Dopamine Transporter Genotype Research Articles

Children’s ADHD and Dysregulation Problems, DAT1 Genotype and Methylation, and their Interplay with Family Environment

BackgroundInternational literature has underlined the complex interplay between genetic and environmental variables in shaping children’s emotional-behavioral functioning.ObjectiveThis study aimed to explore the dynamic relationship between children’s Dopamine Transporter (DAT1) genotype and methylation, and maternal and paternal affective environment, on children’s Attention Deficit Hyperactivity Disorder (ADHD) problems and dysregulation problems.MethodIn a community sample of 76 families with school-aged children, we assessed children’s DAT1 genotype and methylation, their own ADHD problems and dysregulation profile (CBCL 6–18 DP), and maternal and paternal psychopathological risk, parenting stress, and marital adjustment. Hierarchical regressions were carried out to verify the possible moderation of children’s genotype on the relationship between children’s methylation and psychopathological risk, parental environment and children’s methylation, and parental environment and children’s psychopathological risk.ResultsThe levels of methylation at M1 CpG significantly predicted ADHD problems among children with 10/10 genotype, whereas high levels of methylation at M6 CpG predicted low ADHD problems for children with 9/x genotype. High levels of methylation at M3 CpG were associated with high scores of CBCL DP. DAT1 genotype moderated the relationship between maternal and paternal variables with children’s methylation and psychopathological risk. The scores of maternal and paternal Dyadic Adjustment Scale showed indirect effects on children’s methylation and psychopathological risk in relation to those exerted by risk factors.ConclusionOur study has supported the emerging evidence on the complex nature of children’s emotional-behavioral functioning and the associated risk and protective factors, with important implications for the planning of preventive programs.

Effects of the dopamine transporter gene on neuroimaging findings in different attention deficit hyperactivity disorder presentations.

Attention-Deficit/Hyperactivity Disorder (ADHD) is a phenotipically and neurobiologically heterogeneous disorder. Deficiencies at different levels in response inhibition, differences in dopamine transporter genotype (DAT1) and various symptomatic presentations contribute to ADHD heterogeneity. Integrating these three aspects into a functional neuroimaging research could help unreval specific neurobiological components of more phenotipically homogeneous groups of patients with ADHD. During the Go-NoGo trial, we investigated the effect of the DAT1 gene using 3T MRI in 72 ADHD cases and 24 (TD) controls that typically developed between the ages 8 and 15years. In the total ADHD group, DAT1 predicted homozygosity for the 10R allele and hypoactivation in the anterior cingulate cortex and paracingulate cortex. There were no significant activation differences between DAT1 10R/10R homozygotes and 9R carriers in TD controls. Subjects with predominantly inattentive ADHD (ADHD-I) presentation with DAT1 10R/10R homozygous reduced neuronal activation during Go trial particularly in the frontal regions and insular cortex, and in the parietal regions during NoGo trial (brain regions reported as part of Default Mode Network- DMN). Additionally, DAT1 10R/10R homozygousness was associated with increased occipital zone activation during only the Go trial in the ADHD combined presentation (ADHD-C) group. Our results point the three main findings: 1) The DAT1 gene is 10R homozygous for differentiated brain activation in ADHD cases but not in the TD controls, supporting the DAT1 gene as a potential marker for ADHD, 2) The relationship between the DAT1 gene and the occipital regions in ADHD-C group which may reflect compensatory mechanisms, 3) The relationship between DAT1 gene and the reduced DMN suppression for 9R carriers probabaly stems from the ADHD-I group.

DAT1 and Its Psychological Correlates in Children with Avoidant/Restrictive Food Intake Disorder: A Cross-Sectional Pilot Study

International research has underlined the role played by children’s and maternal psychopathological symptoms on the onset of avoidant/restrictive food intake disorder (ARFID) in early childhood. No study has considered the possible interplay between children’s dopamine transporter (DAT1) genotype and methylation, dysregulation problems and maternal psychopathological risk. This study aimed to investigate the complex relationship between these variables, considering the possible mediation role played by children’s DAT1 methylation on the relationship between mothers’ psychopathological risk and children’s dysregulation problems, moderated by children’s DAT1 genotype. Our sample consisted of 94 early children and their mothers, divided into four subgroups, based on children’s ARFID subtypes (irritable/impulsive (I/I), sensory food aversions (SFA), post-traumatic feeding disorders subtypes (PTFD), and a non-clinical group (NC)). We addressed children’s dysregulation problems and maternal psychopathological risk, and collected children’s DNA through buccal swabs. Results showed that children’s 9/x genotype was associated with PTFD and NC groups, whereas the 10/10 genotype was associated with the SFA group, with large effect size. There were significant large differences in the study groups on children’s DAT1 total methylation, children’s dysregulation problems, and maternal psychopathological risk. Children’s DAT1 methylation did not mediate the relationship between mother’s psychopathological risk and children’s dysregulation problems, but there was a significant large direct effect. Children’s 9/x genotype moderated the relationship between maternal psychopathological risk and children’s DAT1 methylation but, respectively, with a large and small effect. Our pilot study suggested that the relationship between children’s DAT1 genotype and methylation, dysregulation problems, and maternal psychopathological risk has a crucial contribution to ARFID.

Gene polymorphisms and motor levodopa-induced complications in Parkinson's disease.

ObjectiveThe aim of the study was to evaluate the association of individual and combined single‐nucleotide polymorphisms in brain‐derived neurotrophic factor (BDNF), dopamine transporter (DAT), and catechol‐O‐methyltransferase (COMT) genes with the occurrence of motor levodopa‐induced complications (MLIC) in Parkinson's disease (PD).Materials and MethodsWe studied 76 patients with PD (MLIC occurred in 56.6%) and 60 controls. Allelic discrimination of rs6265 BDNF (Val66Met), rs397595 DAT (SLC6A3), and rs4680 COMT (Val158Met) genes were genotyped. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using multinominal logistic regression. Orthogonal partial least squares (OPLS) analysis and OPLS discriminant analysis (OPLS‐DA) were used to analyze qualitative genetic data.ResultsThe risk of PD in subjects with the AG BDNF genotype was increased sixfold (OR = 6.12, 95% CI = 2.88–13.02, p < .0001), and AG BDNF and AG DAT genotypes were correlated with PD in OPLS‐DA (VIP > 1). There were no differences in distributions of BDNF, DAT and COMT genotypes between PD groups with and without MLIC, while OPLS model showed that genotype combination of AG BDNF, AG DAT, and GG COMT was correlated with MLIC and genotypes combination of GG BDNF, AA DAT, and AA COMT with lack of MLIC in PD patients (VIP > 1).ConclusionsOur results confirmed the association of rs6265 BDNF (Val66Met) with the risk of PD and suggest a synergic effect of rs6265 BDNF (Val66Met), rs397595 DAT (SLC6A3), and rs4680 COMT (Val158Met) polymorphisms on the occurrence of MLIC.

Dopamine transporter genotype modulates brain activity during a working memory task in children with ADHD

Dopamine active transporter gene (DAT1) is a candidate gene associated with attention-deficit/hyperactivity disorder (ADHD). The DAT1 variable number tandem repeat (VNTR)-3’ polymorphism is functional and 9R carriers have been shown to produce more DAT than 10R homozygotes. We used functional magnetic resonance imaging (fMRI) to investigate the effects of this polymorphism on the neural substrates of working memory (WM) in a small but selected population of children with ADHD, naïve of any psychotropic treatment and without comorbidity. MRI and genotype data were obtained for 36 children (mean age: 10,36 +/− 1,49 years) with combined-type ADHD (9R n = 15) and 25 typically developing children (TDC) (mean age: 9,55 +/− 1,25 years) (9R n = 12). WM performance was similar between conditions. We found a cross-over interaction effect between gene (9R vs. 10R) and diagnosis (TDC vs. ADHD) in the orbito-frontal gyrus, cerebellum and inferior temporal lobe. In these areas, WM-related activity was higher for 9R carriers in ADHD subjects and lower in TDC. In ADHD children only, 10R homozygotes exhibited higher WM-related activity than 9R carriers in a network encompassing the parietal and the temporal lobes, the ventral visual cortex, the orbito-frontal gyrus and the head of the caudate nucleus. There was no significant results in TDC group. Our preliminary findings suggest that DAT1 VNTR polymorphism can modulate WM-related brain activity ADHD children.

Interactive effects of dopamine transporter genotype and aging on resting-state functional networks.

Aging and dopamine modulation have both been independently shown to influence the functional connectivity of brain networks during rest. Dopamine modulation is known to decline during the course of aging. Previous evidence also shows that the dopamine transporter gene (DAT1) influences the re-uptake of dopamine and the anyA9 genotype of this gene is associated with higher striatal dopamine signaling. Expanding these two lines of prior research, we investigated potential interactive effects between aging and individual variations in the DAT1 gene on the modular organization of brain acvitiy during rest. The graph-theoretic metrics of modularity, betweenness centrality and participation coefficient were assessed in 41 younger (age 20–30 years) and 37 older (age 60–75 years) adults. Age differences were only observed in the participation coefficient in carriers of the anyA9 genotype of the DAT1 gene and this effect was most prominently observed in the default mode network. Furthermore, we found that individual differences in the values of the participation coefficient correlated with individual differences in fluid intelligence and a measure of executive control in the anyA9 carriers. The correlation between participation coefficient and fluid intelligence was mainly shared with age-related differences, whereas the correlation with executive control was independent of age. These findings suggest that DAT1 genotype moderates age differences in the functional integration of brain networks as well as the relation between network characteristics and cognitive abilities.

Time-on-Task Effect During Sleep Deprivation in Healthy Young Adults Is Modulated by Dopamine Transporter Genotype.

The time-on-task (TOT) effect and total sleep deprivation (TSD) have similar effects on neurobehavioral functioning, including increased performance instability during tasks requiring sustained attention. The TOT effect is exacerbated by TSD, suggesting potentially overlapping mechanisms. We probed these mechanisms by investigating genotype-phenotype relationships on psychomotor vigilance test (PVT) performance for 3 a-priori selected genes previously linked to the TOT effect and/or TSD: dopamine active transporter 1 (DAT1), catechol-O-methyltransferase (COMT), and tumor necrosis factor alpha (TNFα). N = 82 healthy adults participated in 1 of 3 laboratory studies. A 10-min PVT was administered repeatedly during 38 h of TSD. We assessed changes in response time (RT) across each minute of the PVT as a function of time awake and genotype. Additionally, cumulative relative RT frequency distributions were constructed to examine changes in performance from the first to the second 5 min of the PVT as a function of genotype. DAT1, COMT, and TNFα were associated with differences in the build-up of the TOT effect across the 10-min PVT. DAT1 additionally modulated the interaction between TSD and the TOT effect. Subjects homozygous for the DAT1 10-repeat allele were relatively protected against TOT deficits on the PVT during TSD compared to carriers of the 9-repeat allele. DAT1 is known to regulate dopamine reuptake and is highly expressed in the striatum. Our results implicate striatal dopamine in mechanisms involved in performance instability that appear to be common to TSD and the TOT effect. Furthermore, DAT1 may be a candidate biomarker of resilience to the build-up of performance impairment across TOT due to TSD.

The polymorphism of dopamine receptor D4 (DRD4) and dopamine transporter (DAT) genes in the men with antisocial behaviour and mixed martial arts fighters

Objectives: Variable-number tandem repeat (VNTR) polymorphisms of DRD4 and DAT genes were studied in the Russian and Chechen men convicted of crimes, and two control groups comprised of the MMA fighters and a sample of general population. A group of MMA fighters included only the subjects without history of antisocial behaviour.Methods: DNA was isolated by phenol–chloroform extraction from the blood. Genotyping VNTR polymorphisms of the DRD4 and DAT genes were performed by PCR on published methods.Results: Among those convicted of felonies and most grave crimes, carriers of DRD4 long alleles are found more frequently, similarly to the cohort of MMA fighters (lacking criminal record in both paternal lines). The 9/9 DAT genotype carriers are more frequently encountered among the habitual offenders. A frequency of the combination of the DRD4 genotype 4/7 and DAT genotype 10/10 is clearly higher among the convicts of violent crimes and the MMA fighters. One can speculate the presence of a ‘controlled aggression’ without a predisposition to pathological violence in the MMA fighters.Conclusions: Our study supports the hypothesis of genetic predisposition to different variants of extreme behaviour mediated by genetic determinants involved in the functioning of neuromediator systems including those controlling dopamine pathways.

Potential for diagnosis versus therapy monitoring of attention deficit hyperactivity disorder: a new epigenetic biomarker interacting with both genotype and auto-immunity.

In view of the need for easily accessible biomarkers, we evaluated in ADHD children the epigenetic status of the 5'-untranslated region (UTR) in the SLC6A3 gene, coding for human dopamine transporter (DAT). We analysed buccal swabs and sera from 30 children who met DSM-IV-TR criteria for ADHD, assigned to treatment according to severity. Methylation levels at six-selected CpG sites (among which, a CGGCGGCGG and a CGCG motif), alone or in combination with serum titers in auto-antibodies against dopamine transporter (DAT aAbs), were analysed for correlation with CGAS scores (by clinicians) and Conners' scales (by parents), collected at recruitment and after 6weeks. In addition, we characterized the DAT genotype, i.e., the variable number tandem repeat (VNTR) polymorphisms at the 3'-UTR of the gene. DAT methylation levels were greatly reduced in ADHD patients compared to control, healthy children. Within patients carrying at least one DAT 9 allele (DAT 9/x), methylation at positions CpG2 and/or CpG6 correlated with recovery, as evident from delta-CGAS scores as well as delta Conners' scales ('inattentive' and 'hyperactive' subscales). Moreover, hypermethylation at CpG1 position denoted severity, specifically for those patients carrying a DAT 10/10 genotype. Intriguingly, high serum DAT-aAbs titers appeared to corroborate indications from high CpG1 versus high CpG2/CpG6 levels, likewise denoting severity versus recovery in DAT 10/10 versus 9/x patients, respectively. These profiles suggest that DAT 5'UTR epigenetics plus serum aAbs can serve as suitable biomarkers, to confirm ADHD diagnosis and/or to predict the efficacy of treatment.

Cingulate Cortical Thickness and Dopamine Transporter (DAT1) Genotype in Children and Adolescents With ADHD

Objective: This study aimed to examine the influence of dopamine transporter gene (DAT1) 3’UTR genotype on cingulate cortical thickness in a large sample of children and adolescents with ADHD. Method: Brain MRIs were acquired from 46 ADHD patients with homozygosity for the 10-repeat allele and 52 ADHD patients with a single copy or no copy of the allele. The cingulate cortex of each MRI scan was automatically parceled into sulci and gyri as well as into Brodmann areas (BA). Results: There were no group differences in age, gender, full-scale intelligence quotient, symptom severity, treatment status, comorbidity, or mean overall cortical thickness. Sulcus/gyrus- and BA-based analyses revealed that patients homozygous for the 10-repeat allele showed significantly greater thickness in right cingulate gyrus and right BA 24 compared with 9-repeat carriers. Conclusion: These findings suggest that thickness of cingulate cortex is influenced by the presence of the 10-repeat allele in ADHD.

The effects of DAT1 genotype on fMRI activation in an emotional go/no-go task.

Dopaminergic brain circuits participate in emotional processing and impulsivity. The dopamine transporter (DAT) modulates dopamine reuptake. A variable number tandem repeat (VNTR) in the dopamine transporter gene (DAT1) affects DAT expression. The influence of DAT1 genotype on neural activation during emotional processing and impulse inhibition has not been examined. Forty-two healthy subjects were classified as 9DAT (n=17) or 10DAT (n=25) based on DAT1 genotype (9DAT=9R/9R and 9R/10R; 10DAT=10R/10R). Subjects underwent fMRI during non-emotional and emotional go/no-go tasks. Subjects were instructed to inhibit responses to letters, happy faces, or sad faces in separate blocks. Accuracy and reaction time did not differ between groups. Within group results showed activation in regions previously implicated in emotional processing and response inhibition. Between groups results showed increased activation in 9DAT individuals during inhibition. During letter inhibition, 9DAT individuals exhibited greater activation in right inferior parietal regions. During sad inhibition, 9DAT Individuals exhibited greater activation in frontal, posterior cingulate, precuneus, right cerebellar, left paracentral, and right occipital brain regions. The interaction between DAT genotype and response type in sad versus letter stimuli showed increased activation in 9DAT individuals during sad no-go responses in the anterior cingulate cortex, extending into frontal-orbital regions. 9DAT individuals have greater activation than 10DAT individuals during neutral and sad inhibition, showing that genotypic variation influencing basal dopamine levels can alter the neural basis of emotional processing and response inhibition. This may indicate that 9R carriers exert more effort to overcome increased basal dopamine activation when inhibiting responses in emotional contexts.

The potential role of myostatin and neurotransmission genes in elite sport performances.

Elite athletes are those who represent their sport at such major competition as the Olympic Games or World contests. The most outstanding athletes appear to emerge as a result of endogenous biologic characteristics interacting with exogenous influences of the environment, often described as a 'Nature and Nurture' struggle. In this work, we assessed the contribution given by 4 genes involved in muscles development (MSTN) and behavioural insights (5HTT, DAT and MAOA) to athletic performances. As for neurotransmission, 5HTT, DAT and MAOA genes have been considered as directly involved in the management of aggressiveness and anxiety. Genotypes and allelic frequencies of 5HTTLPR, MAOA-u VNTR, DAT VNTR and MSTN K153R were determined in 50 elite athletes and compared with 100 control athletes. In this work we found a significant correlation between the dopamine transporter genotype 9/9 and allele 9 and elite sport performances. On the contrary, no association was found between muscle development regulation or serotonin pathway and elite performances. Our data, for the first time, suggest a strong role of dopamine neurotransmitter in determining sport success, highlighting the role of emotional control and psycological management to reach high-level performances.

Cortical thickness differences in the prefrontal cortex in children and adolescents with ADHD in relation to dopamine transporter (DAT1) genotype

Several lines of evidence suggest that the dopamine transporter gene (DAT1) plays a crucial role in attention deficit hyperactivity disorder (ADHD). Concretely, recent data indicate that the 10-repeat (10R) DAT1 allele may mediate neuropsychological functioning, response to methylphenidate, and even brain function and structure in children with ADHD. This study aimed to investigate the influence of 10R DAT1 on thickness of the prefrontal cortex in children and adolescents with ADHD. To this end, brain magnetic resonance images were acquired from 33 patients with homozygosity for the 10R allele and 30 patients with a single copy or no copy of the allele. The prefrontal cortex of each MRI scan was automatically parceled into regions of interest (ROIs) based on Brodmann areas (BA). The two groups were matched for age, gender, IQ, ADHD subtype, symptom severity, comorbidity and medication status. However, patients with two copies of the 10R allele exhibited significantly decreased cortical thickness in right BA 46 relative to patients with one or fewer copies of the allele. No other prefrontal ROI differed significantly between the two groups. Present findings suggest that cortical thickness of right lateral prefrontal cortex (BA 46) is influenced by the presence of the DAT1 10 repeat allele in children and adolescents with ADHD.

Region-specific dendritic spine loss of pyramidal neurons in dopamine transporter knockout mice.

Dopamine transporter (DAT) knockout (KO) mice show numerous behavioral alterations, including hyperlocomotion, cognitive deficits, impulsivity and impairment of prepulse inhibition of the startle reflex (PPI), phenotypes that may be relevant to frontostriatal disorders such as schizophrenia. Dendritic spine changes of pyramidal neurons in the dorsolateral prefrontal cortex (DLPFC) are among the most replicated of findings in postmortem studies of schizophrenia. The mechanisms that account for dendritic changes in the DLPFC in schizophrenia are unclear. Here, we report basal spine density of pyramidal neurons in the medial prefrontal cortex (mPFC), the motor cortex, the CA1 region of the hippocampus, and the basolateral amygdala in DAT KO mice. Pyramidal neurons were visualized using DAT KO mice crossbred with a Thy1-GFP transgenic mouse line. We observed a significant decrease in spine density of pyramidal neurons in the mPFC and the CA1 region of the hippocampus in DAT KO mice compared to that in WT mice. On the other hand, no difference was observed in spine density of pyramidal neurons in the motor cortex or the basolateral amygdala between DAT genotypes. These results suggest that decreased spine density could cause hypofunction of the mPFC and the hippocampus, and contribute to the behavioral abnormalities observed in DAT KO mice, including cognitive deficits. This might suggest that aberrant dopaminergic signaling may trigger dystrophic changes in dendrites of hippocampal and prefrontocortical pyramidal neurons in schizophrenia.

Genetically mediated resistance to distraction: Influence of dopamine transporter genotype on attentional selection

Genetically mediated resistance to distraction: Influence of dopamine transporter genotype on attentional selection

Dopamine transporter genotype is associated with a lateralized resistance to distraction during attention selection.

Although lateral asymmetries in orienting behavior are evident across species and have been linked to interhemispheric asymmetries in dopamine signaling, the relative contribution of attentional versus motoric processes remains unclear. Here we took a cognitive genetic approach to adjudicate between roles for dopamine in attentional versus response selection. A sample of nonclinical adult humans (N = 518) performed three cognitive tasks (spatial attentional competition, spatial cueing, and flanker tasks) that varied in the degree to which they required participants to resolve attentional or response competition. All participants were genotyped for two putatively functional tandem repeat polymorphisms of the dopamine transporter gene (DAT1; SLC6A3), which are argued to influence the level of available synaptic dopamine and confer risk to disorders of inattention. DAT1 genotype modulated the task-specific effects of the various task-irrelevant stimuli across both the spatial competition and spatial cueing but not flanker tasks. Specifically, compared with individuals carrying one or two copies of the 10-repeat DAT1 allele, individuals without this allele demonstrated an immunity to distraction, such that response times were unaffected by increases in the number of distractor stimuli, particularly when these were presented predominantly in the left hemifield. All three genotype groups exhibited uniform costs of resolving leftward response selection in a standard flanker task. None of these significant effects could be explained by speed-accuracy trade-offs, suggesting that participants without the 10-repeat allele of the DAT1 tandem repeat polymorphism possess an enhanced attentional ability to suppress task-irrelevant stimuli in the left hemifield.

Methylphenidate effects on brain activity as a function of SLC6A3 genotype and striatal dopamine transporter availability.

We pharmacologically challenged catecholamine reuptake, using methylphenidate, to investigate its effects on brain activity during a motor response inhibition task as a function of the 3'-UTR variable number of tandem repeats (VNTR) polymorphism of the dopamine transporter (DAT) gene (SLC6A3) and the availability of DATs in the striatum. We measured the cerebral hemodynamic response of 50 healthy males during a Go/No-Go task, a measure of cognitive control, under the influence of 40 mg methylphenidate and placebo using 3T functional magnetic resonance imaging. Subjects were grouped into 9-repeat (9R) carriers and 10/10 homozygotes on the basis of the SLC6A3 VNTR. During successful no-go trials compared with oddball trials, methylphenidate induced an increase of blood oxygen level-dependent (BOLD) signal for carriers of the SLC6A3 9R allele but a decrease in 10/10 homozygotes in a thalamocortical network. The same pattern was observed in caudate and inferior frontal gyrus when successful no-go trials were compared with successful go trials. We additionally investigated in a subset of 35 participants whether baseline striatal DAT availability, ascertained with (123)I-FP-CIT single photon emission computed tomography, predicted the amount of methylphenidate-induced change in hemodynamic response or behavior. Striatal DAT availability was nominally greater in 9R carriers compared with 10/10 homozygotes (d=0.40), in line with meta-analyses, but did not predict BOLD or behavioral changes following MPH administration. We conclude that the effects of acute MPH administration on brain activation are dependent on DAT genotype, with 9R carriers showing enhanced BOLD following administration of a prodopaminergic compound.

Dopamine transporter gene susceptibility to methylation is associated with impulsivity in nonhuman primates.

Impulsivity, the predisposition to act without regard for negative consequences, is a characteristic of several psychiatric disorders and is thought to result in part from genetic variation in the untranslated region of the dopamine transporter (DAT) gene. As the exact link between genetic mutations and impulsivity has not been established, we used oculomotor behavior to characterize rhesus monkeys as impulsive or calm and genetic/epigenetic analysis and positron emission tomography (PET) to correlate phenotype to DAT genotype, DAT gene methylation, and DAT availability. We found three single nucleotide polymorphisms (SNPs) in the 3'-UTR of the DAT gene, one of which provided a potential site for methylation in the impulsive group. Bisulfite analysis showed that the DNA of the impulsive but not the calm subjects was methylated at one SNP. Because genetic/epigenetic modifications could lead to differences in protein expression, we measured DAT availability using [(18)F]2β-carbomethoxy-3β-(4-chlorophenyl)-8-(2-fluoroethyl)-nortropane ([(18)F]FECNT) PET and found higher DAT availability in the internal globus pallidus, an output nucleus of the basal ganglia, of the impulsive group. Higher DAT availability lowers dopamine levels, potentially altering neuronal circuits involved in the initiation of action, thus contributing to the impulsive phenotype. The association between increased methylation in the DAT gene and greater DAT availability suggests that mutations to the regulatory portion of the DAT gene lead to a susceptibility to epigenetic modification resulting in a discrete behavioral phenotype.

Reprint of: DAT genotype modulates striatal processing and long-term memory for items associated with reward and punishment

Previous studies have shown that appetitive motivation enhances episodic memory formation via a network including the substantia nigra/ventral tegmental area (SN/VTA), striatum and hippocampus. This functional magnetic resonance imaging (fMRI) study now contrasted the impact of aversive and appetitive motivation on episodic long-term memory. Cue pictures predicted monetary reward or punishment in alternating experimental blocks. One day later, episodic memory for the cue pictures was tested. We also investigated how the neural processing of appetitive and aversive motivation and episodic memory were modulated by dopaminergic mechanisms. To that end, participants were selected on the basis of their genotype for a variable number of tandem repeat polymorphism of the dopamine transporter (DAT) gene. The resulting groups were carefully matched for the 5-HTTLPR polymorphism of the serotonin transporter gene. Recognition memory for cues from both motivational categories was enhanced in participants homozygous for the 10-repeat allele of the DAT, the functional effects of which are not known yet, but not in heterozygous subjects. In comparison with heterozygous participants, 10-repeat homozygous participants also showed increased striatal activity for anticipation of motivational outcomes compared to neutral outcomes. In a subsequent memory analysis, encoding activity in striatum and hippocampus was found to be higher for later recognized items in 10-repeat homozygotes compared to 9/10-repeat heterozygotes. These findings suggest that processing of appetitive and aversive motivation in the human striatum involve the dopaminergic system and that dopamine plays a role in memory for both types of motivational information. In accordance with animal studies, these data support the idea that encoding of motivational events depends on dopaminergic processes in the hippocampus.

P.1.i.019 Epistasis between catechol-O-methyltransferase and dopamine transporter genotypes on hippocampal volume in cannabis users and controls

P.1.i.019 Epistasis between catechol-O-methyltransferase and dopamine transporter genotypes on hippocampal volume in cannabis users and controls