DRD2 Taq1A Research Articles

P-952 - Candidate genes for pharmacogenetic management of methadone optimal dose

Methadone, a Mu-opioid receptor agonist, is currently used as a maintenance treatment in opioid dependant patients. However, its therapeutic index is narrow, and side effects are life threatening. Non-optimal dosing results in withdrawal symptoms and further heroin craving and use. The optimal dose is defined as the dose necessary to obtain a stable substitution. This optimal maximal dose can then be decreased, the final goal being to stop substitution. To identify factors to optimize the methadone optimal daily dose. We aimed to identify genetic variants (SNP) associated with the methadone optimal dose. In a candidate gene approach, we focused on OPRM1 , which encodes the opioid receptor Mu, and on DRD2/ANKK1 SNP's, implied in the reward dopaminergic signalling. Caucasians patients (n = 98) followed for methadone maintenance treatment were included in this prospective study. Candidate SNPs were genotyped ( ANKK1 : TaqI A; DRD2 : c.957C>T; OPRM1 : c.A118G). The plasmatic methadone level was determined using mass spectrometry in 59 patients. Two polymorphisms were significantly associated to the optimal methadone doses: OPRM1 c.A118G (p = 0.03) and DRD2 TaqI A (p = 0.035). The TaqIA polymorphism is located within ANKK1 , which encodes a serine threonine kinase which role remains elusive. Its molecular link to methadone pharmacodynamy remains to be established. None of these polymorphisms was associated neither to the current methadone doses, nor to the methadone plasmatic concentration. This description is the first step to optimize the prescription of methadone in caucasian populations.

P-07 - Association of the DRD2 TaqIA, 5-HT1B A-161T and CNR1 1359 G/A polymorphisms with alcohol dependence: a single center experience in denizli province of turkey

Alcohol dependence is associated with genetic variants of alcohol-metabolizing enzymes and genes related to dopaminergic, gamma-aminobutyric acidergic, glutamatergic, opioid, cholinergic, and serotonergic systems. Genetic variations in the endogenous cannabinoid system are also involved in alcohol dependence. The present study aimed to evaluate the association between three polymorphisms, DRD2 TaqIA, 5-HT1B A-161T, and CNR1 1359 G/A (rs1049353), and alcohol dependence. One hundred twenty three patients who were admitted to the Alcohol and Substance Abuse Center of Denizli State Hospital and diagnosed with alcohol dependence according to the DSM-IV criteria and 125 healthy volunteers were included in the study. Of the three polymorphisms investigated, 5-HT1B A-161T was the only one found to be associated with alcohol dependence. The 5-HT1B receptor A-161T polymorphism might be a promising marker for alcohol dependence; however, future studies are needed to clarify these findings.

Radioligand Binding to Brain Dopamine and Serotonin Receptors and Transporters in Parkinson's Disease: Relation to Gene Polymorphisms

ABSTRACTThe influence of variations in genes coding for dopamine and serotonin transporters and receptors on the expression of these structures in the brains of patients with Parkinson's disease (PD) is not known. In order to investigate the significance of dopamine and serotonin transporter and receptor gene polymorphisms on the expression of dopamine and serotonin transporters and the dopamine D2 and serotonin 5HT2A receptors in brain tissue in PD, we conducted a study on brain autopsy material from 16 patients diagnosed with clinical PD and 11 controls. The polymorphisms studied were DAT1 VTNR, DRD2 Taq1A, 5HTTLPR, and 5HTR2A 102 T>C, 516 C>T, His425Tyr, and Thr25Asn. Compared to control subjects, patients with PD had a significantly lowered radioligand binding to the dopamine transporter (DAT) in nucleus caudatus (p = .001) and putamen (p = .008), and to the serotonin transporter in gyrus cingulatus (p = .010) and nucleus caudatus (p = .032). We did not observe any significant associations between genetic polymorphisms and the extent of radioligand binding or between the polymorphisms and a diagnosis of PD. In conclusion, the density of brain dopamine and serotonin transporters in patients with PD was reduced. However, there were no associations between the investigated genotypes and the expression of the corresponding receptors and transporters.

Generational association studies of dopaminergic genes in reward deficiency syndrome (RDS) subjects: selecting appropriate phenotypes for reward dependence behaviors.

Abnormal behaviors involving dopaminergic gene polymorphisms often reflect an insufficiency of usual feelings of satisfaction, or Reward Deficiency Syndrome (RDS). RDS results from a dysfunction in the “brain reward cascade,” a complex interaction among neurotransmitters (primarily dopaminergic and opioidergic). Individuals with a family history of alcoholism or other addictions may be born with a deficiency in the ability to produce or use these neurotransmitters. Exposure to prolonged periods of stress and alcohol or other substances also can lead to a corruption of the brain reward cascade function. We evaluated the potential association of four variants of dopaminergic candidate genes in RDS (dopamine D1 receptor gene [DRD1]; dopamine D2 receptor gene [DRD2]; dopamine transporter gene [DAT1]; dopamine beta-hydroxylase gene [DBH]). Methodology: We genotyped an experimental group of 55 subjects derived from up to five generations of two independent multiple-affected families compared to rigorously screened control subjects (e.g., N = 30 super controls for DRD2 gene polymorphisms). Data related to RDS behaviors were collected on these subjects plus 13 deceased family members. Results: Among the genotyped family members, the DRD2 Taq1 and the DAT1 10/10 alleles were significantly (at least p < 0.015) more often found in the RDS families vs. controls. The TaqA1 allele occurred in 100% of Family A individuals (N = 32) and 47.8% of Family B subjects (11 of 23). No significant differences were found between the experimental and control positive rates for the other variants. Conclusions: Although our sample size was limited, and linkage analysis is necessary, the results support the putative role of dopaminergic polymorphisms in RDS behaviors. This study shows the importance of a nonspecific RDS phenotype and informs an understanding of how evaluating single subset behaviors of RDS may lead to spurious results. Utilization of a nonspecific “reward” phenotype may be a paradigm shift in future association and linkage studies involving dopaminergic polymorphisms and other neurotransmitter gene candidates.

Role of genetic polymorphisms of the dopaminergic system in Parkinson’s disease patients with impulse control disorders

BackgroundThe mechanisms underlying the development of impulse control disorders (ICDs) like compulsive gambling, buying, sexual, and eating behaviors in Parkinson’s disease (PD) are debated. We assessed whether allelic variants of dopamine D2 receptors (DRD2), catechol-O-methyltransferase (COMT) and dopamine transporter (DAT) were associated with the development of ICDs in PD. MethodWe enrolled 89 idiopathic PD patients (48 without ICDs and 41 with ICDs). All patients were screened with the Minnesota Impulsive Disorders Interview (MIDI) and fulfilled DSM-IV criteria for the ICD positive cohort. Differences in the frequency of the genotypes between ICDs and non-ICDs groups were assessed using the χ2 test. ResultsGenotyping was performed for variants of the DRD2 Taq1A (rs1800497), COMT Val158Met (rs4680), DAT1 (3′ UTR 40bp VNTR). Variants of DRD2 Taq1A, COMT and DAT1 were not associated with the risk of developing ICDs. ConclusionIn our study, there were no differences in the frequency of variant of DRD2 Taq1A, COMT and DAT1 between the two groups. Polymorphisms of dopaminergic genes do not play a relevant role in the development of ICD in PD suggesting that ICD originate from inability to filter inappropriate behaviors triggered by dopaminergic therapy.

DRD2 Taq1A Polymorphism Modulates Prolactin Secretion Induced by Atypical Antipsychotics in Healthy Volunteers

Hyperprolactinemia mediated by antagonism of dopaminergic neurotransmission in the pituitary gland is a common adverse effect of antipsychotics. Recent studies have suggested that polymorphisms of dopamine receptors can affect the therapeutic response to antipsychotics. Thus, our aim was to evaluate whether 2 such polymorphisms (DRD2 Taq1A and DRD3 Ser9Gly) modulate prolactin release in healthy volunteers (n = 119) receiving a single dose of quetiapine (25 mg, n = 26), olanzapine (5 mg, n = 57), or risperidone (1 mg, n = 36). The increases in maximum concentration and in area under the curve were calculated from plasma prolactin levels after subtraction of pretreatment levels. Multiple regression analyses revealed that prolactin increases in maximum concentration and in area under the curve depended on drug (quetiapine < olanzapine < risperidone; P < 0.001), sex (women > men; P < 0.001), and Taq1A polymorphism (A1⁺ > A2/A2; P < 0.05). Analysis of the individual drugs revealed that prolactin secretion was modulated by sex and Taq1A polymorphism in olanzapine and risperidone (P < 0.05); however, these factors were not linked to prolactin secretion in quetiapine.

POSTER SESSION 2: MARKERS, PSYCHIATRY AND TREATMENT * MARKERS * P49 * BIOMARKERS DEMONSTRATE INCREASED CONSUMPTION BUT NOT ABUSE OF ETHANOL IN ESSENTIAL TREMOR

Dopaminergic neurotransmissions play indispensible roles in modulation ofaddictive behaviours through personality and stress response. This study aimsat exploring the relationships among personality traits, salivary cortisol andalcohol craving in alcohol-dependent subjects, and the associations betweenthese parameters and gene polymorphisms involved. Alcohol-dependent subjects(n = 156) were recruited during a 5-day detoxification treatment.Neuroticism (N), extraversion (E) and conscientiousness (C) were measuredby NEO PI-R; harm avoidance (HA), reward dependence (RD), noveltyseeking (NS), persistence (P) and self-directedness (SD) were measured byTridimensional Character Inventory. Alcohol craving level was measured byAlcohol Urge Questionnaire in the morning of day 3–day 5, and a salivasample was collected subsequently for cortisol measurement. Genotyping wasdone on by PCR-RFLP. Results showed that alcohol craving correlated withsalivary cortisol level in female subjects (Spearman’s ρ = 0.430, P = 0.022)but not in male subjects. Alcohol craving is significantly (P < 0.05) correlatedwith N, C, NS and RD scores for male subjects but with E, C, NS and Pscores for female subjects. Significant correlation between alcohol cravingand these personality traits was only observed in DRD2 TaqIA A1-allele carriers,whose craving level was negatively correlated with RD scores (adjustedr2 = 0.191, P < 0.001). Structural equation modeling revealed the effect ofDRD2 TaqIA on alcohol craving is mediated through RD trait. The currentfindings suggest that correlations between alcohol craving, salivary cortisollevel and certain addiction-related personality traits are gender-specific.DRD2 TaqIA polymorphisms may be associated with alcohol craving levelthrough mediation of RD trait: alcohol-dependent A1-carrying patients withmore prominent RD trait may benefit from a detoxification treatment environmentin which alcohol craving level is low.

Monday 29 August 2011

Studies have shown that stress and alcohol-cue exposure can induce alcohol craving with increased cortisol level, hence stress response may be critical in regulating craving and predict relapse. Dopaminergic and serotonergic neurotransmissions play indispensible roles to modulate addictive behaviours through personality and stress response. This study explored the relationships among personality traits, salivary cortisol and alcohol craving in alcohol-dependent subjects, and their associations with gene polymorphisms. Alcohol-dependent subjects ( = 156) were recruited during a five-day detoxification treatment. Personality traits were assessed by NEO PI-R and Tridimensional Character Inventory. Alcohol craving was measured by Alcohol Urge Questionnaire and saliva sample for cortisol measurement. Genotyping was performed by PCR-RFLP. Results showed that alcohol craving correlated with salivary cortisol level in female subjects only (Spearman’s rho = .430, p = 0.022). 5HTTLPR S-allele carriers had significantly higher cortisol level than LL counterparts (Student t test p = 0.019), and a significant correlation between salivary cortisol level and state alcohol craving in females (Spearman’s ρ = 0.466; p = 0.014). Alcohol craving is significantly (p < 0.05) correlated with Neuroticism, Conscientiousness, Novelty-seeking and Reward-dependence personality scores for males with Extraversion, Conscientiousness, Novelty-seeking and Persistence scores for females. Significant correlation between alcohol craving and personality traits was only observed in DRD2 TaqIA A1-allele carriers, whose craving level was negatively correlated with Reward-dependence scores (adjusted r2 = 0.191, p < 0.001). Structural Equation Modeling revealed the effect of DRD2 TaqIA on alcohol craving is mediated through Reward-dependence trait. In conclusion, correlations between alcohol craving, salivary cortisol level and certain personality traits are gender specific. 5HTTLPR S-allele may be associated with higher salivary cortisol level in female alcoholics, which is positively correlated with state alcohol craving. DRD2 A1-allele is associated with alcohol craving level through mediation of the Reward-dependence trait: alcohol-dependent A1-carrying patients with this trait may benefit from a detoxification treatment environment in which alcohol craving level is low.

The aldehyde dehydrogenase 2 gene is associated with heroin dependence

Background Determining the influences of genes involved in metabolizing dopamine and encoding dopamine receptors, such as the aldehyde dehydrogenase 2 ( ALDH2) and dopamine D2 receptor/ankyrin repeat and kinase domain containing 1 ( DRD2/ANKK1) genes, is critical for understanding addictive behavior. Therefore, we investigated the association between the ALDH2 and DRD2/ANKK1 Taq IA polymorphisms and heroin dependence. Methods Heroin-dependent Han Chinese patients (250) and healthy controls (312) were recruited. ALDH2 and DRD2/ANKK1 Taq IA polymorphisms were genotyped. Results The frequency of ALDH2*1/*2 and *2/*2 genotypes was significantly higher in heroin-dependent patients than in controls, but the frequency of DRD2 Taq IA genotypes was not significantly different. Logistic regression analysis showed no significant interaction between ALDH2 and DRD2 Taq IA genotypes in patients. Conclusions The ALDH2 polymorphism, but not the DRD2, was associated with heroin dependence.

Multilocus Genetic Profile for Dopamine Signaling Predicts Ventral Striatum Reactivity

Research integrating neuroimaging and molecular genetics has yielded important insights into how variability in brain chemistry predicts individual differences in brain function, behavior and related risk for psychopathology. However, existing studies have been limited by their focus on the independent effects of single polymorphisms with modest impact on brain chemistry. Here, we explored the effects of five functional polymorphisms affecting dopamine (DA) signaling on reward-related ventral striatum (VS) reactivity, measured with BOLD fMRI, in a sample of 69 Caucasians. We also compiled individual multilocus genetic profile scores reflecting the additive effects of alleles conferring relatively increased DA signaling across the five polymorphic loci: DAT1 9-repeat, DRD4 7-repeat, DRD2 -141C Del, DRD2 Taq1A C (A2), and COMT (158)Met. These multilocus DA profile scores accounted for 10.9% of the inter-individual variability in reward-related VS reactivity. In contrast, none of the individual polymorphisms accounted for significant variability. Our results show that biologically informed multilocus genetic profiles have unique promise as indices of variability in brain chemistry that may yield advances in mapping individual differences in behaviorally relevant brain function. In turn, such genetic profiles may fuel gene-environment interactions research establishing trajectories of risk for psychopathology.

The Genomic Similarities with Linguistic Difference: A Study Among the Oraon and Munda Tribes of the Ranchi District, Jharkhand, India

The present study was conducted on two tribal communities, the Oraon and Munda, inhabiting the Ranchi district of Jharkhand state, India. The study was designed to elucidate genetic similarity, if any, shared between these tribes as they belong to the common Proto-Australoid stock but bear different linguistic affiliations. For this, a total of 98 intravenous blood samples (48 Oraon and 50 Munda) were collected from unrelated individuals of either sex up to first cousins, with their prior informed written consent. The DNA was extracted and studied for a total of 20 autosomal markers, including 7 Alu Indels, 3 DRD2 TaqI sites, 3 β-globin sites, and 7 restriction site polymorphisms. All the 20 studied molecular markers were found to be polymorphic in both the tribal population groups and showed similarities with respect to allele frequencies, with a low coefficient of gene differentiation (G(ST)) value. Moreover, sharing and distribution patterns of haplotypes of the β-globin gene cluster suggest that the Oraon and Munda share a common ancestry. However, small differences between them with reference to the linkage disequilibrium (LD) pattern indicate that the Munda might have emerged as a result of admixture between Proto-Australoids and Austro-Asiatic-speaking Mongoloids as supported by the principal co-ordinate analysis, wherein the Munda are closely placed with the Dravidian-speaking Proto-Australoid tribes of India. A common genetic substratum (Proto-Australoid stock) of the Oraon and Munda was evident in the present study, although these tribes are distinct linguistically.

Allele and Genotype Frequencies of Serotonin and Dopamine Transporter and Receptor Polymorphisms in a Norwegian Population

Polymorphisms in genes coding for dopaminergic and serotonergic receptors and transporters have been associated with the clinical effects and adverse drug reactions of antipsychotic and antidepressant drugs. The objective of this study was to investigate the frequency and combinations of common polymorphisms in the dopamine transporter (DAT1), dopamine D(2) receptor (DRD2), dopamine D(3) receptor (DRD3), serotonin transporter (5HTT), and serotonin 2A receptor (5HTR2A) genes in a Norwegian population. To determine the background frequency in the population, 250 blood samples were consecutively collected from healthy Norwegian blood donors (125 men and 125 women; mean age: 48±11 years). Samples were tested for DAT1 VNTR, DRD2 Taq1A, DRD3 Ser9Gly, 5HTTLPR, and four polymorphisms (102 T>C, His452Tyr, 516 C>T, and Thr25Asn) in the 5HTR2A, using polymerase chain reaction and real-time polymerase chain reaction. We observed the frequency of the nine-repeat allele of DAT1 VNTR polymorphism as 20% (95% confidence interval [CI]: 0.18-0.23), the A1 allele of DRD2 Taq1A polymorphism as 21% (95% CI: 0.19-0.23), the A1 allele of DRD3 Ser9Gly polymorphism as 68% (95% CI: 0.66-0.70), the short allele of 5HTTLPR as 38% (95% CI: 0.36-0.40), and the T allele of 5HTR2A 102 T>C polymorphism as 41% (95% CI: 0.39-0.41), and the frequencies of 5HTR2A His452Tyr and 5HTR2A Thr25Asn were 93% and 95%, respectively. The tested polymorphisms showed differences compared with other European populations. Further studies are necessary to better understand the effect of these alleles and their combinations on personality, mental disorders, drug response, and adverse reactions of psychotropic drugs.

P.6.007 Effect of L-glutamine and its dipeptides on the level of voluntary alcohol consumption in rats

We have performed a case-control analysis of dopamine D2-like receptor (DRD2, DRD3 and DRD4) gene polymorphisms in 118 Han Chinese cases with bipolar affective disorder and 196 control subjects, and replication analysis in 157 English cases and 143 control subjects. We found association between a functional DRD2 promoter variant (P=0.03 by allele) and the DRD2 taq1A polymorphism (P=0.001 by allele) in Chinese bipolar disorder patients. However, this finding was not replicated in the Caucasian subjects, indicating that the significant association we observed in the Chinese population is a false positive finding. An alternative explanation is that these polymorphisms are risk factors in Chinese but not Caucasian populations, a hypothesis which seems unlikely in view of the similarity of the clinical characteristics of bipolar disorder in the two populations. We also report a novel, rare one-repeat variant of the DRD4 exon 3 VNTR repeat in Chinese populations, which appears to be absent in Caucasians and is not associated with disease.

P03-327 - Searching for the genetic markers connected with paranoid schizophrenia and conditioning the treatment efficiency

AimThe aim of the study was to find genetic markers which can influence on susceptibility of paranoid schizophrenia and the treatment efficiency measured by the PANSS. We analyzed genes polymorphisms: DRD2 (Taq 1A, in egzon 8, - 141 C ins/del), DAT, GRIK3, SERT, 5HT2A, MAO-A, COMT.MethodOne hundred and ninety one patients with the diagnosis of paranoid schizophrenia were recruited as study group. To obtain the diagnosis meeting the criteria to ICD-10 we used the polish version of CIDI - Composite International Diagnostic Interview. Exclusion criteria included serious neurological disorders, major somatic disorders impairing cognitive functions and diagnosed mental impairment. The intensity of psychopathological symptoms was examined using the PANSS. Genomic DNA was extracted from leucocytes using the Miller's salting method. Polymorphisms were studied by the PCR method.Statistical analyses were performed by the Statistica computer program, specifically Pearson's chi-square test. Associations between the treatment progress and the genotype were studied by analysis of variance (ANOVA).ResultsWe didn’t find associations between investigated genes polymorphisms and susceptibility of paranoid schizophrenia. Probably, there is no influence of studied polymorphisms on the treatment efficiency.ConclusionsNo differences were found in the genotypes distribution in investigated genes polymorphisms between the whole schizophrenics and the control group. No association was found between any particular genotype and the effect of antipsychotic treatment.

Age at onset in bipolar disorder: Investigation of the role of TaqIA polymorphism of DRD2 gene in a Sardinian sample

Bipolar disorder (BD) is a highly heterogeneous and heritable psychiatric illness. Age at onset has been shown to be a powerful tool for dissecting both the phenotypic and genetic complexity of BD. In this article, we present findings from an association study between the DRD2 TaqIA polymorphism and age at onset, showing that both alleles and genotypes at this locus associate with early onset BD.

Dopaminergic system genes in childhood aggression: Possible role for DRD2

Excessive or deficient levels of extracellular dopamine have been hypothesized to contribute to a broad spectrum of mood, motor, and thought abnormalities, and dopaminergic system genes have been implicated in aggressive behaviour from animal and human studies. Objective. We examined selected members of the dopaminergic system genes for association with child aggression. Method. We analyzed polymorphisms in the dopamine transporter DAT1/SLC6A3, dopamine receptor DRD2, and DRD4 genes in our sample of pervasive childhood aggression consisting of 144 cases paired with 144 healthy controls, matched for sex and ethnicity. Results. Aggressive children were significantly more likely to have the at least one copy of the G allele for the DRD2 A-241G polymorphism (genotypic P=0.02; allelic P=0.01). The DRD2 rs1079598 CC genotype was overrepresented in aggressive children compared to controls (genotype P=0.04). The DRD2 TaqIA T allele (P=0.01) and the TT genotype (P=0.01) were also significantly overrepresented in aggressive children. Conclusions. Our preliminary results suggest that three polymorphisms in DRD2 are associated with childhood aggression. Future studies are required to replicate the current results and to further explore the relationship between the dopamine system and aggressive behaviour in children.

DRD2 and DRD4 in relation to regular alcohol and cannabis use among adolescents: Does parenting modify the impact of genetic vulnerability? The TRAILS study

AimsThe aims of the present study were to determine the direct effect of DRD2 and DRD4, as well as their interaction with parenting (i.e. rejection, overprotection and emotional warmth), on the development of regular alcohol and cannabis use in 1192 Dutch adolescents from the general population. MethodsInformation was obtained by self-report questionnaires. Perceived rejection, overprotection and emotional warmth were assessed at age 10–12. Regular alcohol and cannabis use were determined at age 15–18 and defined as the consumption of alcohol on 10 or more occasions in the past four weeks, and the use of cannabis on 4 or more occasions in the past four weeks. Models were adjusted for age, sex, parental alcohol or cannabis use, and externalizing behavior. ResultsCarrying the A1 allele of the DRD2 TaqIA polymorphism, or the 7 repeat DRD4, was not directly related to regular alcohol or cannabis use. In addition, adolescent carriers of these genetic risk markers were not more susceptible to the influence of less optimal parenting. Main effects for parenting indicated that overprotection increased the risk of regular alcohol use, whereas the risk of cannabis use was enhanced by parental rejection and buffered by emotional warmth. ConclusionsOur findings do not support an association between DRD2/DRD4 and regular alcohol and cannabis use in adolescents. Given the substance-specific influences of rejection, overprotection and emotional warmth, these parenting factors might be promising candidates for prevention work.

Acute Intravenous Synaptamine Complex Variant KB220™ “Normalizes” Neurological Dysregulation in Patients during Protracted Abstinence from Alcohol and Opiates as Observed Using Quantitative Electroencephalographic and Genetic Analysis for Reward Polymorphisms: Part 1, Pilot Study with 2 Case Reports

It is well established that in both food- and drug-addicted individuals, there is dopamine resistance due to an association with the DRD2 gene A1 allele. Evidence is emerging whereby the potential of utilizing a natural, nonaddicting, safe, putative D2 agonist may find its place in recovery from reward deficiency syndrome (RDS) in patients addicted to psychoactive chemicals. Utilizing quantitative electroencephalography (qEEG) as an imaging tool, we show the impact of Synaptamine Complex Variant KB220™ as a putative activator of the mesolimbic system. We demonstrate for the first time that its intravenous administration reduces or “normalizes” aberrant electrophysiological parameters of the reward circuitry site. For this pilot study, we report that the qEEGs of an alcoholic and a heroin abuser with existing abnormalities (ie, widespread theta and widespread alpha activity, respectively) during protracted abstinence are significantly normalized by the administration of 1 intravenous dose of Synaptamine Complex Variant KB220™. Both patients were genotyped for a number of neurotransmitter reward genes to determine to what extent they carry putative dopaminergic risk alleles that may predispose them for alcohol or heroin dependence, respectively. The genes tested included the dopamine transporter (DAT1, locus symbol SLC6A3), dopamine D4 receptor exon 3 VNTR (DRD4), DRD2 TaqIA (rs1800497), COMT val158 met SNP (rs4680), monoamine oxidase A upstream VNTR (MAOA-uVNTR), and serotonin transporter-linked polymorphic region (5HTTLPR locus symbol SLC6A4). We emphasize that these are case studies, and it would be unlikely for all individuals to carry all putative risk alleles. Based on previous research and our qEEG studies (parts 1 and 2 of this study), we cautiously suggest that long-term activation of dopaminergic receptors (ie, DRD2 receptors) will result in their proliferation and lead to enhanced “dopamine sensitivity” and an increased sense of happiness, particularly in carriers of the DRD2 A1 allele. This is supported by a clinical trial on Synaptamine Complex Variant KB220™ using intravenous administration in > 600 alcoholic patients, resulting in significant reductions in RDS behaviors. It is also confirmed by the expanded oral study on Synaptose Complex KB220Z™, published as part 2 of this study. Future studies must await both functional magnetic resonance imaging and positron emission tomography scanning to determine the acute and chronic effects of oral KB220™ on numbers of D2 receptors and direct interaction at the nucleus accumbens. Confirmation of these results in large, population-based, case-controlled experiments is necessary. These studies would provide important information that could ultimately lead to significant improvement in recovery for those with RDS and dopamine deficiency as a result of a multiple neurotransmitter signal transduction breakdown in the brain reward cascade.

Differential genetic susceptibility in diphasic and peak‐dose dyskinesias in Parkinson's disease

To examine whether there is a differential genetic susceptibility in the diphasic and peak-dose forms of levodopa-induced dyskinesias (LID) in patients with Parkinson's disease (PD). The study cohort comprised 503 unrelated Korean PD patients who were treated with levodopa and had a disease duration of at least 5 years. The presence of LID was identified during a routine follow-up and special care was taken to separate the two distinct forms of LID into diphasic and peak-dose dyskinesias (PDSK). Genotyping was performed in the 503 patients and in 559 healthy controls to search for polymorphisms of DRD3 p.S9G, DRD2 Taq1A, GRIN2B c.2664C>T, c.366C>G, c.-200T>G, and the promoter region of SLC6A4. A total of 229 patients expressed LID (peak-dose in 205, diphasic in 57, and both in 33). The presence of diphasic dyskinesia (DDSK) was exclusively associated with the DRD3 p.S9G variant after adjusting for gender, age at PD onset, Hoehn & Yahr stage, and duration of levodopa treatment. Carrying the AA genotype was likely to shorten the onset of DDSK according to the duration of levodopa therapy (P = 0.02). The presence of PDSK was not significantly associated with any of the six genetic variants studied. There may be a genetic susceptibility in the development of DDSK in PD patients on chronic levodopa therapy, and its underlying pathophysiological mechanism might be distinct from that of PDSK.

Hemoglobin, Lead Exposure, and Intelligence Quotient: Effect Modification by the DRD2 Taq IA Polymorphism

BackgroundAnemia and lead exposure remain significant public health issues in many parts of the world, often occurring together. Animal studies suggest that the dopamine D2 receptor (DRD2) mediates the effects of both lead and iron on cognition and behavior.ObjectiveWe tested the hypothesis that the DRD2 Taq IA polymorphism modifies the effects of lead and hemoglobin on intelligence quotient (IQ) among children.MethodsBlood lead and hemoglobin were assessed in 717 children 3–7 years of age attending 12 schools in Chennai, India. IQ was determined using the Binet-Kamat scales of intelligence. Genotyping for the DRD2 polymorphism was carried out using a MassARRAY iPLEX platform. Stratified analyses and interaction models, using generalized estimating equations (GEEs), were used to explore interactions between lead and hemoglobin, and DRD2 Taq IA categories [homozygous variant (A1) vs. presence of wild-type allele (A2)].ResultsAfter we controlled for potential confounders, a one-unit increase in log blood lead was associated with a decrease of 9 IQ points [95% confidence interval (CI), −18.08 to −0.16] in the homozygous-variant children (n = 73) compared with a decrease of 4 IQ points (95% CI, −7.21 to −0.69) among those with the wild-type allele (n = 644). Higher hemoglobin levels were associated with higher IQ in the children who carried the wild-type allele DRD2, but in children homozygous for the variant allele, an increase of 1 g/dL hemoglobin was associated with a decrease in 1.82 points of IQ (95% CI, −5.28 to 1.64; interaction term p-value = 0.02).ConclusionThe results of this study suggest that the DRD2 Taq IA polymorphism disrupts the protective effect of hemoglobin on cognition and may increase the susceptibility to the deficits in IQ due to lead exposure.