate fluoride exposure in drinking water.
Methods
We recruited 567 resident children, aged 6–11 years old, randomly from endemic and non-endemic fluorosis areas in Tianjin, China. Spot urine samples were tested for urinary fluoride concentration, combined Raven`s test was used for intelligence quotient test. Fasting venous blood were collected to analyze ANKK1 Taq1A (rs1800497), COMT Val158Met (rs4680), DAT1 40 bp VNTR and MAOA uVNTR. Multivariable linear regression models were used to assess associations between fluoride exposure and IQ scores. We applied multiplicative and additive models to appraise single gene-environment interaction. Generalized multifactor dimensionality reduction (GMDR) was used to evaluate high-dimensional interactions of gene-gene and gene-environment.
Results
In adjusted model, fluoride exposure was inversely associated with IQ scores (β = −5.957, 95% CI: −9.712, −2.202). The mean IQ scores of children with high-activity MAOA genotype was significantly lower than IQ scores of those with low-activity (P = 0.006) or female heterozygote (P = 0.016) genotype. We detected effect modification by four DA relative genes (ANKK1, COMT, DAT1 and MAOA) on the association between UF and IQ scores. We also found a high-dimensional gene-environment interaction among UF, ANKK1, COMT and MAOA on the effect of IQ (testing balanced accuracy = 0.5302, CV consistency: 10/10, P = 0.0107).
Conclusions
Our study suggests DA relative genes may modify the association between fluoride and intelligence, and a potential interaction among fluoride exposure and DA relative genes on IQ.
... In this study conducted on the Indo-Aryan population from Shillong, we mainly focused on glial cell line-derived neurotrophic factor (GDNF), a gene involved in dopaminergic neuronal development, which has previously been found to be associated with methamphetamine (Yoshimura et al., 2011) and tobacco addiction (Kotyuk et al., 2016). In order to investigate the possible role of epigenetic regulation of gene expression in gambling, different single nucleotide polymorphisms (SNPs) located in 3′ untranslated regions (3′ UTRs) of additional candidate genes associated with gambling, such as catechol-O-methyltransferase (Grant, Potenza, Weinstein, & Gorelick, 2015;Guillot, Fanning, Liang, & Berman, 2015;Verdejo-Garcia et al., 2013), DRD2 (Fagundo et al., 2014;Hillemacher et al., 2016;Joutsa et al., 2014), GDNF (Kotyuk et al., 2016;Ron & Janak, 2005), monoamine oxidase A (Ibanez et al., 2000), and solute carrier family 6 member 3 (Fagundo et al., 2014;Kordi-Tamandani, Tajoddini, & Salimi, 2015;Stolf et al., 2014). Some other genes earlier shown to be associated with either addiction, such as HTR2A (Cao et al., 2014;Perez-Rubio et al., 2017), CNR1 (Clarke et al., 2013;Icick et al., 2015), contactinassociated protein-like 2 (CNTNAP2; Song & Zhang, 2014) and TNF (Heberlein et al., 2014), or with other psychiatric conditions, such as AADAC (Bertelsen et al., 2016), ACP1 (Willour et al., 2012), IL1RN (Kapelski et al., 2016), IMMP2L (Petek et al., 2001), LHX6 (Paschou et al., 2012), MEIS1 (Hammerschlag et al., 2017), MIR302A (Beveridge, Gardiner, Carroll, Tooney, & Cairns, 2010), NTN4 (Paschou et al., 2014), and SLITRK1 (Abelson et al., 2005;Speed et al., 2008) were also included. ...
... In this study conducted on the Indo-Aryan population from Shillong, we mainly focused on glial cell line-derived neurotrophic factor (GDNF), a gene involved in dopaminergic neuronal development, which has previously been found to be associated with methamphetamine (Yoshimura et al., 2011) and tobacco addiction (Kotyuk et al., 2016). In order to investigate the possible role of epigenetic regulation of gene expression in gambling, different single nucleotide polymorphisms (SNPs) located in 3′ untranslated regions (3′ UTRs) of additional candidate genes associated with gambling, such as catechol-O-methyltransferase (Grant, Potenza, Weinstein, & Gorelick, 2015;Guillot, Fanning, Liang, & Berman, 2015;Verdejo-Garcia et al., 2013), DRD2 (Fagundo et al., 2014;Hillemacher et al., 2016;Joutsa et al., 2014), GDNF (Kotyuk et al., 2016;Ron & Janak, 2005), monoamine oxidase A (Ibanez et al., 2000), and solute carrier family 6 member 3 (Fagundo et al., 2014;Kordi-Tamandani, Tajoddini, & Salimi, 2015;Stolf et al., 2014). Some other genes earlier shown to be associated with either addiction, such as HTR2A (Cao et al., 2014;Perez-Rubio et al., 2017), CNR1 (Clarke et al., 2013;Icick et al., 2015), contactinassociated protein-like 2 (CNTNAP2; Song & Zhang, 2014) and TNF (Heberlein et al., 2014), or with other psychiatric conditions, such as AADAC (Bertelsen et al., 2016), ACP1 (Willour et al., 2012), IL1RN (Kapelski et al., 2016), IMMP2L (Petek et al., 2001), LHX6 (Paschou et al., 2012), MEIS1 (Hammerschlag et al., 2017), MIR302A (Beveridge, Gardiner, Carroll, Tooney, & Cairns, 2010), NTN4 (Paschou et al., 2014), and SLITRK1 (Abelson et al., 2005;Speed et al., 2008) were also included. ...
Some form of gambling can be observed in nearly every society, as the gratification felt upon
winning in uncertain conditions is universal. A culturally distinct form of gambling, associated with a traditional
sporting event of archery known as “teer,” is innate to the province of Meghalaya, India. The objective of this study
was to find genetic variants underlying this unique form of behavioral addiction. To better understand game-based
gambling, we studied genetic variants related to dopaminergic pathways and other genes previously linked to various
psychological disorders.
... Moreover, studies of trauma brain injury (TBI) have demonstrated that T + performed worse in WM tasks than Tafter a TBI [24][25][26]. In addition to this, in the field of addiction research, the mutant allele has also been implicated in deficits in EF performance [27]. ...
... Unexpectedly, we only found a trend of association with EF. This is in contrast with findings from the field of addiction disorders and obesity in which the role ANKK1 gene in EF performance has been studied in more detail [27], [48].One possible explanation is that EF in the MCCB is assessed by a single test. The NABmazes subtest measures foresight and planning while positive associations with T allele involved inhibitory control tasks [19], [23], [49]. ...
... A 2007 study found that Taq1A1 allele of the dopamine D2 receptor (DRD2) gene was more prevalent in an excessive online gaming group than in a control group [21]. The dopamine transporter 1 (DAT1) gene has been shown to be associated with pathological gambling [22]; however, Kim et al. [23] found that the DAT1 gene was not associated with IA. Given these inconsistent findings, further evaluation is needed to clarify the association between the DAT1 gene and IGA. ...
... The VNTR polymorphism in the DAT1 gene has been shown to alter DAT1 gene expression [49], and prior studies have demonstrated that the presence of the 9-repeat allele increased susceptibility to addiction more than alleles having more than 9-repeats [50,51]. In Western populations, the DAT1 gene was associated with alcohol dependency [51], substance abuse [52], and pathological gambling [22]. In contrast, we found no association between the 40 bp VNTR polymorphism in the DAT1 gene and IGA. ...
Background
The number of people with Internet gaming addiction (IGA) is increasing around the world. IGA is known to be associated with personal characteristics, psychosocial factors, and physiological factors. However, few studies have examined the genetic factors related to IGA. This study aimed to investigate the association between IGA and stress-related genetic variants.
Methods
This cross-sectional study was conducted with 230 male high school students in a South Korean city. We selected five stress-related candidate genes: DAT1, DRD4, NET8, CHRNA4, and CRHR1. The DAT1 and DRD4 genes were genotyped by polymerase chain reaction, and the NET8, CHRNA4, and CRHR1 genes were genotyped by pyrosequencing analysis. We performed a Chi-square test to examine the relationship of these five candidate genes to IGA.
Results
Having the AA genotype and the A allele of the CRHR1 gene (rs28364027) was associated with higher odds of belonging to the IGA participant group (p = .016 and p = .021, respectively) than to the non-IGA group. By contrast, the DAT1, DRD4, NET8, and CHRNA4 gene polymorphisms showed no significant difference between the IGA group and control group.
Conclusions
These results indicate that polymorphism of the CRHR1 gene may play an important role in IGA susceptibility in the Korean adolescent male population. These findings provide a justification and foundation for further investigation of genetic factors related to IGA.
... Previous studies have demonstrated that pathological gamblers show a dysfunctional executive profile characterized by deficits in cognitive flexibility, inhibition response, planning, and decisionmaking (Goudriaan et al., 2006;Lawrence et al., 2009;Brevers et al., 2014). Moreover, genetic predispositions may explain the higher risk of cognitive flexibility difficulties in pathological gamblers (Fagundo et al., 2014). ...
... To exclude neurocognitive issues, we also performed the following assessments: Mini Mental State Examination-MMSE; Wechsler Adult Intelligence Scale-WAIS-III, subtest of Vocabulary (IQ estimation); Auditory Verbal Learning Test (verbal memory); Rey-Osterrieth Complex Figure Test (Fagundo et al., 2014). Additionally, memory is consistently affected in neurodegenerative diseases and frequently associated with cognitive impairment (Panza et al., 2015). ...
The lifetime prevalence of problem or Gambling disorder (GD) in the elderly (i.e., those over 60 years old) is reported to range from 0.01 to 10.9%. Research has identified several specific risk factors and vulnerabilities in the elderly. Since the late 1990s, an increase in online GD has been observed in the youth population, whereas casinos, slot machines, and bingo seem to be the activities of choice among the elderly. Interestingly, online GD has not been described in the elderly to date.
We report an 83-year-old man who started online casino gambling from the age of 80 years, leading to debts that exceeded €30,000. He underwent a full clinical and neuropsychological assessment, without any evidence of cognitive impairment or any associated neurodegenerative disease. However, he had risk factors for GD, including adjustment disorder, stressful life events, previous offline casino GD when 50 years old, and dysfunctional personality traits. The change to online GD may have been due to his isolation, movement difficulties, and his high level of education, which facilitated his access to the Internet. Care management focused on individual cognitive-behavioral therapy.
The prevalence of online GD may be underestimated among the elderly, and may increase among isolated old people with movement difficulties and ready access to the Internet. However, late-life GD should be considered a diagnosis of elimination, requiring a full medical, psychiatric (including suicide risk), and cognitive assessment. Specific therapeutic approaches need to be proposed and developed.
... Based on decades of data, especially in gambling disorders [87,88], others have questioned dopamine's centrality to addictions. However, recent global data suggest otherwise [89][90][91][92][93][94][95][96][97][98]. ...
Reward Deficiency Syndrome (RDS) encompasses many mental health disorders, including a wide range of addictions and compulsive and impulsive behaviors. Described as an octopus of behavioral dysfunction, RDS refers to abnormal behavior caused by a breakdown of the cascade of reward in neurotransmission due to genetic and epigenetic influences. The resultant reward neurotransmission deficiencies interfere with the pleasure derived from satisfying powerful human physiological drives. Epigenetic repair may be possible with precision gene-guided therapy using formulations of KB220, a nutraceutical that has demonstrated pro-dopamine regulatory function in animal and human neuroimaging and clinical trials. Recently, large GWAS studies have revealed a significant dopaminergic gene risk polymorphic allele overlap between depressed and schizophrenic cohorts. A large volume of literature has also identified ADHD, PTSD, and spectrum disorders as having the known neurogenetic and psychological underpinnings of RDS. The hypothesis is that the true phenotype is RDS, and behavioral disorders are endophenotypes. Is it logical to wonder if RDS exists everywhere? Although complex, “the answer is blowin’ in the wind,” and rather than intangible, RDS may be foundational in species evolution and survival, with an array of many neurotransmitters and polymorphic loci influencing behavioral functionality.
... Moreover, we found no association between the DAT1 genotype and IA. Previous studies have shown that the DAT1 polymorphism is associated with addiction behavior, such as alcoholism [103,104], substance use/abuse [105], and pathological gambling [106]. Some studies [72,107] have suggested that the DAT1 genotype 9/9 is associated with a higher risk for addictive disorders. ...
Background
International research has emphasized that youths are at higher risk for the onset of internet addiction (IA), but studies investigating biological, psychological, and social factors associated with this condition are limited.
Objective
This study aims to investigate the possible association between IA and genetic polymorphisms in monoamine oxidase A (MAO-A), serotonin-transporter (5-HTTPR), dopamine receptor (DRD4), and dopamine transporter (DAT1) genes by considering the role played by the perception of young adults in their family functioning and their depression, anxiety, and avoidant personality problems.
Methods
In a sample of 104 male and female young adults aged between 19 and 23 years (mean age 21.87, SD 2.29 years) recruited from universities in the central southern part of Italy, we addressed the presence of IA using the Young criteria of the IA test. Moreover, the perception of young adults of their family functioning and their psychopathological symptoms were assessed through the Family Assessment Device (FAD) and the Adult Self-Report, respectively.
ResultsWe found no significant association between IA and any genetic polymorphisms, neither among males or females. Young adults with IA reported significantly higher scores in the subscale of FAD affective responsiveness (AR; P=.01) and in depressive problems (P=.02), anxiety problems (P=.009), and avoidant personality problems (P=.003) than those in the control group. Results of mediation analyses showed a mediation role played by depressive symptoms (B=0.99; 95% CI 0.22 to 1.97) and avoidant personality problems (B=1.09; 95% CI 0.32 to 2.05) of young adults on the relationship between the FAD, AR, and IA. Finally, this relationship was moderated by the genotype of the 5-HTTLPR (P
... While studying impulsivity traits Comings and coll., in 1997, showed that there was a higher percentage of subjects with DRD2 A1/A2 genetic variables in the GD group than in the Tourette Syndrome or smokers' group (22). Regarding cognitive domains, Fagundo and colleagues in 2014 reported a significant predisposition to lower cognitive levels in carriers of DRD2Taq1A polymorphism (23). ...
Second-generation antipsychotics (SGA) are a pharmacological class widely used in psychiatry thanks to their efficacy and good tolerability profile. One of the most used SGA is aripiprazole (ARI) because of its several formulations and safe metabolic and cardiac profile. As reported in a recent review, there are growing numbers of reports about ARI-induced gambling disorder (ARI-induced GD) which should encourage clinicians to use ARI more cautiously. Given the common genetic susceptibility of both GD and ARI's clinical response to a genetic polymorphism on the D2 receptor (DRD2/ANKK1 Taq1A; rs1800497), the hypothesis regarding the origin of this phenomenon could be found in the altered sensitization of dopamine's receptors that certain individuals carry genetically. The identification of a possible genetic susceptibility (detectable by genetic tests) could provide clinicians with an explanation for the ARI-induced GD and the possibility of using genetic screening tools for those cases of suspected predisposition; this would allow the clinician to prescribe ARI with less apprehension. The confirmation of this hypothesis through future pharmacogenetic studies may be useful for clinicians to have a correct understanding of the phenomenon.
... The male subgroup showed significant correlations while making perseverative errors (males < 45 y.o.) and non-perseverative errors (males > 45 years old). In both cases, 10R homozygotez scored worse in WCST, which is consistent with findings from the literature [72,73]. ...
Background:
Obesity is a chronic condition associated with poorer cognitive functioning. Wisconsin Card Sorting Test (WCST) is a useful tool for evaluating executive functions. In this study, we assessed the association between dopaminergic gene polymorphisms: DAT1 (SLC6A3), COMTVal158Met, DRD4 (48-bp variable number of tandem repeats - VNTR) and WCST parameters to investigate the functions of the frontal lobes in obese individuals.
Objective:
To find the significant correlations between polymorphisms of DAT1, COMTVal158Met, DRD4 and executive functions in obese subjects.
Methods:
The analysis of the frequency of individual alleles was performed in 248 obese patients (179 women, 69 men). Evaluation of the prefrontal cortex function (operating memory and executive functions) was measured with the Wisconsin Card Sorting Test (WCST). Separate analyzes were performed in age subgroups to determine different activities and regulation of genes in younger and older participants.
Results:
Scores of WCST parameters were different in the subgroups of women and men and in the age subgroups. Regarding the COMT gene, patients with A/A and G/A polymorphisms showed significantly better WCST results in WCST_P, WCST_CC and WCST_1st. Regarding DAT1 men with L/L and L/S made less non-perseverative errors, which was statistically significant. In DRD4, significantly better WCST_1st results were found only in older women with S allele.
Conclusion:
Obtained results indicate the involvement of dopaminergic transmission in the regulation of prefrontal cortex function. Data analysis indicates that prefrontal cortex function may ensue, from different elements such as genetic factors, metabolic aspects of obesity, and hormonal activity (estrogen).
... Epigenetic factors may further complicate such work-e.g., the finding that the methylation status of DRD2 may decline during abstinence from gambling [20]. Other, typically smaller studies have focused on variants in single genes including COMT [21], dopamine beta-hydroxylase [22], and DRD2 and DAT1 [23]. Overall, while some results are suggestive, the small subject numbers and lack of replication in larger studies point to general problems with such work, heroic as it is, in small patient populations. ...
Purpose of Review
To address variation in the severity of gambling disorder, this review evaluates the contribution of mesocorticolimbic dopamine neurons to potential behavioral endophenotypes, the influence of individual differences in the dopamine system on gambling and related behaviors, and the possible role for dopaminergic medications in the treatment of gambling disorder.
Recent Findings
Newer work has suggested that dopaminergic dysfunction can lead to increased reward anticipation and a greater sensitivity to uncertainty, which in turn may drive addictive gambling behaviors. In addition, increased impulsivity, a well-recognized risk factor for gambling disorder, has been linked to dopaminergic dysfunction. More recently, emerging evidence has suggested that dopaminergic medications can influence the discounting of delayed rewards.
Summary
Dopaminergic drugs that increase the salience of long-term over short-term goals may ameliorate symptoms of impulsive individuals with gambling disorder. More broadly, improved understanding of intermediate behavioral and other phenotypes with a defined neurobiological substrate may allow for personalized treatment of gambling disorder and other psychiatric conditions.
... Thus, dopamine exerts modulating activity of the internal clock speed [12,13], acting as a neurobiological substrate for accumulator-pacemaker pulses according to the Scalar Expectation Theory, in which a series of pulses is produced by an internal pacemaker in the presence of an event; These pulses are collected, counted, and then compared with the stored representations, to allow time-judging [32,43]. Therefore, changes in dopamine concentration through genetic polymorphisms [44][45][46][47][48], pharmacological models [49][50][51] and lesions that destroy the dopaminergic pathway [11,13,52] promote variations in the internal clock speed and may modify the activities executive performance, perception and judgment of an event [6,11,14,53]. Models proposed by several studies aim to promote the understanding of how the modifications in functional neurobiology approximate or not the risk of developing diseases, including PD, attention deficit hyperactivity disorder, and tendency to drug abuse [48,54,55]. ...
Background:
Parkinson's disease is described as resulting from dopaminergic cells progressive degeneration, specifically in the substantia nigra pars compacta that influence the voluntary movements control, decision making and time perception.
Aim:
This review had a goal to update the relation between time perception and Parkinson's Disease.
Methodology:
We used the PRISMA methodology for this investigation built guided for subjects dopaminergic dysfunction in the time judgment, pharmacological models with levodopa and new studies on the time perception in Parkinson's Disease. We researched on databases Scielo, Pubmed / Medline and ISI Web of Knowledge on August 2017 and repeated in September 2017 and February 2018 using terms and associations relevant for obtaining articles in English about the aspects neurobiology incorporated in time perception. No publication status or restriction of publication date was imposed, but we used as exclusion criteria: dissertations, book reviews, conferences or editorial work.
Results/discussion:
We have demonstrated that the time cognitive processes are underlying to performance in cognitive tasks and that many are the brain areas and functions involved and the modulators in the time perception performance.
Conclusions:
The influence of dopaminergic on Parkinson's Disease is an important research tool in Neuroscience while allowing for the search for clarifications regarding behavioral phenotypes of Parkinson's disease patients and to study the areas of the brain that are involved in the dopaminergic circuit and their integration with the time perception mechanisms.
... A1 carriers in their study responded more quickly and made fewer errors on a cognitive flexibility task compared with non-carriers. Of note, other studies have found advantages for non-carriers in other tasks, including long-term memory ( Persson, Rieckmann, Kalpouzos, Fischer, & Bäckman, 2015), associative memory ( Papenberg et al., 2017), and the trail-making test ( Fagundo et al., 2014). Vaughn et al. (2016 extended this work by examining the relationship between neural activity and DRD2 genotype in bilingual participants who performed a cognitive flexibility task, a language production task, and an inhibition task. ...
Genetic variants related to dopamine functioning (e.g., the ANKK1/TaqIa polymorphism within the DRD2 gene and the Val158Met polymorphism within the COMT gene) have previously been shown to predict cognitive flexibility and learning (e.g., Colzato et al., 2010; Stelzel et al., 2010). Additionally, researchers have found that these genetic variants may also predict second lan- guage learning (Mamiya et al., 2016), although this relationship may change across the lifespan (Sugiura et al., 2011). The current study examined the role of the ANKK1/TaqIa and Val158Met polymorphisms along with age of second language acquisition (AoA) in order to predict levels of bilingual proficiency in Spanish-English bilinguals. Results indicated a three-way interaction such that the relationship between the genetic variants and bilingual proficiency depended on AoA. At earlier AoAs, having the genetic variant associated with higher levels of subcortical dopamine (A1+) predicted the highest levels of bilingual proficiency. At later AoAs, individuals with the genetic variant associated with cortical dopamine levels that are balanced between stability and flexibility (Val/Met) predicted the highest levels of bilingual proficiency. These results fit with theories about the development of language as a subcortical process early in life and as a cortical process later in life (Hernandez & Li, 2007), as well as the importance of both stability and flexibility in bilingual language development (Green & Abutalebi, 2013). Finally, this study raises questions about the direction of causality between bilingualism and cognitive control, which is central to the debate over the "bilingual advantage."
... Connel et al. [95] examined differences between African Americans and Whites with regard to their attitudes, beliefs, and knowledge about AD. They pointed out that the two groups differed in terms of the following: (1) their knowledge about the disease (e.g., recognizing that AD is not a part of normal aging); (2) concern about AD (e.g., worry about developing the disease); ...
Alzheimer’s disease is an irreversible, progressive brain disorder that slowly destroys cognitive skills and the ability to perform the simplest tasks. More than 5 million Americans are afflicted with Alzheimer’s; a disorder which ranks third, just behind heart disease and cancer, as a cause of death for older people. With no real cure and in spite of enormous efforts worldwide, the disease remains a mystery in terms of treatment. Importantly, African-Americans are two times as likely as Whites to develop late-onset Alzheimer’s disease and less likely to receive timely diagnosis and treatment. Dopamine function is linked to normal cognition and memory and carriers of the DRD2 Taq1A A1 allele have significant loss of D2 receptor density in the brain. Recent research has shown that A1 carriers have worse memory performance during long-term memory (LTM) updating, compared to non-carriers or A2-carriers. A1carriers also show less blood oxygen level-dependent (BOLD) activation in the left caudate nucleus which is important for LTM updating. This latter effect was only seen in older adults, suggesting magnification of genetic effects on brain functioning in the elderly. Moreover, the frequency of the A1 allele is 0.40 in African-Americans, with an approximate prevalence of the DRD2 A1 allele in 50% of an African-American subset of individuals. This is higher than what is found in a non-screened American population (≤ 28%) for reward deficiency syndrome (RDS) behaviors. Based on DRD2 known genetic polymorphisms, we hypothesize that the DRD2 Taq1A A1 allele magnifies the risk of Alzheimer’s in aging African-Americans. Research linking this high risk for Alzheimer’s in the African-American population, with DRD2/ANKK1-TaqIA polymorphism and neurocognitive deficits related to LTM, could pave the way for novel, targeted pro-dopamine homeostatic treatment.
... As such, pre-existing and/or diet-induced alterations in dopamine signaling may produce impairments in executive function, which may increase susceptibility for overeating and weight gain. Consistently, A1 carriers display greater behavioral inflexibility, working memory deficits, and impaired negative outcome learning [98,[105][106][107], and are at greater risk for developing a variety of psychiatric disorders related to impaired striatal dopamine function including smoking [108], alcoholism [109], and obesity [110,111]. ...
Emerging evidence from human and animal studies suggest that consumption of palatable foods rich in fat and/or carbohydrates may produce deleterious influences on brain function independently of body weight or metabolic disease. Here we consider two mechanisms by which diet can impact striatal circuits to amplify food cue reactivity and impair inhibitory control. First, we review findings demonstrating that the energetic properties of foods regulate nucleus accumbens food cue reactivity, a demonstrated predictor of weight gain susceptibility, which is then sensitized by chronic consumption of an energy dense diet. Second, we consider evidence for diet-induced adaptations in dorsal striatal dopamine signaling that is associated with impaired inhibitory control and negative outcome learning.
... Furthermore, 9R-carriers also present with adaptive characteristics indicative of a higher and more stable DA functioning such as lower levels of delay and uncertainty discounting and a better efficiency of executive functions such as working memory, cognitive flexibility, executive attention, response modulation, and response inhibition (Loo et al., 2003;Belgrove et al., 2005;Paloyelis et al., 2010;Stollstorff et al., 2010;Braet et al., 2011;Heitland et al., 2012;Fagundo et al., 2014). Also, in the presence of the A1-allele for the TaqIA-ANKK1 SNP, the 9R-allele has been related to a stronger error related negativity (ERN) of the mPFC in response to a NoGo signal demonstrating better error-learning and behavioral flexibility, whereas 10R-homozygotes showed the weakest ERN in the context of the A1-allele (Meyer et al., 2012). ...
... On the basis of these data, DA-PHEN could be considered a valuable candidate for successive studies as dopaminergic modulator. However, the high value of brain half-life suggests that before complete cleavage DA-PHEN could act per se as a drug, regulating dopaminergic neurotransmission and, as a consequence, altering motor and executive functions (mediated by distinct cortico-striato-thalamo-cortical circuits) or memory, reasoning, attention and mood (cognitive enhancement) as integrated neural processes, so underlying also reward representation and cognitive set transitions [8][9][10][11]. ...
2-Amino-N-[2-(3,4-dihydroxy-phenyl)-ethyl]-3-phenyl-propionamide (DA-PHEN) has been previously synthesized to obtain a potential prodrug capable of release dopamine (DA) into CNS. However, DA-PHEN could act per se as a dopaminergic drug. In this study, the permeability transport (Pe), obtained by parallel artificial permeability assay (PAMPA), indicated a low passive transcellular transport (Pe = 0.32 ± 0.01 × 10−6 cm/s). Using the Caco-2 cell system, the Papp AP-BL in absorptive direction (3.36 ± 0.02 × 10−5 cm/s) was significantly higher than the Papp BL-AP in secretive direction (1.75 ± 0.07 × 10−5 cm/s), suggesting a polarized transport. The efflux ratio (Papp AP-BL/Papp BL-AP = 0.52 ± 0.02) indicated a low affinity of DA-PHEN to efflux carriers. The forced swim test highlighted a reduction of immobility time in both pre-test and test sessions (p < 0.0001), with an exacerbation in the number of headshakes and divings in the pretest (p < 0.0001). Morris water maze strengthened the hypothesis that DA-PHEN induces adaptive responses to environmental challenges which are involved on cognitive functions (DA-PHEN versus CTR: escape latency; p < 0.001; distance swum p < 0.001, time spent on target quadrant p < 0.001), without any change in locomotor activity for the administered dose. The molecular docking revealed the interaction of DA-PHEN with the identified D1 site mapping human brain receptor.
... The blood samples were processed and DNA isolated and split to analyze the HTR1B (rs130058) and the TPH1 (rs1799913) polymorphisms by RT-PCR (ABI 7500, Life Technologies). Controls were chosen from anonymous donors without any history of drug use or behavioral alterations [3,4]. ...
It is technically feasible to perform paternity diagnosis testing solely involving an alleged father and his descendent. However, there are serious legal and ethical problems for forensic genetics laboratories when it comes to paternity testing cases for investigating the alleged father-child relationship if the biological mother has not given consent to access her genetic information. Based on the Spanish Constitution, the new Code of Ethics of the Spanish Medical Association includes several articles on studies about genetic information and their acceptance by all the individuals involved. This problem is greater when the child is a minor, mentally incapacitated or psychologically incapable, because current Spanish law requires informed consent from legal representatives, but the law does not typify what happens when one parent gives consent (the putative father) and the other parent (the mother) does not agree. The aim of this study is to put forward legal solutions to avoid potential legal problems.
This study investigated the interactive effect of Dopamine D2 receptor gene Taq 1A (DRD2 rs1800497) and parental behavior on creativity and examined whether a potential gene–parenting interaction (G × E) would be consistent with one of two models of gene–environment interplay (diathesis-stress vs. differential susceptibility). In a sample of university undergraduates (N = 517), we found evidence of G × E between the DRD2 TaqIA polymorphism and perceived maternal overprotection behavior, but not maternal care, with regard to creativity. Confirmatory model indicates that this interaction effect conformed to the differential susceptibility, rather than diathesis-stress model. Thus, individuals with A1A1 genotype of the DRD2 gene are more creative than A2 carriers when their mothers were less involved in overprotection but less creative under condition of high maternal overprotection. No significant interaction of DRD2 TaqIA polymorphism and paternal behavior was found. Our findings provide initial evidence for the differential susceptibility model in the field of creativity, suggesting DRD2 TaqIA polymorphism may operate as a “plasticity gene.” Further studies need to test these effects.
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.
Este estudo investigou a ação da dopamina associada ao gene D4 sobre a motivação para
comportamentos de risco. Trata-se de uma pesquisa bibliográfica na qual se utilizou o método
estado da questão. Consultou-se, inicialmente, a plataforma de periódicos CAPES, utilizando a
combinação dos descritores: “Comportamento de risco”, “Procura por sensações”, “Motivação
para o comportamento de risco”, “Dopamina”, “gene D4”, porém, não foi encontrado material
publicado no Brasil em língua portuguesa. Em seguida, utilizando os mesmos descritores em
língua inglesa, buscou-se nas bases de dados eletrônicas: American Psychological Association (APA),
Sagepub, Springer e Elsevier, e o periódico The Journal of Neuroscience (JN), selecionaram-se
artigos e trabalhos acadêmicos em língua estrangeira publicados a partir de 2010. Compreendeu-se
que a ação dopaminérgica no sistema de recompensa cerebral associada à função do gene D4
é um preditor do desenvolvimento de comportamentos exploratórios, necessidade de fortes
sensações fisiológicas externas e que está diretamente implicado no desenvolvimento da
motivação intrínseca de procura por fortes sensações, levando os indivíduos a desenvolver
comportamentos de risco. Os indivíduos com alelos 7R+ longos estão predispostos a desenvolver
motivação intrínseca ao risco que se manifesta como comportamentos de procura por fortes
sensações.
An optimal biochemical marker for addiction would be some easily traced molecules in body specimens, which indicates indulgent addictive behaviors, or susceptibility to certain addictive stimuli. In this chapter, we discussed existing literature about possible biomarkers, and classified them into three categories: origin forms and metabolites of substances, markers from biochemical responses to certain addiction, and genetic and epigenetic biomarkers suggesting susceptibility to addiction. In every category, we examined studies concerning certain type of addiction one by one, with focuses mainly on opiates, psychostimulants, and pathological gambling. Several promising molecules were highlighted, including those of neurotrophic factors, inflammatory factors, and indicators of vascular injury, and genetic and epigenetic biomarkers such as serum miRNAs. DNA methylation signatures and signal nucleotide polymorphism of candidate gene underlying the addiction.
Similar symptomatology manifestations and high co-morbidity in substance and non-substance addictions suggest that there may be a common pathogenesis between them. Associated with impulse control and emotional processing, the monoamine neurotransmitter system genes are suggested to be related to both substance and non-substance addictions, such as dopamine (DA) system, 5-hydroxytryptamine/serotonin (5-HT) system, the endogenous opioid system and so on. Here we reviewed the similarities and differences in genetics between classic substance addiction and common types of non-substance addiction, e.g. pathological gambling, Internet addiction, binge-eating disorder etc. It is necessary to systematically compare genetic mechanisms of non-substance addiction and substance addiction, which could reveal similarities and differences of substance addiction and non-addictive substances essentially, enhance our understanding of addiction theory and improve clinical practice with research results.
The familial aggregation of gambling disorders has been documented in the literature since the late 1980s. Currently, studies in large twin samples have confirmed that genetic factors contribute to the development of gambling disorders. In comparison to other psychiatric disorders, molecular genetic studies on gambling disorders are at an early stage; however, the use of larger samples and of new methodologies has provided important insights into its genetic underpinnings. The purpose of this article is to review twin and molecular genetics studies on gambling disorders published in the past 5 years and to discuss possible future directions of research in this area.
The increase in suicides produced as a consequence of the economic brutal drift on middle and poor income families, in recent years, has accelerated the number of studies on the genetic mechanisms involved in these attitudes. In order to rigorously analyze them, we need to dispose of very well defined groups and dissect the right molecular pathways in search of single nucleotide polymorphisms (SNP), with special emphasis in neurotransmission pathways.
In this study, we collected samples from suicidal victims and analyzed SNPs for the serotonin receptor HTR1B (rs130058) gene and the tryptophan hydroxylase (TPH1, rs1799913) gene.
We have detected differences in the frequencies of men that are victims of suicide in relation to the control group for TPH1, rs1799913.
Background:
The ability to generate and flexibly change concepts is of great importance for the development of academic and adaptive skills. This paper analyses the conceptual reasoning ability of children with mild intellectual disability (MID) by their achievements on the Wisconsin Card Sorting Test (WCST).
Method:
The sample consisted of 95 children with MID aged between 10 years and 13 years 11 months. The following variables from the WCST were analysed: number of categories completed, initial conceptualisation, total number of errors, non-perseverative errors, perseverative errors, number of perseverative responses, and failures to maintain set.
Results:
The observed WCST predictive variables account for 79% of the variability in the number of categories completed (p < .000). The total number of errors was the most significant predictor of performance on the WCST.
Conclusion:
We can conclude that there is a significant progress of conceptual abilities between the age of 13 years to 13 years 11 months, compared to other assessed age groups. The results of our research suggests that the development of mental set flexibility is the basis of progress in conceptual abilities, thus intervention programs should offer specially designed activities that vary in their attentional demands, content, conceptual patterns, and actions required.
Impairments in self-regulatory behaviour reflect a deficit in executive functioning and decision-making, as well as higher levels of self-reported impulsivity, and may be involved in the development and maintenance of addictive disorders. We sought to explore the association between self-reported impulsivity and neurocognitive measures, and their association with treatment outcome in pathologic gambling.
We assessed patients with pathologic gambling using executive functioning and decision-making tests and self-report measures of impulsivity. Patients underwent cognitive-behavioural therapy (CBT) for pathologic gambling.
We included 88 patients (8% women) in our study. High self-reported extravagance was associated with poor performance in the Iowa Gambling Task (IGT)-ABCD version. High impulsiveness, low disorderliness, high exploratory excitability (trend), poor backward block span and poor IGT-EFGH scores (trend) predicted dropout. We observed no self-reported or neurocognitive predictors of relapse or number of treatment sessions attended.
Most participants were slot-machine gamblers seeking treatment. No follow-up data and no control group were included in the study. The missing sample (i.e., individuals who were recruited and assessed in the pretreatment stage but who chose not to begin treatment) had higher extravagance scores than the final sample.
Neurocognitive reward sensitivity was related to self-reported overspending behaviour. Self-regulatory impairments (especially rash impulsiveness and punishment sensitivity) and executive dysfunction predicted only dropout of CBT in participants with pathologic gambling. Different neurocognitive processes and personality traits might mediate treatment response to psychological therapy of pathologic gambling according to the specific target variable assessed.
Background:
Over 50 years of evidence from research has established that the central dopaminergic reward pathway is likely involved in alcohol dependence (AD). Additional evidence supports a role for dopamine (DA) in other disinhibitory psychopathology, which is often comorbid with AD. Family and twin studies demonstrate that a common genetic component accounts for most of the genetic variance in these traits. Thus, DA-related genes represent putative candidates for the genetic risk that underlies not only AD but also behavioral disinhibition. Many linkage and association studies have examined these relationships with inconsistent results, possibly because of low power, poor marker coverage, and/or an inappropriate correction for multiple testing.
Methods:
We conducted an association study on the products encoded by 10 DA-related genes (DRD1-D5, SLC18A2, SLC6A3, DDC, TH, COMT) using a large, ethnically homogeneous sample with severe AD (n = 545) and screened controls (n = 509). We collected genotypes from linkage disequilibrium (LD)-tagging single nucleotide polymorphisms (SNPs) and employed a gene-based method of correction. We tested for association with AD diagnosis in cases and controls and with a variety of alcohol-related traits (including age-at-onset, initial sensitivity, tolerance, maximum daily drinks, and a withdrawal factor score), disinhibitory symptoms, and a disinhibitory factor score in cases only. A total of 135 SNPs were genotyped using the Illumina GoldenGate and Taqman Assays-on-Demand protocols.
Results:
Of the 101 SNPs entered into standard analysis, 6 independent SNPs from 5 DA genes were associated with AD or a quantitative alcohol-related trait. Two SNPs across 2 genes were associated with a disinhibitory symptom count, while 1 SNP in DRD5 was positive for association with the general disinhibitory factor score.
Conclusions:
Our study provides evidence of modest associations between a small number of DA-related genes and AD as well as a range of alcohol-related traits and measures of behavioral disinhibition. While we did conduct gene-based correction for multiple testing, we did not correct for multiple traits because the traits are correlated. However, false-positive findings remain possible, so our results must be interpreted with caution.
Recent studies suggest an association of dopamine D2 receptor (DRD2) availability with flexibility in reward-based learning. We extend these results by demonstrating an association of genetically based differences in DRD2 density with the ability to intentionally switch between nonrewarded tasks: noncarriers of the A1 allele of the DRD2/ANKK1-TaqIa polymorphism, associated with higher DRD2 density, show increased task-switching costs, increased prefrontal switching activity in the inferior frontal junction area, and increased functional connectivity in dorsal frontostriatal circuits, relative to A1 allele carriers. A DRD2 haplotype analysis in the same sample confirmed these results, indicating an association between high D2 density and increased task-switching effort. Our results provide evidence that converges with that from association studies relating increased D2 density to deficits in cognitive flexibility in schizophrenia. We suggest that individual differences in striatal D2 signaling in healthy humans modulate goal-directed gating to prefrontal cortex, thus leading to individual differences in switching intentionally to newly relevant behaviors.
Many of the individual differences in cognition, motivation, and learning-and the disruption of these processes in neurological conditions-are influenced by genetic factors. We provide an integrative synthesis across human and animal studies, focusing on a recent spate of evidence implicating a role for genes controlling dopaminergic function in frontostriatal circuitry, including COMT, DARPP-32, DAT1, DRD2, and DRD4. These genetic effects are interpreted within theoretical frameworks developed in the context of the broader cognitive and computational neuroscience literature, constrained by data from pharmacological, neuroimaging, electrophysiological, and patient studies. In this framework, genes modulate the efficacy of particular neural computations, and effects of genetic variation are revealed by assays designed to be maximally sensitive to these computations. We discuss the merits and caveats of this approach and outline a number of novel candidate genes of interest for future study.
The ability to rapidly and flexibly adapt decisions to available rewards is crucial for survival in dynamic environments. Reward-based decisions are guided by reward expectations that are updated based on prediction errors, and processing of these errors involves dopaminergic neuromodulation in the striatum. To test the hypothesis that the COMT gene Val(158)Met polymorphism leads to interindividual differences in reward-based learning, we used the neuromodulatory role of dopamine in signaling prediction errors. We show a behavioral advantage for the phylogenetically ancestral Val/Val genotype in an instrumental reversal learning task that requires rapid and flexible adaptation of decisions to changing reward contingencies in a dynamic environment. Implementing a reinforcement learning model with a dynamic learning rate to estimate prediction error and learning rate for each trial, we discovered that a higher and more flexible learning rate underlies the advantage of the Val/Val genotype. Model-based fMRI analysis revealed that greater and more differentiated striatal fMRI responses to prediction errors reflect this advantage on the neurobiological level. Learning rate-dependent changes in effective connectivity between the striatum and prefrontal cortex were greater in the Val/Val than Met/Met genotype, suggesting that the advantage results from a downstream effect of the prefrontal cortex that is presumably mediated by differences in dopamine metabolism. These results show a critical role of dopamine in processing the weight a particular prediction error has on the expectation updating for the next decision, thereby providing important insights into neurobiological mechanisms underlying the ability to rapidly and flexibly adapt decisions to changing reward contingencies.
A variety of evidence suggests important commonalities in the neurochemical basis of reinforcement in pathological gambling (PG) and psychostimulant addiction. This article focuses on the parallel and specific roles that dopamine (DA) activation plays in these two disorders, beyond its generic role in reinforcement. A psychostimulant-mimetic model for PG is proposed based on evidence from the following domains: Acute subjective-behavioral effects of gambling and psychostimulants; Effects of anticipated rewards and uncertainty of reward delivery (key elements of gambling) on DA release; Relationship between DA release and positive arousal; Cross-priming of motivation for gambling by amphetamine; Effects of DA D2 antagonists on gambling and amphetamine reward; Effects of mixed D1-D2 antagonists on clinical symptoms of PG; Effects of DA D2 agonists on experimental measures of risk-taking, gambling, and induction of PG in patients with Parkinson's disease; Electrophysiological and cognitive disturbances associated with chronic exposure to gambling and psychostimulants, and the possible role of sensitization in these effects. Limitations of the model regarding the exclusive role of DA are discussed with particular reference to genetic risk, co-morbidity, and sub-types of PG. Suggestions for future research include isolating the roles of DA receptor subtypes in PG, and parallel within-subject assessment of DA manipulations on gambling and psychostimulant reinforcement in PG subjects and controls.
Problem gambling has been proposed to represent a 'behavioural addiction' that may provide key insights into vulnerability mechanisms underlying addiction in brains that are not affected by the damaging effects of drugs. Our aim was to investigate the neurocognitive profile of problem gambling in comparison with alcohol dependence. We reasoned that shared deficits across the two conditions may reflect underlying vulnerability mechanisms, whereas impairments specific to alcohol dependence may reflect cumulative effects of alcohol consumption.
Cross-sectional study.
Out-patient addiction treatment centres and university behavioural testing facilities.
A naturalistic sample of 21 male problem and pathological gamblers, 21 male alcohol-dependent out-patients and 21 healthy male control participants.
Neurocognitive battery assessing decision-making, impulsivity and working memory.
The problem gamblers and alcohol-dependent groups displayed impairments in risky decision-making and cognitive impulsivity relative to controls. Working memory deficits and slowed deliberation times were specific to the alcohol-dependent group.
Gambling and alcohol-dependent groups shared deficits in tasks linked to ventral prefrontal cortical dysfunction. Tasks loading on dorsolateral prefrontal cortex were selectively impaired in the alcohol-dependent group, presumably as a consequence of long-term alcohol use.
For over four decades the Wisconsin Card Sorting Test (WCST) has been one of the most distinctive tests of prefrontal function. Clinical research and recent brain imaging have brought into question the validity and specificity of this test as a marker of frontal dysfunction. Clinical studies with neurological patients have confirmed that, in its traditional form, the WCST fails to discriminate between frontal and non-frontal lesions. In addition, functional brain imaging studies show rapid and widespread activation across frontal and non-frontal brain regions during WCST performance. These studies suggest that the concept of an anatomically pure test of prefrontal function is not only empirically unattainable, but also theoretically inaccurate. The aim of the present review is to examine the causes of these criticisms and to resolve them by incorporating new methodological and conceptual advances in order to improve the construct validity of WCST scores and their relationship to prefrontal executive functions. We conclude that these objectives can be achieved by drawing on theory-guided experimental design, and on precise spatial and temporal sampling of brain activity, and then exemplify this using an integrative model of prefrontal function [i.e., Miller, E. K. (2000). The prefrontal cortex and cognitive control. Nature Reviews Neuroscience, 1, 59-65.] combined with the formal information theoretical approach to cognitive control [Koechlin, E., & Summerfield, C. (2007). An information theoretical approach to prefrontal executive function. Trends in Cognitive Sciences, 11, 229-235.].
In humans, presence of an A1 allele of the DRD2/ANKK1-TaqIa polymorphism is associated with reduced expression of dopamine (DA) D(2) receptors in the striatum. Recently, it was observed that carriers of the A1 allele (A1+ subjects) showed impaired learning from negative feedback in a reinforcement learning task. Here, using functional MRI (fMRI), we investigated carriers and noncarriers of the A1 allele while they performed a probabilistic reversal learning task. A1+ subjects showed subtle deficits in reversal learning. In particular, these deficits consisted of an impairment in sustaining the newly rewarded response after a reversal and in a generally decreased tendency to stick with a rewarded response. Both genetic groups showed increased fMRI signal in response to negative feedback in the rostral cingulate zone (RCZ) and anterior insula. Negative feedback that incurred a change in behavior additionally engaged the ventral striatum and a region of the midbrain consistent with the location of dopaminergic cell groups. The response of the RCZ to negative feedback increased as a function of preceding negative feedback. However, this graded response was not observed in the A1+ group. Furthermore, the A1+ group also showed diminished recruitment of the right ventral striatum and the right lateral orbitofrontal cortex (lOFC) during reversals. Together, these results suggest that a genetically driven reduction in DA D(2) receptors leads to deficient feedback integration in RCZ. This, in turn, was accompanied by impaired recruitment of the ventral striatum and the right lOFC during reversals, which might explain the behavioral differences between the genetic groups.
The A1 allele of the ANKK1 TaqIA polymorphism (previously reported as located in the D2 dopamine receptor (DRD2) gene) is associated with reduced DRD2 density in the striatum and with clinical disorders, particularly addiction. It was hypothesized that impulsivity represents an endophenotype underlying these associations with the TaqIA and that environmental stress would moderate the strength of the gene-behavior relationship.
TaqIA genotyping was conducted on 72 healthy young adults who were randomly allocated to either an acute psychosocial stress or relaxation induction condition. Behavioral phenotypes of impulsivity were measured using a card-sorting index of reinforcement sensitivity and computerized response inhibition and delay discounting tasks.
Separate analyses of variance revealed associations between the A1 allele and two laboratory measures of impulsivity. The presence of the TaqIA allele (A1+) was associated with slower card-sorting in the presence of small financial reinforcers, but was overcome in a second administration after either a five-minute rest or psychosocial stress induction. A1+ participants also demonstrated significantly poorer response inhibition and faster response times on a computerized stop inhibition task, independent of acute stress exposure.
These findings indicate the A1 allele is associated with an endophenotype comprising both a "rash impulsive" behavioral style and reinforcement-related learning deficits. These effects are independent of stress.
The South Oaks Gambling Screen is a 20-item questionnaire based on DSM-III criteria for pathological gambling. It may be self-administered or administered by nonprofessional or professional interviewers. A total of 1,616 subjects were involved in its development: 867 patients with diagnoses of substance abuse and pathological gambling, 213 members of Gamblers Anonymous, 384 university students, and 152 hospital employees. Independent validation by family members and counselors was obtained for the calibration sample, and internal consistency and test-retest reliability were established. The instrument correlates well with the criteria of the revised version of DSM-III (DSM-III-R). It offers a convenient means to screen clinical populations of alcoholics and drug abusers, as well as general populations, for pathological gambling.
The dopaminergic and glutamate systems have been implicated in cognitive function. We tested the associations between the dopamine D2 receptor (DRD2) and N-methyl-D-aspartate receptor 2B subunit (GRIN2B) gene variants and intelligence quotient (IQ). Subjects with the DRD2 A1/A1 genotype had a significantly higher mean performance IQ than A2/A2 carriers, while no significant differences in IQ scores were determined for the three GRIN2B genotype groups. These results suggest that genetic variants of the DRD2 gene may play a role in cognitive function. Considering the major role played by the dopaminergic system in general cognitive function, genetic variants of the dopamine receptors and those involved in metabolism and modulation of reuptake should be tested to improve gene-based prediction of general cognitive function.
Post mortem studies have revealed a loss of dopamine D2 receptors in the temporal lobes in Alzheimer's disease (AD). Moreover, the role of hippocampal D2 receptors on memory performance has been suggested in experimental studies. However, there are no previous in vivo studies on extrastriatal D2 receptors in AD. Our aim was to examine in vivo whether hippocampal or temporal cortical dopamine D2 receptors are affected in AD and whether D2 receptor availability is associated with the memory dysfunction seen in AD. Fourteen patients with probable AD and 11 age- and sex-matched controls were studied with positron emission tomography using a dopamine D2/D3 receptor antagonist [(11)C]FLB 457. The D2 receptor binding potentials (BPs) were measured in extrastriatal brain regions and a neuropsychological investigation was performed on the patients with AD. In AD, the D2 receptor availability was reduced in the hippocampus: by 34% (P = 0.03) in the right hippocampus and by 14% (P = 0.78) in the left hippocampus as compared with controls. Multiple linear regression analysis showed that the BP in the right hippocampus had a significant positive association with verbal memory performance (Wechsler Memory Scale - Revised) (P = 0.001) and picture naming (the Boston Naming Test) (P = 0.002). Our findings suggest a role for temporal lobe D2 receptors in the memory and naming performance in AD, and suggest that studies to evaluate the efficiency of dopaminergic medication on patients with early AD might be warranted.
Dopamine (DA) input to the prefrontal cortex (PFC), acting on D1 receptors, plays an essential role in mediating working memory functions. In comparison, less is known about the importance of distinct PFC DA receptor subtypes in mediating executive functions such as set-shifting. The present study assessed the effects of microinfusion of D2 and D4 receptor antagonists, and D1, D2, and D4 receptor agonists into the PFC on performance of a maze-based set-shifting task. In Experiment 1, rats were trained on a response discrimination task, and then on a visual-cue discrimination task requiring rats to suppress the use of the response strategy and approach the previously irrelevant cue to locate food. In Experiment 2, the order of training was reversed. Infusions of the D2 antagonist eticlopride, or the D4 agonist PD-168,077, impaired shifting from a response to a visual-cue discrimination strategy and vice versa, and caused a selective increase in perseverative errors. In contrast, infusions of the D4 antagonist L-745,870 improved set-shifting. Infusions of the D1 agonist SKF81297 or the D2 agonist quinpirole caused no reliable effect. These data, in combination with previous reports of impaired set-shifting following D1 receptor blockade, suggest that multiple receptors in the PFC are essential for set-shifting and that the mechanisms by which PFC DA mediates behavioral flexibility may be different from those underlying working memory. These findings may have important implications for developing novel treatments for cognitive deficits observed in disorders such as attentional deficit and hyperactivity disorder and schizophrenia.
Individual differences in striatal dopamine (DA) signaling have been associated both with individual differences in executive function in healthy individuals and with risk for psychiatric disorders defined by executive dysfunction. We used resting-state functional connectivity in 50 healthy adults to examine whether a polymorphism of the dopamine transporter gene (DAT1), which regulates striatal DA function, affects striatal functional connectivity in healthy adults, and whether that connectivity predicts executive function. We found that 9/10 heterozygotes, who are believed to have higher striatal DA signaling, demonstrated stronger connectivity between dorsal caudate (DC) and insular, dorsal anterior cingulate, and dorsolateral prefrontal regions, as well as between ventral striatum and ventrolateral prefrontal cortex, than 10/10 homozygotes. Across subjects, stronger DC-seeded connectivity predicted superior N-back working memory performance, while stronger ventral striatum-seeded connectivity predicted reduced impulsivity in everyday life. Further, mediation analysis suggested that connectivity strength mediated relationships between DAT1 genotype and behavior. These findings suggest that resting-state striato-frontal connectivity may be an endophenotype for executive function in healthy individuals.
"The Trail Making Test was administered to 200 patients with clear evidence of brain damage and to 84 Ss without anamnestic or clinical evidence of brain damage. The groups were comparable with respect to sex, CA, and… education. The results showed… significant differences in the performances of the two groups for Parts A and B of the test individually as well as for their total. Frequency distributions were given that may serve as preliminary norms for use in evaluating results obtained with individual Ss. Some comments were offered regarding possible reasons why the Trail Making Test differentiated the groups so well, relating known aspects of brain function to the structure and requirements of the test." (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Although pathological gambling is a relatively common disorder, there are only limited data available about the validity of its diagnosis as an impulse control disorder. Interestingly, there is no single conceptual widely accepted model that adequately accounts for the multiple biological, psychological and ecological variables contributing to the development of pathological gambling. In this paper, the authors demonstrate aspects of addictive behavior of pathological gambling. It is suggested that despite conceptual difficulties associated with the variable of self-control, contemporary research into the addictive behavior of gambling has clearly demonstrated its closeness to addictions as compared to impulse control disorders.
The adjustment of behavior to changing goals and environmental constraints requires the flexible switching between different task sets. Cognitive flexibility is an endophenotype of executive functioning and is highly heritable, as indicated by twin studies. Individual differences in global flexibility as assessed by reaction-time measurement in a task-switching paradigm were recently related to a single nucleotide polymorphism in the vicinity of the dopamine d2 receptor gene DRD2. In the present study, we assessed whether the DRD2 gene is related to backward inhibition, a control mechanism that contributes to cognitive flexibility by reducing proactive interference by no longer relevant task sets. We found that carriers of the DRD2 A1+ variant who have a lower striatal dopamine d2 receptor density than A1- carriers show a larger backward inhibition effect. This is in line with previous results demonstrating increased behavioral flexibility in carriers of this genetic variant. The discussion relates the present finding to those of previous studies assessing the neurogenetic foundations of inhibitory control.
Brain dopamine (DA) has long been implicated in cognitive control processes, including working memory. However, the precise role of DA in cognition is not well-understood, partly because there is large variability in the response to dopaminergic drugs both across different behaviors and across different individuals. We review evidence from a series of studies with experimental animals, healthy humans, and patients with Parkinson's disease, which highlight two important factors that contribute to this large variability. First, the existence of an optimum DA level for cognitive function implicates the need to take into account baseline levels of DA when isolating the effects of DA. Second, cognitive control is a multifactorial phenomenon, requiring a dynamic balance between cognitive stability and cognitive flexibility. These distinct components might implicate the prefrontal cortex and the striatum, respectively. Manipulating DA will thus have paradoxical consequences for distinct cognitive control processes, depending on distinct basal or optimal levels of DA in different brain regions.
The DAT1 gene codes for the dopamine transporter, which clears dopamine from the synaptic cleft, and a variant of this gene has previously been associated with compromised response inhibition in both healthy and clinical populations. This variant has also been associated with ADHD, a disorder that is characterised by disturbed dopamine function as well as problems with response inhibition. In the present study we used fMRI to investigate the role of dopaminergic genetic variation on executive functioning by comparing how activation associated with successful and unsuccessful inhibitions differs based on DAT1-genotype and ADHD-diagnosis in adolescents performing a go/nogo task. The results identify regional specificity concerning which functional differences can be attributed to the possession of the high risk DAT1 genotype, the clinical condition or an interaction between the two. During response inhibition, individuals with two copies of the 10-repeat allele showed increased activation in frontal, medial, and parietal regions, which may indicate that inhibition is more effortful for this group. Conversely, this group displayed a reduced error response in the parahippocampal gyrus, suggestive of reduced learning from errors. There were also a number of frontal, parietal, medial and occipital regions, where the relationship between genotype and fMRI-activation differed between the ADHD group and the typically developing adolescents. Finally, the ADHD group displayed decreased activation in parietal and (pre)frontal regions during response inhibition, and in frontal and medial brain regions on error trials.
Implicit learning, the non-conscious acquisition of sequential and spatial environmental regularities, underlies skills such as language, social intuition, or detecting a target in a complex scene. We examined relationships between a variation of the dopamine transporter (DAT1) gene (SLC6A3), which influences dopamine transporter expression in the striatum, and two forms of implicit learning that differ in the regularity to be learned and in striatal involvement. Participants, grouped as 9-repeat carriers or 10/10 homozygotes, completed the triplets learning task (TLT) and the spatial contextual cueing task (SCCT). The TLT assesses sequence learning, recruiting the striatal system, particularly as training continues. In contrast, the SCCT assesses spatial context learning, recruiting medial temporal brain networks. For both tasks, participants demonstrated learning in faster and/or more accurate responses to repeating patterns or spatial arrays. As predicted, TLT learning was greater for the 9-repeat carriers than the 10/10 group (despite equal overall accuracy and response speed) whereas there were no significant group differences in SCCT. Thus, presence of the DAT1 9-repeat allele was beneficial only for implicit sequence learning, indicating the influence of DAT1 genotype on one form of implicit learning and supporting evidence that implicit learning of sequential dependencies and spatial layouts recruit different neural systems.
The dopaminergic neurotransmitter system of the brain is involved in working memory and other cognitive functions. Studies suggest an important role for dopamine synthesis and uptake in modulation of human cognitive processes. We studied the association between polymorphisms in the catechol-o-methyl transferase (COMT) and dopamine receptor D2 (DRD2) genes and general cognitive ability in a secondary analysis of 2091 men and women, aged 55-80 years living in Scotland. General cognitive ability 'g' was derived from five cognitive tests of different domains. COMT was not associated with cognitive ability in this population. The DRD2 C:C genotype of rs6277 was associated with decreased general cognitive ability 'g' (p = 0.003), and DRD2 rs1800497 heterozygotes had lowest mean general cognitive ability 'g' (p = 0.007). There was an indication of a potential interaction between the DRD2 SNPs.
Although studies have indicated that the frontal lobe plays an important role in performance on the Wisconsin Card Sorting Test (WCST) and that basal ganglia play a specific role in frontal lobe function, the role of striatal dopamine (DA) activity in performance on the WCST remains unclear.
We assessed the relation between the availability of striatal dopamine transporters (DATs) and performance on the WCST as a measure of executive function in healthy individuals. We approximated the availability of DATs in 53 healthy volunteers aged 19-61 years by use of single photon emission computed tomography with technetium-99m (99mTc)-TRODAT-1 as the ligand. The WCST was administered to all participants.
The availability of DAT was significantly negatively correlated with perseverative errors on the WCST, both before and after adjustment for body mass index (r(before) = -0.39, p = 0.004; r(after) = -0.39, p = 0.005).
This was an association study; thus, a causal relation between DAT availability and performance cannot be confirmed.
Our results suggest that striatal DAT availability may play a role in executive function as measured by the WCST.
Dopamine (DA) is implicated in working memory (WM) functioning. Variations in the DA transporter (DAT1) gene (SLC6A3) regulate DA availability in striatum. Compared to DAT1 9/10-repeat carriers, homozygosity of the DAT1 10-repeat allele has been related to less active dopaminergic pathways. A group of younger adults received 4 weeks of computerized adaptive training on several WM tasks. All participants improved their performance as a function of training. However, DAT1 9/10-repeat carriers showed larger training-related gains than DAT1 10-repeat carriers in visuospatial WM. By contrast, the two groups were indistinguishable in baseline WM performance as well as in a variety of tasks assessing different cognitive abilities. This pattern of results provides novel evidence that WM plasticity is a more sensitive indicator of DAT1 gene-related cognitive differences than single-assessment performance scores.
Impulsivity is a complex and multidimensional trait that is of interest to both personality psychologists and to clinicians. For investigators seeking the biological basis of personality traits, the use of neuroimaging techniques such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) revolutionized personality psychology in less than a decade. Now, another revolution is under way, and it originates from molecular biology. Specifically, new findings in molecular genetics, the detailed mapping and the study of the function of genes, have shown that individual differences in personality traits can be related to individual differences within specific genes. In this article, we will review the current state of the field with respect to the neural and genetic basis of trait impulsivity.
Cognitive flexibility is a crucial human ability allowing efficient adaptation to changing task challenges. Although a person's degree of flexibility can vary from moment to moment, the conditions regulating such fluctuations are not well understood. Using a task-switching procedure with fMRI, we found several brain regions in which neural activity preceding each trial predicted subsequent cognitive flexibility. Specifically, as pretrial activity increased, performance improved on trials when the task switched but did not improve when the task repeated. Regions from which flexibility could be predicted reliably included the basal ganglia, anterior cingulate cortex, prefrontal cortex, and posterior parietal cortex. Although further analysis revealed similarities across the regions in how flexibility was predicted, results supported the existence of multiple independent sources of prediction. These results reveal distinct neural mechanisms underlying fluctuations in cognitive flexibility.
• basal ganglia
• fMRI
• task switching
• cognitive control
This review attempts to summarize current knowledge of the biochemistry and pharmacology of the dopamine (DA) innervation to the frontal cortex, a rapidly expanding area of brain research which has existed for less than a decade. Most of the studies reviewed were conducted with rats, although relevant data from other species are also cited. Brief discussions of the role of the prefrontal cortex in behavior and of behavioral and anatomical studies on the mesocortical DA neurons are also included in order to consider the possible functional significance of this DA system.
Since 1990, association studies have amassed strong evidence implicating the D(2) dopamine receptor (DRD2) gene in alcoholism. Specifically, the TaqI A minor (A1) allele of the DRD2 gene has been associated with alcoholism. The DRD2 gene has also been found to be involved in other substance use disorders including cocaine, nicotine and opioid dependence, and obesity. Beyond association studies, pharmacologic studies have shown reduced brain D(2) dopamine receptor numbers in A1(+) allele carriers (A1A1 and A1A2 genotypes) compared to A1(-) allele carriers (A2A2 genotype). Through a number of other approaches, different phenotypes have also been identified in subjects with the A1(+) and A1(-) alleles. These include metabolic, neurophysiological, neuropsychological, personality, stress and treatment studies. It is hypothesized that in an effort to compensate for deficiencies in the dopaminergic system, substance abusers may seek to stimulate the mesocorticolimbic circuits of the brain, long thought to be important in behavioral reward and reinforcement. In effect, one form of the DRD2 gene, the A1 allele, renders the dopaminergic system inefficient and rewards substance abuse that increases brain dopamine levels.
Several problems in understanding executive functions and their relationships to the frontal lobes are discussed. Data are then presented from several of our studies to support the following statements: (1) the examination of patients with focal frontal lobe lesions is a necessary first step in defining the relation of executive functions to the frontal lobes; (2) there is no unitary executive function. Rather, distinct processes related to the frontal lobes can be differentiated which converge on a general concept of control functions; (3) a simple control-automatic distinction is inadequate to explain the complexity of control-automatic processes; (4) the distinction between complex and simple tasks cannot explain the differences in functions between the frontal lobes and other brain regions; and (5) the most important role of the frontal lobes may be for affective responsiveness, social and personality development, and self-awareness and unconsciousness.
Significantly diminished intellectual functioning, as indicated by appropriately administered IQ tests with scores below 70, is a frequent mental handicap leading to severe social disadvantages and serves as a paradigm for molecular genetic research of complex disorders and traits due to its multitude of known and unknown, genetic as well as environmental causes. Since the number of confounding variables is expected to be considerably reduced in the normal population at the opposite ends of the IQ distribution, we employed a contrast of extremes approach by comparing adults of high (N = 71) and average IQ (N = 78) in association studies to search for genes involved in the multigenic forms of familial mental retardation. The dopamine D2 receptor gene (DRD2) was chosen as a candidate gene for general cognitive ability (g) since it has been found to be associated with visuospatial ability which in turn is highly correlated with g. Confirming two similar studies in children, however, no significant differences were obtained. Given three negative studies, the DRD2 gene is unlikely to pay a major role in g.
Twin studies have established that there are substantial genetic influences on alcoholism (0.5-0.6) in both men and women. Our knowledge of behaviors predisposing to alcoholism, including anxiety and impulsivity, is advancing rapidly through animal and human studies. Although alcoholism is often comorbid with other substance abuse and psychiatric disorders, recent studies have shown that, with the exception of nicotine, the heritability of alcoholism is largely substance-specific. Increasing understanding of the neurobiology of addiction has identified neural pathways in which genetic variation at candidate genes could influence vulnerability. Some functional variants of these genes have been identified. Recent linkage analyses in humans and rodents have pointed to genomic regions harboring genes that influence alcoholism. Refinement of clinical phenotypes and use of intermediate phenotypes will improve chances of gene identification. All these advances in the understanding of the genetics of alcoholism should facilitate the development of more accurately targeted therapies using molecular diagnostic approaches.
The dopamine transporter is a plasma membrane protein that controls the spatial and temporal domains of dopamine neurotransmission through the accumulation of extracellular dopamine. The dopamine transporter may play a role in numerous dopamine-linked neuropsychiatric disorders. We review the cloning and organization of the human dopamine transporter gene, polymorphisms in its coding and noncoding sequence, and emerging data on its transcriptional regulation.
We studied the relationship among dopamine receptor D2 (DRD2) Taq I genetic polymorphism, caudate nucleus volumetry as measured using MRI and neuropsychological functions in 49 memory impaired older people. Compared with DRD2 A1 carriers, subjects homozygous for the DRD2 A2 allele performed poorer in a measure of general cognitive functioning (MMSE) and in long term verbal memory, and presented reduced left caudate nucleus volumes. Caudate nucleus atrophy correlated with cognitive measures influenced by the genetic polymorphism and with visual memory performance. Our findings suggest that among the aged with cognitive impairments, the homozygous status for the A2 allele of the DRD2 Taq I polymorphism is associated with diminished cognitive performance and increased atrophy in the striatum.
Genetic association studies provide considerable evidence that the 10-repeat allele of a variable number tandem repeat (VNTR) in the 3'-untranslated region (3'-UTR) of the dopamine transporter gene (DAT1) is associated with a range of psychiatric phenotypes, most notably, attention deficit hyperactivity disorder. The mechanism for this association is not yet understood, although several lines of evidence implicate variation in gene expression. In this study, we measured DAT1 messenger RNA levels in cerebellum, temporal lobe, and lymphocytes using quantitative real-time reverse-transcription polymerase chain reaction. Relative to a set of four control housekeeping genes (beta-actin, GAPD, ribosomal 18S, and beta2-microglobulin) we observed that increased levels of DAT1 expression were associated with the number of 10-repeat alleles. These data provide direct evidence that the VNTR, or another polymorphism in linkage disequilibrium with the VNTR, is involved in regulating expression of this gene.
The D2 dopamine receptor (DRD2) has been one of the most extensively investigated gene in neuropsychiatric disorders. After the first association of the TaqI A DRD2 minor (A1) allele with severe alcoholism in 1990, a large number of international studies have followed. A meta-analysis of these studies of Caucasians showed a significantly higher DRD2 A1 allelic frequency and prevalence in alcoholics when compared to controls. Variants of the DRD2 gene have also been associated with other addictive disorders including cocaine, nicotine and opioid dependence and obesity. It is hypothesized that the DRD2 is a reinforcement or reward gene. The DRD2 gene has also been implicated in schizophrenia, posttraumatic stress disorder, movement disorders and migraine. Phenotypic differences have been associated with DRD2 variants. These include reduced D2 dopamine receptor numbers and diminished glucose metabolism in brains of subjects who carry the DRD2 A1 allele. In addition, pleiotropic effects of DRD2 variants have been observed in neurophysiologic, neuropsychologic, stress response, personality and treatment outcome characteristics. The involvement of the DRD2 gene in certain neuropsychiatric disorders opens up the potential of a targeted pharmacogenomic approach to the treatment of these disorders.
This paper examines whether dopamine transporter gene (DAT1) allele status mediates medication-related change in cognitive and neurophysiological measures among children with attention-deficiency/hyperactivity disorder (ADHD).
A single 10-mg dose of methylphenidate was given in a double-blind, placebo-controlled fashion to children with ADHD who were seen for cognitive testing and EEG recording. Buccal samples were obtained and genotyped for the DAT1 polymorphism.
DAT1 allele status was associated with performance on a sustained attention task and medication-related EEG changes. Compared with those with one or more copies of the DAT1 9-repeat allele (9R), children with two copies of the 10-repeat allele (10R) exhibited poorer performance on the vigilance task. In addition, children with 10R exhibited medication-related EEG changes of increased central and parietal beta power, decreased right frontal theta power, and lower theta/beta ratios; 9R carriers showed the opposite pattern.
The data suggest that the DAT1 polymorphism mediates medication-related changes in cortical activity among children with ADHD.
Dopamine (DA) D(2) receptor antagonists have been shown to produce similar impairments to those seen in Parkinson's disease. These include working memory and set-shifting deficits. Theories of DA function have predicted that distraction or impaired switching may be important determinants of such deficits.
In order to test these hypotheses, we have followed up our previous findings with more refined tests (1) that allow measurement of spatial working memory (SWM) and distraction, (2) that allow separation of executive and mnemonic components of SWM and (3) that allow isolation of set-shifting from learning deficits.
Thirty-six young healthy male volunteers were tested on two occasions after oral administration of either 400 mg sulpiride or placebo. All participants performed the delayed response task. Sixteen participants received task-irrelevant distractors during this task, and were also given a self-ordered SWM test. The remaining participants were given delayed response tasks with task-relevant distractors, and tests of attentional and task set-shifting.
Sulpiride impaired performance of the delayed-response task both without distraction and with task-relevant distraction. By contrast, the drug protected against deficits from task-irrelevant distraction seen in the placebo group. Task set-switching was also impaired by sulpiride, with participants being slower to respond on switch trials compared with non-switch trials. There was also a trend for attentional set-shifting to be impaired following sulpiride. In contrast, self-ordered SWM performance was enhanced by sulpiride on the second test session only.
These results support models of central DA function that postulate a role in switching behaviour, and in certain aspects of working memory.
The dopamine D2 receptor has been extensively studied in relation to alcoholism, substance abuse, and nicotine dependence. The most frequently examined polymorphism linked to this gene is the Taq1A restriction fragment length polymorphism (RFLP) (dbSNP rs1800497; g.32806C>T in GenBank AF050737.1), which has been associated with a reduction in D2 receptor density, although this is not universally accepted. The Taq1A RFLP lies 10 kB downstream of DRD2 and may therefore fall within a different coding region than the DRD2 gene or within a regulatory region. Within this downstream region, we have identified a novel kinase gene, named ankyrin repeat and kinase domain containing 1 (ANKK1), which contains a single serine/threonine kinase domain and is expressed at low levels in placenta and whole spinal cord RNA. This gene is a member of an extensive family of proteins involved in signal transduction pathways. The DRD2 Taq1A RFLP is a single nucleotide polymorphism (SNP) that causes an amino acid substitution within the 11th ankyrin repeat of ANKK1 (p.Glu713Lys), which, while unlikely to affect structural integrity, may affect substrate-binding specificity. If this is the case, then changes in ANKK1 activity may provide an alternative explanation for previously described associations between the DRD2 Taq1A RFLP and neuropsychiatric disorders such as addiction.
Problematic gambling is thought to be influenced by neurobiological mechanisms. However, the neuroendocrine response to gambling is largely unknown. Therefore, the effect of casino gambling on the sympathoadrenal system, the HPA-axis, and pituitary hormones were analyzed. Fourteen male problem gamblers and 15 non-problem gamblers were examined in a balanced cross-over design. In the experimental session, participants played blackjack in a casino wagering their own money. During the control session, subjects played cards for accumulation of points. Heart rate and endocrine measures were recorded at baseline, at 30, 60 and 90 min during gambling/card playing, and after the game. Heart rate and norepinephrine levels increased with the onset of blackjack in both groups, with problem gamblers showing significantly higher levels across the entire gambling session. In addition, dopamine levels were significantly higher in problem gamblers during casino gambling compared to non-problem gamblers. Cortisol levels were transiently increased with the onset of blackjack in both groups. Casino gambling as a "real life" situation induces activation of the HPA-axis and the sympathoadrenergic system, with significantly more pronounced changes in problem gamblers. These findings may contribute to a better understanding of neuroendocrine disturbances in problem gambling.
Association of alleles at the Taq1 A, Taq1 B, intron 6, Taq1 D, exon 7, exon 8, and promoter-141C sites of the D2 dopamine receptor gene with D2 dopamine receptor binding characteristics in the caudate nucleus of Caucasian alcoholic and nonalcoholic subjects was determined. For the Taq1 D, exon 7, exon 8, and promoter- 141C sites there were no significant allelic differences in Bmax (number of binding sites) or Kd (binding affinity) of the D2 dopamine receptors. However, subjects having the minor alleles at the Taq1 A, Taq1 B, and intron 6 sites had significantly lower Bmax than subjects not having them. None of these three polymorphisms had any significant effect on Kd. Highly significant linkage disequilibria were observed among the Taq1 A, Taq1 B, and intron 6 polymorphic sites, but linkage disequilibria between these three sites and each of the Taq1 D, exon 7, exon 8, and promoter-141C sites were of lesser or of no significance. Taken together, these findings suggest that the Taq1 A, Taq1 B, and intron 6 polymorphisms, but not the Taq1 D, exon 7, exon 8, and promoter-141C polymorphisms, are in linkage disequilibrium with a functional allelic variant that affects D2 dopamine receptor expression.
Many pharmacological and clinical studies have demonstrated the importance of the dopaminergic (DA) system for cognitive functioning but little is known about the genetic basis of general cognitive ability that has been demonstrated to be highly heritable. Attempts to detect associations between certain gene loci and endophenotypes of general cognitive ability have turned out to be more promising. Therefore, the aim of the present study was to investigate two dopaminergic candidate genes (COMT VAL158MET and DRD2 TAQ IA) for endophenotypes of cognitive functioning i.e. attention, vigilance, interference, time estimation and sensoric and motoric reaction times. Out of a gene data bank of more than 600 healthy Caucasian participants, 96 subjects (n = 48 males and n = 48 females) were recruited according to their genotype/allele pattern, resulting in six independent groups (COMT: VAL/VAL, VAL/MET, MET/MET)x(DRD2: A1-, A1+) of n = 16 subjects each. Results showed associations of the COMT gene with attention and with time estimation but most noteworthy was an interaction effect DRD2xVAL on interference performance as measured by the STROOP-test explaining 13% of the variance. Findings suggest that a balance between DA related catabolic enzyme activity and receptor density are good predictors for the endophenotype of cognitive interference and that the COMT gene is in accordance with previous studies related to cognitive functioning.