Disease relevance of DRD2

• We analyzed nine known polymorphisms of the DRD2 in 665 schizophrenic patients with European Caucasian ethnic background and compared the intensity of acute dystonia, extrapyramidal symptoms, akathisia, and tardive dyskinesia between carriers of different DRD2 genotypes [1].
• For the subgrouped analysis, no results were significant after correction for multiple testing, although homozygosity of DRD2/A2A2 in subjects displaying vocal or motor tics approached significance compared to controls (Fisher exact test, P = 0.008) [2].
• Evaluation of four candidate genes encoding proteins of the dopamine pathway in familial and sporadic Parkinson's disease: evidence for association of a DRD2 allele [3].
• Allele 1 of the TG dinucleotide intronic noncoding polymorphism of the DRD2 locus was the individual allele that appeared to be in disequilibrium with migraine without aura (p = 0.02) [4].
• To test our hypothesis, we examined 79 pituitary tumors, mostly prolactinomas and mixed GH/PRL-secreting, for mutations in the coding exons of the DRD2 gene [5].
• Our results further support evaluation of DRD2 antagonists for obesity therapies [6].

Psychiatry related information on DRD2

• Our finding provides evidence for the involvement of DRD2 in a disorder of the central nervous system and should lead to further insight into the function of the dopaminergic system in dystonia and other movement and mood disorders [7].
• In the 755 cases in which DNA was successfully genotyped, we examined associations between the polymorphisms in DRD2 and DBH, and smoking cessation [8].
• (3) The genotype frequency of the DRD2 gene Ser311Cys was significantly higher in patients with persecution-type delusional disorder (21%), compared with schizophrenic patients (6%) or controls (6%) [9].
• Association of multiple DRD2 polymorphisms with anorexia nervosa [10].
• We propose that an interaction of the DRD2 C957T and COMT Val158Met may be involved in the generation of some working memory deficits in schizophrenia [11].

High impact information on DRD2

• METHODS: In this prospective, randomized, double-blind study, we compared the safety and efficacy of the dopamine D2-receptor agonist ropinirole with that of levodopa over a period of five years in 268 patients with early Parkinson's disease [12].
• Treatment of Tourette's syndrome with RO22-1319, a D-2-receptor antagonist [13].
• Schizophrenia is believed to involve altered activation of dopamine receptors, and support for this hypothesis comes from the antipsychotic effect of antagonists of the dopamine D2 receptor (D2R) [14].
• In a double-blind study, bromocriptine, a DRD2 agonist, or placebo was administered to alcoholics with either the A1 (A1/A1 and A1/A2 genotypes) or only the A2 (A2/A2 genotype) allele of the DRD2 gene [15].
• An important role of the mesolimbic dopamine system has been suggested in the reinforcing effects of alcohol and recent molecular genetic studies are implicating the gene for the D2 dopamine receptor (DRD2) in alcoholism [15].

Chemical compound and disease context of DRD2

• The preliminary results suggest that variations in the DRD2 gene influence risperidone treatment response for positive, negative, and cognitive symptoms, general psychopathology, and social functioning [16].
• One hundred twenty-four depressed inpatients affected by bipolar disorder (DSM-IV) were treated with TSD and were genotyped for DRD3 first exon Gly/Ser variants and DRD2 codon 311 Ser/Cys variants using polymerase chain reaction techniques [17].
• Role of functional genetic variation in the dopamine D2 receptor (DRD2) in response to bupropion and nicotine replacement therapy for tobacco dependence: results of two randomized clinical trials [18].
• Dopamine D2 receptor gene polymorphism and the risk of levodopa-induced dyskinesias in PD [19].
• The dopamine D2 receptor has been extensively studied in relation to alcoholism, substance abuse, and nicotine dependence [20].

Biological context of DRD2

• The human dopamine D2 receptor gene (DRD2) has three polymorphic variants that predict the amino acid substitutions Val96 --> Ala, Pro310 --> Ser, and Ser311 --> Cys in the receptor protein [21].
• A functional polymorphism in the promoter region of the DRD2 gene has been found to be associated with schizophrenia in Japanese(1,2) and Swedish populations.(3) We attempted to replicate these findings in a genetically homogeneous Portuguese population using a family-based study design [22].
• 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) [23].
• We conclude that mutations in the DRD2 gene do not occur in PRL or GH/PRL-secreting pituitary tumors and that allelic loss of 11q13 is uncommon in prolactinomas [5].
• To investigate whether the dopaminergic system plays a role in the etiology of anorexia nervosa (AN) via the dopamine D2 receptor, we investigated association and transmission disequilibrium at seven single-nucleotide polymorphisms (SNPs) spanning about 75 kbp of the gene DRD2 [10].

Anatomical context of DRD2

• Dopamine DRD2 Taq I polymorphism associates with caudate nucleus volume and cognitive performance in memory impaired subjects [24].
• Surprisingly, HCR expressed higher levels of DR-D2 autoreceptor mRNA in the midbrain, while simultaneously expressing greater DR-D2 postsynaptic mRNA in the striatum compared to LCR [25].
• Over-expression of dopamine D2 receptor and inwardly rectifying potassium channel genes in drug-naive schizophrenic peripheral blood lymphocytes as potential diagnostic markers [26].
• In the DRD2/DARPP-32 combination, the (+/-) group was significantly correlated with pathologic stage (P = 0.0006), lymph node metastasis (P = 0.0001), pT (P = 0.0287), and tumor size (P = 0.0202) [27].
• The COMT and DRD2 genes may influence dopamine dependent cognitive processes such as executive/frontal lobe functions [28].

Associations of DRD2 with chemical compounds

• This region contains an excellent candidate gene for involvement in the etiology of MD, the D2 dopamine receptor (DRD2) gene [7].
• Individuals with specific DRD2 and TH allele and genotype configurations significantly differed in HVA and MHPG concentrations [29].
• The findings suggest a pharmacogenetic influence of DRD2 E8 genotype on tiapride efficacy in alcohol withdrawal [30].
• OBJECTIVE: This study attempted to relate the alleles of the D2 (DRD2), D4 (DRD4), and dopamine transporter (DAT1) genes to the behavioral outcome of methylphenidate therapy [31].
• In the present study, the relationship between this polymorphism and prolactin response to nemonapride, an antipsychotic drug with selective and potent DRD2 antagonistic property, was investigated in 25 Japanese schizophrenic inpatients (13 males, 12 females) [32].
• This suggests that DRD2 Taq1A polymorphism status may be associated with the clinical response to aripiprazole [33].
• The average and maximum daily methadone doses were significantly associated with the DRD2 rs6275C>T SNP (P=0.016 and 0.005 for average and maximum dose, respectively) [34].

Physical interactions of DRD2

• DRD2 C957T polymorphism interacts with the COMT Val158Met polymorphism in human working memory ability [11].
• We identified CAPS1 (calcium-dependent activator protein for secretion) as a D2 dopamine receptor interacting protein (DRIP) in a yeast two-hybrid screen of a human brain library using the second intracellular domain of the human D2 receptor (D2IC2) [35].
• A significant association was observed between a DRD2 allele and AFSI and an even stronger association when the DRD2 allele was interacted with a DRD1 allele [36].
• From week 12 onward they expressed several other markers of dopamine transmission, i.e., D2R mRNA, D2R binding sites and DAT mRNA [37].
• It is concluded that a high somatostatin and dopamine D2 receptor binding potential in vivo in a TSH/PRL-producing adenoma does not necessarily predict a successful outcome of medical treatment [38].

Co-localisations of DRD2

• These results demonstrate that there is a high expression of adenosine A2A receptor mRNA in the primate striatum that is extensively co-localized with dopamine D2 receptor and preproenkephalin A mRNAs [39].

Regulatory relationships of DRD2

• 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 [40].
• Furthermore, in voltage-clamped oocytes, D2R activation enhanced both DA uptake and DAT-mediated steady-state currents by as much as 70% [41].
• Analysis of D2 receptors expressed in human embryonic kidney 293 cells indicates that NCS-1 attenuates agonist-induced receptor internalization via a mechanism that involves a reduction in D2 receptor phosphorylation [42].
• In somata and dendrites of the midbrain dopaminergic neurons, D2R labeling is expressed in most dendrites that contain VMAT2 storage vesicles, as well as in both excitatory and inhibitory afferents [43].
• In addition, the D2R-mediated NF-kappaB activation was enhanced by over-expression of beta-arrestin 1 [44].

Other interactions of DRD2

• Recent evidence shows that the dopamine D2 receptor (DRD2) and SSTR5 interact physically to form heterodimers with enhanced functional activity [45].
• The results suggest that specific DRD2, DRD3, and TH genotypes participate in the regulation of monoamine turnover in the central nervous system [29].
• Neither the DRD2 S311C polymorphism nor the presence of long alleles for the DRD4 exon III repeat sequence was associated with psychosis or aggression [46].
• Polymorphisms in DRD2, MDR1, and GSTT1 were never significant [47].
• No coding region sequence variations were identified in the DRD2 gene that met our requirements for prevalence to be considered a candidate variant contributing to susceptibility for ADHD [48].

Analytical, diagnostic and therapeutic context of DRD2

• However, we found significant differences in microsatellite allele frequencies between schizophrenic and control groups for DRD2 in the whole sample and for DRD2 and NT-3 only in women [49].
• The purpose of the present European multicenter study (13 centers) was to test the potential role in BPAD and UPAD of two candidate dopaminergic markers, DRD2 and DRD3, using a case-control association design [50].
• METHODS: Considering the pro-impulsiveness role of ethanol observed in clinical practice and epidemiological studies, we analysed the Barratt impulsiveness scores in a sample of 92 alcohol-dependent French patients (57 men and 35 women), according to the TaqI A polymorphism of the DRD2 gene [51].
• A 310 bp (base pair) region surrounding Taq I site at the DRD2 locus was amplified by polymerase chain reaction (PCR) and the PCR product was incubated with Taq I restriction enzyme [52].
• DRD2 -141C insertion/deletion polymorphism is not associated with schizophrenia: results of a meta-analysis [53].

References