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Ernest P Noble - One of the best experts on this subject based on the ideXlab platform.
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drd2 genotypes and substance use in adolescent children of alcoholics
Drug and Alcohol Dependence, 2005Co-Authors: Bradley T Conner, Ernest P Noble, Terry Ritchie, Steven M Berman, Tulin Ozkaragoz, Tim Antolin, Courtney SheenAbstract:Research has identified children of alcoholics (COAs) as a population at increased risk for developing substance use problems. Genetic studies support the Al allele of the D2 Dopamine Receptor Gene (DRD2) as a risk marker for alcoholism and substance use disorders. In this study, substance use was assessed in 48 adolescent boys of alcoholics with the DRDR A1(+) allele (A1A1/A1A2 genotypes) or the A1(-) allele (A2A2 genotype). The results revealed that boys with the A1(+) allele tried (p=0.0001) and got intoxicated on alcohol more often (p=0.009) than boys with the A1(-) allele. Boys with the A1(+) allele tried more (p=0.004) and used more substances overall (p=0.008) than boys with the A1(-) allele. Boys with the A1(+) allele developed a tobacco habit more often (p=0.03) and experienced marijuana high at an earlier age (p=0.001) than boys with the A1(-) allele. The best predictors of substance use severity in boys with the A1(+) allele were Psychoticism (p=0.01) and Negative Affect (p=0.04). The results provide support for the DRD2 A1 allele as a marker identifying a subgroup of COAs at high risk for developing substance use problems.
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d2 Dopamine Receptor Gene polymorphism paroxetine and social functioning in posttraumatic stress disorder
European Neuropsychopharmacology, 2003Co-Authors: Bruce R Lawford, Ernest P Noble, Ross Mcd Young, Burnett Kann, Leanne Arnold, J Rowell, Terry RitchieAbstract:This study examined whether allelic status of the D2 Dopamine Receptor (DRD2) Gene was associated with response to a selective serotonin reuptake inhibitor, paroxetine, in the treatment of posttraumatic stress disorder (PTSD). Sixty-three Caucasian war veterans with combat-related PTSD were treated with paroxetine for 8 weeks. Patients were assessed at baseline and at follow-up using the General Health Questionnaire-28 (GHQ). TaqI A DRD2 alleles were determined by PCR. Before paroxetine treatment, patients with the DRD2 A1+ allele (A1A2 genotype) compared to those with the A1− allele (A2A2 genotype) had higher total GHQ psychopathological scores (P=0.040) and higher GHQ subscale scores for anxiety/insomnia (0.046), social dysfunction (P=0.033) and depression (P=0.011). In an intention-to-treat analysis, paroxetine was associated with significant improvement in total GHQ scores (P=0.014) and in the factor scores of social dysfunction (P=0.033), anxiety (P=0.009) and depression (P=0.026). Furthermore, there was a significant allele by time interaction on the social dysfunction scale, with A1+ allelic patients showing significant improvement in social functioning compared to A1− allelic patients (P=0.031), an effect independent of changes in depression or anxiety. This suggests changes in social functioning induced by paroxetine may be, in part, mediated via D2 Dopamine Receptors. The DRD2 A1 allele may prove to be a useful marker to assist clinicians in predicting which patients with PTSD are likely to obtain improvements in social functioning with paroxetine treatment.
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d2 Dopamine Receptor Gene in psychiatric and neurologic disorders and its phenotypes
American Journal of Medical Genetics, 2003Co-Authors: Ernest P NobleAbstract: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. © 2003 Wiley-Liss, Inc.
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association of seven polymorphisms of the d2 Dopamine Receptor Gene with brain Receptor binding characteristics
Neurochemical Research, 2003Co-Authors: Terry Ritchie, Ernest P NobleAbstract:Association of alleles at the Taql A, Taql B, intron 6, Taql 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 Taql 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 Taql A, Taql 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 Taql A, Taql B, and intron 6 polymorphic sites, but linkage disequilibria between these three sites and each of the Taql D, exon 7, exon 8, and promoter-141C sites were of lesser or of no significance. Taken together, these findings suggest that the Taql A, Taql B, and intron 6 polymorphisms, but not the Taql D, exon 7, exon 8, and promoter-141C polymorphisms, are in linkage disequilibrium with a functional allelic variant that affects D2 Dopamine Receptor expression.
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addiction and its reward process through polymorphisms of the d2 Dopamine Receptor Gene a review
European Psychiatry, 2000Co-Authors: Ernest P NobleAbstract: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.
George R Uhl - One of the best experts on this subject based on the ideXlab platform.
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d2 Dopamine Receptor Gene taqi a1 and b1 restriction fragment length polymorphisms enhanced frequencies in psychostimulant preferring polysubstance abusers
Biological Psychiatry, 1996Co-Authors: Antonio M Persico, Geoffrey S Bird, Frances H Gabbay, George R UhlAbstract:Several lines of evidence suggest that presence of a D2 Dopamine Receptor (DRD2) Gene variant marked by TaqI restriction fragment length polymorphisms (RFLPs) might contribute to vulnerability to substance abuse. Psychostimulants display the most robust enhancement of Dopamine activity in mesolimbic/mesocortical circuits important for behavioral reward. The present study tests the hypothesis that a DRD2 Gene variant might be more prominent in polysubstance users who preferentially use psychostimulants than in addicts with preferential opiate use or in those with no drug preference. Polysubstance users with histories of heavy daily preferential psychostimulant use more often displayed one or two copies of the TaqI A1 (27/62 = 43.5% vs 33/119 = 27.7% for controls), and B1 (20/62 = 32.3% vs 23/119 = 19.8% for controls) markers at the DRD2 locus. DRD2 Gene marker distributions in abusers with more prominent opiate use, or those with no history of drug preference, were similar to control genotypes. Psychostimulant-preferring drug users also reported earlier onset of psychostimulant use. Our data are consistent with the hypothesis that DRD2 Gene variants marked by these polymorphisms may work, probably in concert with other Genetic and environmental factors, to enhance vulnerability to psychostimulant abuse.
Maral M Mouradian - One of the best experts on this subject based on the ideXlab platform.
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zic2 and sp3 repress sp1 induced activation of the human d1a Dopamine Receptor Gene
Journal of Biological Chemistry, 2000Co-Authors: Young Yang, Cheol Kyu T Hwang, Eunsung Junn, Gwang Lee, Maral M MouradianAbstract:The human D1A Dopamine Receptor is transcribed from a tissue-specific regulated Gene under the control of two promoters. An activator region (AR1) located between nucleotides −1154 and −1136 (relative to the first ATG) enhances transcription from the upstream promoter that is active in the brain. In this investigation, we sought to identify the nuclear factors that regulate the D1A Gene through their binding to AR1 using yeast one-hybrid screening. Sp3 and Zic2 were among the positive clones isolated. Although Sp1 was not isolated from this screening and purified Sp1 alone does not bind to AR1 in gel shift experiments, this General transcription factor binds to AR1 in the presence ofD1A expressing NS20Y nuclear extract and activates the D1A promoter. Thus, Sp1 appears to require an unknown factor(s) or post-translational modification to interact with AR1. On the other hand, Zic2 and Sp3 inhibit Sp1-induced activation of the D1A Gene in an AR1-dependent manner. Zic2 and D1A Genes have reciprocal brain regional distributions; Zic2 is expressed primarily in the cerebellum, and D1A is highly expressed in corpus striatum. These observations collectively suggest that one of the physiologic functions of Zic2 is repression ofD1A Gene transcription and that the intracellular balance among Sp1, Sp3 and Zic2 is important for regulating the tissue-specific expression of this Dopamine Receptor.
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Dopamine d1a Receptors and renin release in rat juxtaglomerular cells
Hypertension, 1997Co-Authors: Ikuyo Yamaguchi, Robert M Carey, Lynne Yao, Hironobu Sanada, Ryoji Ozono, Maral M Mouradian, Pedro A Jose, Robin A FelderAbstract:Two Dopamine D1-like Receptors have been cloned from mammals, the D1 and D5 Receptors, also known as D1A and D1B Receptors, respectively, in rodents. Although D1-like Receptors are known to stimulate renin release, the Receptor subtype mediating this action has not been determined. We investigated D1 Receptor subtype expression in rat juxtaglomerular cells obtained after enzymatic dispersion of kidney cortex and differential centrifugation. Juxtaglomerular cells in primary culture were immunocytochemically 85% to 95% renin positive. These cells expressed the D1A but not the D1B Receptor (mRNA and protein). D1-like Receptor function was demonstrated by a concentration-dependent stimulation of cAMP production by Dopamine (n = 5-9 per group). Fenoldopam, a D1-like Receptor agonist, also caused a concentration-dependent increase in cAMP production and renin secretion that was blocked by the selective D1-like Receptor antagonist SCH23390 (n = 4-13 per group). Although the D1 ligands do not distinguish between the cloned D1-like Receptors, the actions of fenoldopam were due to occupancy of the D1A Receptor: (1) the D1B Receptor, the only other mammalian D1-like Receptor, is not expressed in juxtaglomerular cells; (2) antisense but not sense D1A oligonucleotides completely blocked the stimulatory effect of fenoldopam on cAMP production and renin secretion. We conclude that there is selective Dopamine Receptor Gene expression in juxtaglomerular cells; the Dopamine Receptor subtype linked to the stimulation of cAMP and renin secretion in juxtaglomerular cells is the D1A subtype.
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characterization of the 5 flanking region of the human d1a Dopamine Receptor Gene
Proceedings of the National Academy of Sciences of the United States of America, 1992Co-Authors: Mari T Minowa, Takashi Minowa, Frederick J Monsma, David R Sibley, Maral M MouradianAbstract:Abstract To study how the expression of the D1A Dopamine Receptor Gene is regulated, a human genomic clone was isolated by using a rat cDNA as probe. A 2.3-kilobase genomic fragment spanning -2571 through -236 relative to the adenosine of the first methionine codon was sequenced. The Gene has an intron of 116 base pairs in the 5' noncoding region, nucleotides -599 through -484 as determined by S1 mapping and reverse transcription-PCR. It has multiple transcription initiation sites located between -1061 and -1040. The promoter region lacks a TATA box and a CAAT box, is rich in G+C content, and has multiple putative binding sites for transcription factor Sp1. Thus, the promoter region of the human D1A Gene has features of "housekeeping" Genes. However, it also has consensus sequences for AP1 and AP2 binding sites and a putative cAMP response element. The ability of four deletion mutants of the 2.3-kilobase fragment to modulate transcription of the heterologous chloramphenicol acetyltransferase Gene in the promoterless plasmid pCAT-Basic was determined. All mutants demonstrated substantial transcriptional activity in the murine neuroblastoma cell line NS20Y, which expresses the D1A Gene endogenously. Transient expression assays suggested the presence of a positive modulator between nucleotides -1340 and -1102, and a negative modulator between -1730 and -1341. The four genomic fragments had no or very low transcriptional activity in NB41A3, C6, and Hep G2 cells, which are not known to express this Gene. Thus, the human D1A Gene belongs to the category of tissue-specific, regulated Genes that have housekeeping-type promoters.
Terry Ritchie - One of the best experts on this subject based on the ideXlab platform.
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drd2 genotypes and substance use in adolescent children of alcoholics
Drug and Alcohol Dependence, 2005Co-Authors: Bradley T Conner, Ernest P Noble, Terry Ritchie, Steven M Berman, Tulin Ozkaragoz, Tim Antolin, Courtney SheenAbstract:Research has identified children of alcoholics (COAs) as a population at increased risk for developing substance use problems. Genetic studies support the Al allele of the D2 Dopamine Receptor Gene (DRD2) as a risk marker for alcoholism and substance use disorders. In this study, substance use was assessed in 48 adolescent boys of alcoholics with the DRDR A1(+) allele (A1A1/A1A2 genotypes) or the A1(-) allele (A2A2 genotype). The results revealed that boys with the A1(+) allele tried (p=0.0001) and got intoxicated on alcohol more often (p=0.009) than boys with the A1(-) allele. Boys with the A1(+) allele tried more (p=0.004) and used more substances overall (p=0.008) than boys with the A1(-) allele. Boys with the A1(+) allele developed a tobacco habit more often (p=0.03) and experienced marijuana high at an earlier age (p=0.001) than boys with the A1(-) allele. The best predictors of substance use severity in boys with the A1(+) allele were Psychoticism (p=0.01) and Negative Affect (p=0.04). The results provide support for the DRD2 A1 allele as a marker identifying a subgroup of COAs at high risk for developing substance use problems.
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d2 Dopamine Receptor Gene polymorphism paroxetine and social functioning in posttraumatic stress disorder
European Neuropsychopharmacology, 2003Co-Authors: Bruce R Lawford, Ernest P Noble, Ross Mcd Young, Burnett Kann, Leanne Arnold, J Rowell, Terry RitchieAbstract:This study examined whether allelic status of the D2 Dopamine Receptor (DRD2) Gene was associated with response to a selective serotonin reuptake inhibitor, paroxetine, in the treatment of posttraumatic stress disorder (PTSD). Sixty-three Caucasian war veterans with combat-related PTSD were treated with paroxetine for 8 weeks. Patients were assessed at baseline and at follow-up using the General Health Questionnaire-28 (GHQ). TaqI A DRD2 alleles were determined by PCR. Before paroxetine treatment, patients with the DRD2 A1+ allele (A1A2 genotype) compared to those with the A1− allele (A2A2 genotype) had higher total GHQ psychopathological scores (P=0.040) and higher GHQ subscale scores for anxiety/insomnia (0.046), social dysfunction (P=0.033) and depression (P=0.011). In an intention-to-treat analysis, paroxetine was associated with significant improvement in total GHQ scores (P=0.014) and in the factor scores of social dysfunction (P=0.033), anxiety (P=0.009) and depression (P=0.026). Furthermore, there was a significant allele by time interaction on the social dysfunction scale, with A1+ allelic patients showing significant improvement in social functioning compared to A1− allelic patients (P=0.031), an effect independent of changes in depression or anxiety. This suggests changes in social functioning induced by paroxetine may be, in part, mediated via D2 Dopamine Receptors. The DRD2 A1 allele may prove to be a useful marker to assist clinicians in predicting which patients with PTSD are likely to obtain improvements in social functioning with paroxetine treatment.
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association of seven polymorphisms of the d2 Dopamine Receptor Gene with brain Receptor binding characteristics
Neurochemical Research, 2003Co-Authors: Terry Ritchie, Ernest P NobleAbstract:Association of alleles at the Taql A, Taql B, intron 6, Taql 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 Taql 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 Taql A, Taql 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 Taql A, Taql B, and intron 6 polymorphic sites, but linkage disequilibria between these three sites and each of the Taql D, exon 7, exon 8, and promoter-141C sites were of lesser or of no significance. Taken together, these findings suggest that the Taql A, Taql B, and intron 6 polymorphisms, but not the Taql D, exon 7, exon 8, and promoter-141C polymorphisms, are in linkage disequilibrium with a functional allelic variant that affects D2 Dopamine Receptor expression.
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3h naloxone binding in the human brain alcoholism and the taqi a d2 Dopamine Receptor polymorphism
Brain Research, 1996Co-Authors: Terry Ritchie, Ernest P NobleAbstract:[3H]Naloxone binding was measured in frontal gray cortex, caudate nucleus, amygdala, hippocampus and cerebellar cortex obtained post mortem from human alcoholic and nonalcoholic subjects. Binding was found to be higher in alcoholics than in nonalcoholics for all of the brain regions examined, with a significant difference in the frontal cortex. When subjects were grouped by the presence or absence of the A1 (minor) allele of the D2 Dopamine Receptor Gene, [3H]naloxone binding was lower in all brain regions examined of subjects with the A1 allele than in those without this allele, with a significant difference in the caudate nucleus. These findings suggest that one of the consequences of chronic alcohol exposure in humans is an enhancement of the brain opiate Receptor system. However, the decreased [3H]naloxone binding observed in subjects with the A1 allele may be a compensatory response to their decreased Dopaminergic modulation of opiate Receptor activity.
Leonard L Heston - One of the best experts on this subject based on the ideXlab platform.
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the d5 Dopamine Receptor Gene in schizophrenia identification of a nonsense change and multiple missense changes but lack of association with disease
Human Molecular Genetics, 1995Co-Authors: Janet L Sobell, Leonard L Heston, Tammy J Lind, Christine D Sigurdson, David H Zald, Beth E Snitz, William M Grove, Steve S SommerAbstract:To determine whether mutations in the D5 Dopamine Receptor Gene (DRD5) are associated with schizophrenia, the Gene was examined in 78 unrelated schizophrenic individuals (156 DRD5 alleles). After amplification by the polymerase chain reaction, products were examined by dideoxy fingerprinting (ddF), a screening method related to single strand conformational polymorphism analysis that detects essentially 100% of mutations. All samples with abnormal ddF patterns were sequenced. Nine different sequence changes were identified. Five of these were sequence changes that would result in protein alterations; of these, one was a nonsense change (C335X), one was a missense change in an amino acid conserved in all Dopamine Receptors (N351D), two were missense changes in amino acids that are identical in only some Dopamine Receptors and in only some species (A269V; S453C), and one was a missense change in a non-conserved amino acid (P330Q). To investigate whether the nonsense change (C335X), predicted to prematurely truncate the Receptor protein and result in a 50% diminution of functional protein, was associated with schizophrenia, other neuropsychiatric diseases, or specific neuropsychological, psychophysiological, or personality traits, both case-control and family analyses were performed. No statistically-significant associations were detected with schizophrenia or other neuropsychiatric disease. There also were no significant associations between any one measure of neuropsychological function. However, a post-hoc analysis of combined measures of frontal lobe function hinted that heterozygotes for C335X may have a vulnerability to mild impairment, but these findings must be interpreted with caution.(ABSTRACT TRUNCATED AT 250 WORDS)
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a common exonic polymorphism in the human d5 Dopamine Receptor Gene
Human Genetics, 1993Co-Authors: Steve S Sommer, Janet L Sobell, Leonard L HestonAbstract:We report what is to our knowledge the first defined polymorphism in the human D5 Dopamine Receptor Gene (D5DR).