The regulation of D2 dopamine receptor expression

Hitzemann, Robert

doi:10.1038/sj.mp.4000388

Cited by 22 publications

(9 citation statements)

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“…This latter suggestion has been recently confirmed by Pohjalainen et al (1998), but was contradicted by Laruelle et al (1998). At the moment, it is still unclear whether or not the Al allele is associated with lower D 2 expression (Hitzemann, 1998). Since other reports of associations between the A2 allele and similar neuropsychiatric disorders are scarce, the association of the A2 allele in our sample is difficult to interpret.…”

Section: Discussionmentioning

confidence: 44%

“…In addition, one might theorize that lower densities of the D 2 receptor in OCD patients are caused by genetic factors. The A1 allele of Taq I A polymorphism in the D 2 receptor (DRD2) gene locus has been suggested to be associated with reduced DRD2 receptor densities (Hitzemann, 1998;Jonsson et al, 1999). Data on the DRD2 TaqI A polymorphism in OCD are limited, but Nicolini et al found a higher frequency of the DRD2 TaqI A2 allele in a small subgroup of OCD patients (n = 12) with tics, when compared to controls (Nicolini et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

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Association between the dopamine D2 receptor TaqI A2 allele and low activity COMT allele with obsessive–compulsive disorder in males

Denys

Nieuwerburgh

Deforce

et al. 2006

European Neuropsychopharmacology

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Background: Mounting evidence suggests the involvement of the dopamine system in the pathophysiology of obsessive-compulsive disorder. Method: The relationship of the dopamine D 2 receptor (DRD2) TaqI A, and catechol-O-methyltransferase (COMT) NlaIII High/Low activity polymorphism to obsessive-compulsive disorder (OCD) was examined in a sample of 150 patients and 150 controls. Results: OCD patients did not show significant differences in genotype distribution and allele frequency for polymorphisms investigated relative to controls. However, when the sample was stratified by gender, there was a trend to a significant predominance of the DRD2 A2A2 genotype ( p = 0.049), and a higher frequency of the DRD2 A2 allele ( p = 0.020) and low-activity COMT allele ( p = 0.035) in male OCD patients compared to male controls. In addition, we observed an association of the DRD2 A2A2 genotype in patients with an early onset of disease (V15 years) ( p = 0.033). Conclusions: Our findings replicate previous reports and provide support for a potential role of the COMT and DRD2 locus in subgroup of male, early onset patients with OCD.

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Section: Discussionmentioning

confidence: 44%

Section: Introductionmentioning

confidence: 99%

Association between the dopamine D2 receptor TaqI A2 allele and low activity COMT allele with obsessive–compulsive disorder in males

Denys

Nieuwerburgh

Deforce

et al. 2006

European Neuropsychopharmacology

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“…23 In their normal controls, however, the direction of the result was decreased binding potential for A1A2 genotypes vs A2A2 genotypes, as found by Pohjalainen et al (the rare A1A1 genotype could not be evaluated). In a review of both papers, 24 Hitzemann argued, based on data from mouse linkage studies of DRD2 receptorbinding potential, that the majority of variation in receptor density is due to genes that lie elsewhere from DRD2 in the genome, but that a polymorphism that affects receptor density also may exist in or near the mouse DRD2 gene.…”

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The DRD2 TaqI polymorphism and symptoms of attention deficit hyperactivity disorder

et al. 1999

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Keywords: DRD2; dopamine receptor 2; attention deficit hyperactivity disorder (ADHD)The relationship of the DRD2 TaqI-A1 allele to hyperactive/impulsive and inattentive symptoms of attention deficit hyperactivity disorder (ADHD) in children and adolescents was examined in a sample of clinic-referred children and their siblings, and control children and their siblings (n = 236). The contribution of genetic dominance and additivity to mean differences among the A2A2, A1A2, and A1A1 genotypes was estimated using structural equation modeling. The effect of genetic additivity was statistically significant for both traits in an analysis of all children. The heritability from the DRD2 locus was estimated at 4.27% for hyperactiveimpulsive symptoms and 2.12% for inattentive symptoms. Children with the A2A2 genotype had the highest mean level of symptoms. To control for any possible effects of population stratification, this analysis was repeated with parental genotypes as controls. In this smaller sample, although the direction of the effect was the same as that in the whole sample, the genotypic differences failed to reach conventional significance levels and the effect sizes were smaller (h 2 = 1.62% and 0.79%, respectively). Furthermore, a genotype relative risk test of children who had questionnaire-based diagnoses of ADHD also failed to yield evidence of either association or linkage. Given that the A1 allele was expected to be the high risk allele, and that results were non-significant in tests that controlled for population heterogeneity, we doubt that this DRD2 polymorphism influences symptoms of ADHD in childhood.The dopamine receptor 2 gene (DRD2) has been the focus of considerable research linking genetic polymorphisms with behavioral traits. The most frequently studied mutation in DRD2 is a TaqI restriction site in the 3Ј untranslated region of the gene. 1 It does not alter the amino acid sequence of the DRD2 protein, and its functional significance, if any, is unknown. This study examines the relation of the TaqI polymorphism to symptoms of hyperactivity-impulsivity and inattention, the symptom dimensions that underlie DSM-IV diagnoses of attention deficit hyperactivity disorder (ADHD).There is reason to expect genes in dopaminergic brain pathways to be related to childhood ADHD. The dopaminergic pathway mediates responsiveness to reward and is implicated in the rewarding action of abused drugs such as cocaine and alcohol. 2,3 Further evidence for the importance of the dopaminergic pathway to ADHD comes from a knockout-gene study in mice. 4 In this study, mice that were homozygous for deactivation of the dopamine transporter gene (DAT1) were five to six times more active and had dopamine remain active in the synaptic cleft 100 times longer than heterozygous and wild-type mice. In our previous work, we found association and linkage between ADHD and a polymorphism in DAT1 and association between ADHD and another polymorphism in the dopamine receptor D4 gene (DRD4). 5,6 There was also some evidence for heteroge...

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“…[16][17][18][19][20][21][22][23][24] In inbred mice strains a genome-wide search for catalepsy-related genes using a quantitative trait loci approach detected a locus near or at the DRD2. 25 Therefore, also in humans several attempts have been performed searching for associations between dopamine D2 receptor polymorphisms and different measures of dopaminergic binding parameters or glucose metabolism in brain regions containing dopaminergic innervation (Table 1).…”

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Polymorphisms in the dopamine D2 receptor gene and their relationships to striatal dopamine receptor density of healthy volunteers

et al. 1999

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The density of striatal dopamine D2 receptors has been shown to vary considerably among healthy subjects. 1This variability might be due to genetic or environmental factors. In the present analysis we searched for relationships between dopamine D2 receptor gene (DRD2) polymorphisms and striatal dopamine D2 receptor density in vivo, as measured by positron emission tomography and [ 11 C]raclopride in 56 healthy subjects. There was a significant association between presence of a putative functional DRD2 promoter allele (−141C Del) and high striatal dopamine receptor density (t = 2.32, P = 0.02). In agreement with some previous studies 2-4 the presence of the DRD2 TaqIA1 allele was associated with measures of low dopamine receptor density (t = 2.58, P = 0.01). Also the DRD2 TaqIB1 allele was associated with low dopamine receptor density (t = 2.58, P = 0.01) wheras there was no significant relationship between another common silent intronic DRD2 short tandem repeat polymorphism (STRP) and striatal dopamine D2 receptor density. The results suggest that DRD2 genotypes may participate differentially in the regulation of striatal dopamine D2 receptor density in healthy human subjects. The results should be interpreted with caution because of the limited sample size.Positron emission tomography (PET) has been used to demonstrate a considerable variability of dopamine D2 receptor density in healthy subjects in vivo.1 This variability has recently been associated with the personality trait Detachment, 5 indicating that dopamine D2 receptor density may have functional importance for personality characteristics in human subjects. A fundamental issue is the extent to which the dopamine D2 receptor variability is due to environmental influences or genetic contributions. A number of environmental influences such as antipsychotic medication, 6 age 7-9 and menstrual phases 10 have been suggested to alter dopamine D2 receptor density. Low dopamine D2 receptor binding in subjects with alcohol, 11,12 cocaine, 13,14 and opiate 15 dependence may suggest that these drugs also have an effect on D2 receptor density. However, the degree to which these factors may alter the receptor density cannot explain the two to threefold variability seen among healthy subjects.1 Animal data suggest a genetic contribution to the variation in dopamine receptor density. Differences in dopamine D2 receptor-binding characteristics between different inbred mice and rat strains have been repeatedly confirmed. [16][17][18][19][20][21][22][23][24] In inbred mice strains a genome-wide search for catalepsy-related genes using a quantitative trait loci approach detected a locus near or at the DRD2.25 Therefore, also in humans several attempts have been performed searching for associations between dopamine D2 receptor polymorphisms and different measures of dopaminergic binding parameters or glucose metabolism in brain regions containing dopaminergic innervation (Table 1).In a recent PET investigation of Finnish healthy individuals the DRD2 TaqIA1 allele, suggeste...

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The regulation of D2 dopamine receptor expression

Cited by 22 publications

References 50 publications

Association between the dopamine D2 receptor TaqI A2 allele and low activity COMT allele with obsessive–compulsive disorder in males

Association between the dopamine D2 receptor TaqI A2 allele and low activity COMT allele with obsessive–compulsive disorder in males

The DRD2 TaqI polymorphism and symptoms of attention deficit hyperactivity disorder

Polymorphisms in the dopamine D2 receptor gene and their relationships to striatal dopamine receptor density of healthy volunteers

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