Dopamine-related Genes Research Articles

P.6.b.003 Dopamine-related gene polymorphisms and alcohol withdrawal symptoms in patients with alcohol dependence

P.6.b.003 Dopamine-related gene polymorphisms and alcohol withdrawal symptoms in patients with alcohol dependence

Educating executive attention

Researchers in the newly emerging field of developmental cognitive neuroscience seek to understand how postnatal brain development relates to changes in perceptual, cognitive, and social abilities in infants and children (1). One of the areas of cognitive development that has benefited most from a developmental cognitive neuroscience approach is attention. The ability to attend to individual objects, people, and spatial locations within our complex and varied sensory environment is fundamental to human cognition. One important aspect of attention, so-called executive attention, refers to our ability to regulate our responses, particularly in conflict situations where several responses are possible. This aspect of attention is thought to develop until early adulthood but seems to undergo a particularly rapid development between 2 and 7 years of age (2, 3), and problems with this function as well as other executive functions may underlie some of the difficulties observed in children with Attention-Deficit/Hyperactivity Disorder (ADHD) (4). In this issue of PNAS, Rueda et al. (5) present a study that elucidates several aspects of executive attention in young children. In their work, they have gathered measures of brain activity, cognition, and behavior in children aged 4 and 6 years. These measures include behavioral assessments of executive attention and intelligence, genotyping of a dopamine-related gene (DAT1), recording electrical activity at the scalp generated by neuronal function (ERPs), and parental questionnaires relating to the child's temperament. For each age group, half of the participants received a specific educational intervention designed to enhance executive attention. This training program, adapted to be child-friendly from a method originally used to prepare macaque monkeys for space travel, was given for 5 days over a 2- to 3-week period. Rueda et al. (5) build on previous work showing that executive attention has a specific developmental course and strong genetic associations. For …

Genetic Factors in Neuromuscular Pain

Recent evidence suggests that fibromyalgia, a chronic widespread pain condition and related syndromes (chronic fatigue syndrome, irritable bowel syndrome, etc.) may share heritable pathophysiologic features. We review the recent literature on genetic and familial factors found to participate in the pathogenesis of these syndromes, specifically fibromyalgia, including evidence suggesting that serotonin- and dopamine-related genes may play a role in the pathogenesis of these illnesses. The importance of environmental factors triggering these conditions in predisposed individuals is also discussed.

P.3.031 Association study of 90 candidategenetic polymorphisms in panic disorder: Positive findings with SNPs in serotonin, cholecystokinin and dopamine related genes

P.3.031 Association study of 90 candidategenetic polymorphisms in panic disorder: Positive findings with SNPs in serotonin, cholecystokinin and dopamine related genes

Effects of dopamine D2 receptor (DRD2) and transporter (SLC6A3) polymorphisms on smoking cue-induced cigarette craving among African-American smokers.

Cue-induced craving for addictive substances has long been known to contribute to the problem of persistent addiction in humans. Research in animals over the past decade has solidly established the central role of dopamine in cue-induced craving for addictive substances, including nicotine. Analogous studies in humans, however, are lacking, especially among African-American smokers, who have lower quit rates than Caucasian smokers. Based on the animal literature, the study's objective was to test the hypothesis that smokers carrying specific variants in dopamine-related genes previously associated with risk for addictive behaviors would exhibit heightened levels of cigarette craving following laboratory exposure to cues. To this end, cigarette craving was induced in healthy African-American smokers (n=88) through laboratory exposure to smoking cues. Smokers carrying either the DRD2 (D2 dopamine receptor gene) TaqI A1 RFLP or the SLC6A3 (dopamine transporter gene) 9-repeat VNTR polymorphisms had stronger cue-induced cravings than noncarriers (Ps <0.05 and 0.01, respectively). Consistent with the separate biological pathways involved (receptor, transporter), carriers of both polymorphisms had markedly higher craving responses compared to those with neither (P<0.0006), reflecting additive effects. Findings provide support for the role of dopamine in cue-induced craving in humans, and suggest a possible genetic risk factor for persistent smoking behavior in African-American smokers.

Short interfering RNAs (siRNAs) for reducing dopaminergic phenotypic markers

Short interfering RNAs (siRNAs) are double-stranded RNAs of ∼19–29 nucleotides designed to suppress the expression of homologous genes by a process known as RNA interference (RNAi). In this study we have characterized several short interfering RNAs to reduce (knockdown) the expression of genes related to the dopaminergic system of the ventral mesencephalon. We report here effective suppression of all targeted genes, tyrosine hydroxylase (TH), the transcription factor Nr4a2 (Nurr1) and the GDNF receptor moiety cRet, by co-transfection of plasmids expressing gene specific siRNAs under control of the human U6 promoter with a reporter plasmid coding for firefly luciferase and fused in tandem to the cDNA for the gene of interest. The effective suppression of Nr4a2, cRet and tyrosine hydroxylase suggest that the U6 expression cassette could be used to deliver siRNA to mammalian cells in vivo and actively suppress the expression of dopamine related mammalian genes. The characterization of highly effective siRNAs for DA phenotypic markers may open new avenues for loss-of-function phenotypic analysis, and may lead to new approaches for gene therapy.

Polymorphisms in the dopamine D5 receptor (DRD5) gene and ADHD.

There is considerable evidence to support a role of dopamine-related genes in the molecular aetiology of attention-deficit hyperactivity disorder (ADHD). A microsatellite located near the dopamine D5 receptor (DRD5) gene has been associated with ADHD in a number of studies, but other polymorphisms within the vicinity of this gene have not been examined. In this study we genotyped three microsatellites spanning the DRD5 region in a large clinical sample. Overall, we found little evidence to support a role for DRD5 in ADHD. We found no evidence of association with either the previously associated DRD5 marker, or a repeat in the promoter region of the gene. We did, however, find significant association for an allele of D4S615, a dinucleotide repeat located 131 kb 3' of DRD5 that has been previously associated with schizophrenia. A global test incorporating all alleles of this marker, however, was not significant and thus this finding needs replication before any conclusions can be made.

No evidence for association and linkage disequilibrium between dyslexia and markers of four dopamine-related genes.

Dopamine genes are candidate genes for dyslexia in the light of the well-known comorbidity between dyslexia and ADHD. Within-family association and linkage disequilibrium were tested between four genetic markers at DRD4, DRD3, DRD2, and DAT loci, and dyslexia, in a sample of 130 Italian dyslexic children, 16.9% of whom had comorbid ADHD. No evidence of either association or linkage disequilibrium was found, neither in the total sample nor in the comorbid subgroup. Negative results do not support a common genetic basis between these two disorders for these markers.

Polymorphisms in the dopamine D4 receptor gene and attention-deficit hyperactivity disorder.

There is considerable evidence to support a role of dopamine-related genes in the molecular aetiology of attention-deficit hyperactivity disorder (ADHD). A 48 bp repeat in exon three of the dopamine D4 receptor gene has been widely studied in clinical ADHD samples, and a meta-analysis of published studies suggests it is associated with ADHD. A number of other polymorphisms across this gene have been characterised but not so thoroughly investigated in relation to ADHD. In this study we have genotyped five polymorphisms (a 120 bp promoter-region duplication, the -616 C/G substitution, the -521 C/T substitution, a poly-G repeat in intron 1, and the 48 bp exon 3 repeat) across the gene in a large clinical sample (n = 188) and their families. We found that none of the markers is individually associated with ADHD, although there is evidence to suggest that a haplotype of markers in the 5' promoter region of the gene (allele 2 of the 120 bp duplication, the C allele of the -616 substitution, and the C allele of the -521 substitution) may confer susceptibility.

The genetics of chronic headaches.

Patients with chronic daily headaches (CDH) bear similarities to drug or substance abuse patients, for whom genetic liability loci have been implicated. We reviewed papers dealing with the metabolic and the genetic aspects of CDH. The relative risk for CDH in first-degree relatives is 2.1- to 3.9-fold increased compared to the general population. Genetic variation at the dopamine receptor 2 has been associated with co-morbidity of migraine with aura with major depression and anxiety, and allele D of the angiotensin converting enzyme increases the frequency of migraine without aura attacks. In CDH, analgesic abuse was significantly associated with specific functional polymorphisms at the DRD 4 and at the dopamine transporter (DAT) genes, findings implicating dopamine-related genes in CDH with drug abuse. CDH carries a substantial genetic predisposition. Molecular genetic studies are, however, still few and preliminary.

Elevated D3 dopamine receptor mRNA in dopaminergic and dopaminoceptive regions of the rat brain in response to morphine

As opiates increase dopamine transmission, we measured the effects of morphine on dopamine-related genes using a real-time optic PCR assay that reliably detects small differences in mRNA in discrete brain regions. Tissue from dopaminoceptive and dopaminergic brain regions was collected from rats injected twice daily for 7 days with saline or increasing doses of morphine. Tissues were assayed for D1, D2 and D3 dopamine receptor mRNAs (D1R, D2R and D3R), as well as for mRNAs for tyrosine hydroxylase (TH) and the dopamine transporter (DAT). The neuron-associated mRNAs for SNAP-25 and synaptophysin, as well as the glial-associated mRNA for S100-β and three ‘housekeeping’ mRNAs, were also measured. As reported previously by others, there was no alteration in D1R mRNA and a 25% decrease in D2R mRNA in the caudate-putamen, 2 h after the final morphine injection. Importantly, in the same RNA extracts, D3R mRNA showed significant increases of 85% in the caudate-putamen and 165% in the ventral midbrain, including the substantia nigra and ventral tegmental area. There were no other significant morphine effects. Mapping of brain regions in saline control rats agreed with previous studies, including showing the presence of low abundance TH mRNA and the absence of DAT mRNA in the caudate-putamen. The finding that chronic, intermittent injections of morphine caused an increase in D3R mRNA extends our understanding of the ability of D3R agonists to reduce the effects of morphine.

Early-onset schizophrenia and dopamine-related gene polymorphism.

Schizophrenic patients with an onset before age 16 years (early-onset schizophrenia, EOS) would be a rare but attractive subpopulation for genetic studies. This study explored the relationship between the polymorphism of four dopamine-regulating-enzymes (tyrosine hydroxylase, dopamine-beta-hydroxylase, catechol-O-methyltransferase, monoamine oxidase-A) genes, four dopamine-receptors (dopamine D1, D2, D3, D4 receptors) genes and susceptibility to EOS in a Japanese sample. Subjects comprised 51 Japanese patients who met DSM-IV criteria for schizophrenia with an onset before age 16 (by age 15) and 148 Japanese healthy controls. DNA was extracted from whole blood and genotyping was carried out by PCR-RELP using each restriction endonuclease. No significant difference was found in the allele frequencies or genotype distributions of any of the eight genes examined between EOS and the control groups. We did not find the relationship between the polymorphism of eight dopamine-related genes and susceptibility to EOS in a Japanese sample.

Opaminergic System Genes in ADHD: Toward a Biological Hypothesis

Converging evidence has implicated abnormalities of dopamine neurotransmission to the pathology of attention deficit hyperactivity disorder (ADHD). Several genetic association studies have been published, but so far, no DNA variants have been unequivocally demonstrated as contributing to ADHD susceptibility. Four dopamine related gene loci have been implicated, however: DAT1, DRD4, DBH, and DRD5. Each of these may influence the liability of ADHD to a small degree. Notably, all are involved in signal transduction at the neuronal synapse. In this article, we investigate as candidate genes for ADHD, DNA polymorphisms at dopamine receptors, the dopamine transporter, and genes known to be involved in dopamine synthesis and metabolism. In a recent article, we confirmed the previously reported association of DAT1 (480bp allele) with ADHD and identified polymorphisms at two additional loci showing preferential transmission to ADHD children of alleles at DRD5 (148bp allele) and at DBH (allele 2, Taq I polymorphism). Increased transmission of the 4bp deletion in the untranslated exon 1 of the DOPA decarboxylase gene was also observed but was of marginal significance. Nonsignificant trends of association were found for TH (allele 2) and DRD2 (Ser-311). No preferential transmission of alleles to ADHD children was observed for polymorphisms at DRD1, DRD2 (Taq I), DRD3, DRD4, and COMT. Analyzing the data by sex of transmitting parent showed significant preferential paternal transmission of alleles at TH (allele 2) and a nonsignificant trend for paternal transmission for DRD2 (Ser-311). We attempt to put these findings together with what is known of the function of the particular proteins, and suggest working hypotheses.

Evidence for allelic association of the dopamine beta-hydroxylase gene (DBH) with susceptibility to typical migraine.

Migraine is a debilitating neurological disorder characterized by recurrent attacks of severe headache. The disorder is highly prevalent, affecting approximately 12% of Caucasian populations. It is well known that migraine has a strong genetic component, although the type and number of genes involved is not yet clear. However, the calcium channel gene, CACNA1A, on chromosome 19 contains mutations responsible for familial hemiplegic migraine, a rare and severe subtype of migraine. There is also evidence to suggest that serotonin- and dopamine-related genes may be involved in the pathogenesis of migraine. This study employed a linkage and association approach to investigate neurotransmitter-related migraine candidate genes. Polymorphisms within the dopamine beta-hydroxylase (DBH) gene, serotonin transporter gene (SERT), and dopamine receptor gene (DRD2) were tested in 177 unrelated Caucasian migraineurs and 182 control individuals. In addition, an independent sample of 82 families affected with migraine was examined. Unrelated case-control association analysis of a DBH intragenic dinucleotide polymorphism indicated altered allelic distribution between migraine and control groups (chi2 = 16.53, P=0.019). Furthermore, the transmission/disequilibrium test, which was implemented on the family data, also indicated distortion of allele transmission for the same DBH marker (chi2 = 4.44, P=0.035). Together, these results provide evidence for allelic association of the DBH gene with typical migraine susceptibility (Fisher's combined P value =0.006) and indicate that further research into the role of the DBH gene in the etiology of migraine is warranted.

A 'sticky' interhemispheric switch in bipolar disorder?

Despite years of research into bipolar disorder (manic depression), its underlying pathophysiology remains elusive. It is widely acknowledged that the disorder is strongly heritable, but the genetics are complex with less than full concordance in monozygotic twins and at least four susceptibility loci identified. We propose that bipolar disorder is the result of a genetic propensity for slow interhemispheric switching mechanisms that become 'stuck' in one or the other state. Because slow switches are also 'sticky' when compared with fast switches, the clinical manifestations of bipolar disorder may be explained by hemispheric activation being 'stuck' on the left (mania) or on the right (depression). Support for this 'sticky' interhemispheric switching hypothesis stems from our recent observation that the rate of perceptual alternation in binocular rivalry is slow in euthymic subjects with bipolar disorder (n = 18, median = 0.27 Hz) compared with normal controls (n = 49, median = 0.60 Hz, p < 0.0005). We have presented evidence elsewhere that binocular rivalry is itself an interhemispheric switching phenomenon. The rivalry alternation rate (putative interhemispheric switch rate) is robust in a given individual, with a test-retest correlation of more than 0.8, making it suitable for genetic studies. The interhemispheric switch rate may provide a trait-dependent biological marker for bipolar disorder.

Genetic study of dopamine-related genes in unipolar affective disorder

Genetic study of dopamine-related genes in unipolar affective disorder

Alcoholism and gene polymorphisms related to central dopaminergic transmission in the Japanese population.

We examined the association between gene polymorphisms related to central dopaminergic transmission and alcoholism in the Japanese population. Polymorphic gene loci examined included those encoding the dopamine D2 receptor (NcoI site and Ser-Cys site), the dopamine D3 receptor (BalI site), the dopamine D4 receptor (48 bp tandem repeat) and the dopamine transporter (40 bp tandem repeat). The genotype distribution at the NcoI site in the dopamine D2 receptor gene differed significantly (p < 0.5) between alcoholic patients and control subjects. The frequency of 7 repeats at the 40 bp/DAT tended to be higher (p < 0.1), and that of 9 repeats tended to be lower (p < 0.1) in alcoholic patients than in control subjects. The possible effects of dopamine-related gene polymorphisms, which might predispose individuals to alcoholism, are discussed.

Dopamine-related genes and their relationships to monoamine metabolites in CSF

Monoamine metabolite (MM) levels in lumbar cerebrospinal fluid (CSF) are extensively used as indirect estimates of monoamine turnover in the brain. In this study we investigated genotypes for DNA polymorphisms in the D2 (DRD2), D3 (DRD3), and D4 (DRD4) dopamine receptor and tyrosine hydroxylase (TH) genes and their relationships to CSF MM in healthy volunteers (n = 66). Concentrations of homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylglycol (MHPG), and 5-hydroxyindoleacetic acid (5-HIAA) were corrected for back length, a confounding variable. Corrected MM levels were not related to age, gender, height, weight heredity, season or atmospheric pressure at sampling. Individuals with specific DRD2 and TH allele and genotype configurations significantly differed in HVA and MHPG concentrations. DRD3 homo- and heterozygotic genotypes had significantly different CSF 5-HIAA levels. DRD4 genotypes were not related to MM concentrations. The results suggest that specific DRD2, DRD3, and TH genotypes participate in the regulation of monoamine turnover in the central nervous system. Accordingly monoamine receptors and synthesizing enzyme genotypes appear to be variance factors influencing MM concentrations in CSF. The relationships found in this study support MM concentrations as markers for monoamine transmission in the human brain.

Tourette, ADHD inheritance

Three specific dopamine-related genes have been associated with a spectrum of disorders including Tourette syndrome (TS), attention deficit hyperactivity disorder (ADHD), conduct disorders and stuttering, reports May 31, 1996, American Journal of Medical Genetics . The genes9 effect was found to be additive, meaning severity increases with each one of the three genes a person carries. Subjects were 225 TS patients, 60 patient relatives with TS, 132 relatives without TS and 67 controls at a California medical center9s Tourette clinic.