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PubMed2003

Does the DRD2-Taq1 A polymorphism influence treatment response to bupropion hydrochloride for reduction of the nicotine withdrawal syndrome?

Bupropion hydrochloride is effective in promoting long-term abstinence from smoking and may reduce risk for relapse through attenuation of withdrawal symptoms and craving. Bupropion is a weak dopamine reuptake inhibitor, and individual genetic variation in the dopamine D2 receptor has been associated with nicotine dependence in case-control studies. Thirty smokers were randomly assigned to bupropion or placebo and interviewed using the Minnesota Nicotine Withdrawal Scale on two occasions: prior to starting medication and after 14 days on bupropion or placebo. The individual symptoms of craving, irritability, and anxiety were significantly reduced in the bupropion group, whereas no withdrawal symptoms were diminished in the placebo group. Within the bupropion group, subgroup analyses with stratification by genotype demonstrated that craving, irritability, and anxiety were significantly attenuated only among subjects with DRD2-Taq1 A2/A2 genotypes. In the DRD2-Taq1 A1/A1 and A1/A2 groups, no significant reduction was seen in any individual symptom of the nicotine withdrawal syndrome. These data suggest that bupropion attenuates specific symptoms of the nicotine withdrawal syndrome and that this effect may be modified by genotype for the dopamine D2 receptor.

Adult↗
PubMed2004

The effects of the DRD2 polymorphism on smoking cessation and negative affect: evidence for a pharmacogenetic effect on mood.

This study evaluated the relationship between smoking cessation treatment outcome and the DRD2 polymorphism. Participants were 134 smokers who took part in a larger clinical trial evaluating the effects of an antidepressant medication (venlafaxine or placebo) plus standard care (brief counseling and nicotine replacement therapy). Venlafaxine is an antidepressant that inhibits the reuptake of serotonin and norepinephrine. A1 smokers were expected to quit significantly less often on placebo, although the abstinence rates between A1s and A2s on active drug were not expected to differ (i.e., an interaction between genotype and drug was hypothesized). In addition, antidepressant therapy was expected to have a similar genotype x treatment interaction on negative affect reduction. The results showed that smokers carrying the DRD2 A1 allele (A1/A1/A2) quit significantly less often than the homozygous A2s (OR=1.54, 95% CI=1.01-2.36). No interaction with treatment was observed. A significant pharmacogenetic effect of the drug on negative mood while quitting also was noted. Smokers absent the A1 allele (A2/A2) responded to the drug with a substantial reduction in negative affect, whereas those with the A1 allele showed no significant reduction in negative mood, F(1, 130)=5.95, p=.01. These results are contrary to expectations and suggest that although A1s may have more difficulty quitting, adding venlafaxine does not improve abstinence or mood. However, the results for the A2s provide evidence for a genotype-specific response to a pharmacological intervention, which could have implications for the development of future treatments.

Adult↗
PubMed2005

Dopamine receptor (DRD2) genotype-dependent effects of nicotine on attention and distraction during rapid visual information processing.

The effects of nicotine, distractor type, and dopamine type-2 receptor (DRD2) genotype on rapid visual information processing (RVIP) task performance were assessed in habitual smokers. Four RVIP tasks differed in terms of distractor location (central vs. peripheral) and distractor type (numeric vs. emotional). Each participant performed each of the tasks on two different days, once while wearing an active nicotine patch and once while wearing a placebo patch. Overall, the nicotine patch produced more accurate detection of and faster reaction times to target sequences; however, these effects varied with distractor type and genotype. Nicotine speeded reaction time more with left-visual-field (LVF) than right-visual-field (RVF) emotional distractors but speeded reaction time more with RVF than LVF numeric distractors, especially when the distractor digit matched the target sequence in terms of numeric oddness or evenness. Nicotine tended to facilitate performance more in individuals with at least one A1 allele than in homozygous A2A2 individuals, especially with numeric distractors presented to the left hemisphere. Nicotine tended to reduce distraction by negative stimuli more than other types of stimuli. Few gender differences were observed. The overall pattern of results was consistent with the view that nicotine modulates selective attention or subsequent information processing in a manner that depends partly on the emotional versus numeric nature of task distractors, DRD2 genotype, and the brain hemisphere that initially processes the distractors (visual field of distractor).

Adolescent↗
PubMed1996

The dopamine D2 receptor (DRD2) gene: a genetic risk factor in smoking.

Of a group of 312 non-Hispanic Caucasians who smoked at least one pack per day, had unsuccessfully attempted to stop smoking, and were free of alcohol or other drug dependence, 48.7% carried the A1 allele of the DRD2 gene. This was significantly greater than the 25.9% prevalence in the 714 known non-Hispanic Caucasian controls without alcohol or drug abuse, p < 10(-8), and significantly greater than in a smaller set of our study controls. There was a significant, inverse relationship between the prevalence of the D2A1 allele and the age of onset of smoking, p = 0.02, and the maximum duration of time the smokers had been able to quit smoking on their own, p = 0.02. These results suggest the DRD2 gene is one of a multifactorial set of risk factors associated with smoking.

Adult↗
PubMed1995

A weak association between TH and DRD2 genes and bipolar affective disorder in a Spanish sample.

Genetic factors play an important role in the aetiology of bipolar affective disorder (BP). So far, results of linkage studies have been largely disappointing. We have searched for a possible association between polymorphic DNA markers of two candidate genes (tyrosine hydroxylase, TH; dopamine D2 receptor gene, DRD2) and BP in a population from central Spain. Our results are consistent with the existence of a weak association between these two genes and BP, in such a way that TH and DRD2 could be considered as minor genes contributing to susceptibility.

Adult↗
PubMed1992

Linkage map of eight human chromosome 11q markers, including DRD2, spanning 60 cM.

We have constructed a linkage map of eight RFLP markers located on chromosome 11q in the region of the dopamine D2 receptor gene (DRD2) recognized by probe hD2G1. Abnormalities in dopaminergic neurotransmission mediated by this receptor have been implicated in several psychiatric disorders. The map was generated using six large reference families (from 294 to 419 individuals per locus), which are largely independent of the CEPH families, primarily using the LINKMAP and ILINK programs of the LINKAGE package of Lathrop and Lalouel. The most likely order and recombination frequencies are: [sequence: see text] The relative order of D11S84-STMY, DRD2-D11S29, and D11S146-INT2 could not be resolved reliably. There were no significant sex differences in recombination frequency. We introduce here a version of LINKMAP adapted to run under distributed parallel processing (LINDA-LINKMAP). Using pairwise analyses, we have also placed D11S421 proximal to this group.

Chromosome Mapping↗
PubMed2006

DRD2 promoter region variation as a predictor of sustained response to antipsychotic medication in first-episode schizophrenia patients.

OBJECTIVE: All antipsychotics act on the dopamine D(2) receptor. The present study extends prior pharmacogenetic investigations of the D(2) receptor gene (DRD2) by examining, in first-episode schizophrenia patients, promoter region variation as a predictor of response time to two first-line atypical antipsychotics. METHOD: Patients experiencing their first episode of schizophrenia (N=61) were genotyped for two DRD2 promoter region polymorphisms (A-241G and -141C Ins/Del) and were randomly assigned to receive 16 weeks of treatment with either risperidone or olanzapine. Time until sustained response (two consecutive ratings without significant positive symptoms) for rare allele carriers versus wild types was examined by using Kaplan-Meier curves. RESULTS: Relative to wild type homozygotes, G carriers (A-241G) exhibited a significantly faster time until response, whereas -141C Del carriers took a significantly longer time to respond. Diplotype analysis revealed similar results. CONCLUSIONS: These findings suggest that variation in the D(2) receptor gene can, in part, explain variation in the timing of clinical response to antipsychotics in patients with first-episode schizophrenia.

Adolescent↗
PubMed2005

Sequence analysis of Drd2, Drd4, and Dat1 in SHR and WKY rat strains.

BACKGROUND: The Spontaneously Hypertensive Rat (SHR) shows a number of behaviours that closely parallel those seen in children with attention-deficit hyperactivity disorder. These include motor hyperactivity, excessive responses under a fixed-interval/extinction schedule, difficulty in acquiring operant tasks and increased sensitivity to immediate behavioural reinforcement. As in children with ADHD, the behavioural and cognitive deficits in the SHR are responsive to stimulants, including d-amphetamine and d,l-methylphenidate. The non-hyperactive Wistar Kyoto (WKY) rat strain is often used as a control in behavioural studies of the SHR, and WKY itself has been suggested to be a useful animal model of depression. Numerous studies have shown that dopaminergic neurotransmission is altered between the two strains. Human genetic studies have found associations between several dopaminergic genes and both ADHD and depression. METHODS: We sequenced three candidate dopaminergic genes (Drd2, Drd4, and Dat1) in the SHR and WKY to identify between-strain sequence differences. RESULTS: No between-strain sequence differences were found in either Drd2 or Drd4, but several variations were found in the Dat1 gene that encodes the dopamine transporter. CONCLUSION: It is plausible that DNA sequence changes in the Dat1 gene account for some of the behavioural differences observed between the SHR and WKY strains. Future work will focus on elucidating the functional effects of the observed polymorphisms.

Journal Article↗
PubMed2004

A polymorphism of DRD2 gene and brain atrophy in methamphetamine psychosis.

Our group, Ujike et al., recently reported that the A1 allele of TaqI A polymorphism of the dopamine receptor D2 (DRD2) gene, associated with transient psychosis, significantly differs from that of patients with prolonged psychosis in methamphetamine psychosis. Therefore, we examined the association between the TaqI A polymorphism of the DRD2 gene and the brain MRI view for patients with methamphetamine psychosis. The subjects underwent brain MRI scans using the FLAIR method. Genotyping was performed by PCR-RFLP methods using genomic DNA extracted from peripheral blood by the phenol method. Ten subjects had the A1/A2 genotype, eleven subjects had the A2/A2 genotype, and no subject had the A1/A1 genotype. The domain size, including the thalamus and basal ganglia that were inside each side of the putamens, did not differ between the three groups (the A1/A2-group, the A2/A2-group, and the young healthy person group). In the comparison based on this domain, the temporal lobe tended to narrow in the A2/A2-group compared to the A1/A2-group (P = .06). The other domain (cerebrum, corpus callosum, etc.) showed no difference between the A1/A2-group and the A2/A2-group. It is suggested that in methamphetamine psychosis the TaqI A polymorphism not only regulates prolongation of psychosis symptoms but also influences the form of the temporal lobe.

Adult↗
PubMed2001

The association study of DRD2, ACE and AGT gene polymorphisms and metamphetamine dependence.

We investigated the association between metamphetamine dependence and TaqI A polymorphism of the dopamine receptor D2 gene (DRD2), I/D polymorphism in angiotensin-converting enzyme (ACE) and M235T polymorphism of the angiotensinogen gene (AGT) in 93 unrelated metamphetamine-dependent subjects and 131 controls. Our results did not prove any association of TaqI A polymorphism of the DRD2 gene, I/D polymorphism of ACE gene, and M235T polymorphism of AGT gene with the metamphetamine dependence in Caucasians of Czech origin. However, a significant difference in allele I frequency between male and female control groups for the I/D ACE polymorphism (p<0.03) was found.

Adult↗
PubMed1993

The DRD2 dopamine receptor and the candidate gene approach in alcoholism.

The cloning of the DRD2 dopamine receptor gene and discovery of an associated polymorphism permitted genetic association and linkage studies to alcoholism. Extensive allele frequency differences between populations provide an alternative explanation for explaining a DRD2 association to alcoholism which has been observed in some studies, but more frequently has not been replicated.

Alcoholism↗
PubMed1993

Linkage analysis of DRD2, a marker linked to the ataxia-telangiectasia gene, in 64 families with premenopausal bilateral breast cancer.

Recent reports suggest that subjects who are heterozygous for the ataxia-telangiectasia gene are at increased risk of breast cancer. We conducted linkage analyses of 64 families with premenopausal bilateral breast cancer using DRD2, a marker linked to the ataxia-telangiectasia locus at 11q22-23. We assumed a model with dominant transmission of breast cancer. Lod scores summed over all families provided strong evidence against tight linkage (e.g., a lod score of -6.08 at theta = 0.00001), although a single family provides suggestive evidence of tight linkage to DRD2. Evidence against linkage to 11q was strongest among families that may involve the BRCA1 breast cancer susceptibility gene on 17q21. However, we did not observe evidence of linkage to 11q among the remaining subgroup with neither a family history of ovarian cancer nor the appearance of linkage to 17q21.

Adult↗
PubMed1996

Polygenic inheritance of Tourette syndrome, stuttering, attention deficit hyperactivity, conduct, and oppositional defiant disorder: the additive and subtractive effect of the three dopaminergic genes--DRD2, D beta H, and DAT1.

Polymorphisms of three different dopaminergic genes, dopamine D2 receptor (DRD2), dopamine beta-hydroxylase (D beta H), and dopamine transporter (DAT1), were examined in Tourette syndrome (TS) probands, their relatives, and controls. Each gene individually showed a significant correlation with various behavioral variables in these subjects. The additive and substractive effects of the three genes were examined by genotyping all three genes in the same set of subjects. For 9 of 20 TS associated comorbid behaviors there was a significant linear association between the degree of loading for markers of three genes and the mean behavior scores. The behavior variables showing the significant associations were, in order attention deficit hyperactivity disorder (ADHD), stuttering oppositional defiant, tics, conduct, obsessive-compulsive, mania, alcohol abuse and general anxiety-behaviors that constitute the most overt clinical aspects of TS. For 16 of the 20 behavior scores there was a linear progressive decrease in the mean score with progressively lesser loading for the three gene markers. These results suggest that TS, ADHD, stuttering oppositional defiant and conduct disorder, and other behaviors associated with TS, are polygenic, due in part to these three dopaminergic genes, and that the genetics of other polygenic psychiatric disorders may be deciphered using this technique.

Adolescent↗
PubMed2001

Relationship between Taq1 A dopamine D2 receptor (DRD2) polymorphism and prolactin response to bromperidol.

The dopamine D2 receptor (DRD2) gene has a Taq1 A restriction fragment length polymorphism yielding two alleles, A1 and A2. We have previously shown that female patients with the A1 allele show greater prolactin response to nemonapride, a selective antagonist for D2-like dopamine receptors, in schizophrenic patients. In the present study, the relationship between this polymorphism and prolactin response to bromperidol was investigated in 32 untreated schizophrenic inpatients (16 males, 16 females). The daily dose of bromperidol was fixed at 6 (n = 10), 12 (n = 13), or 18 mg (n = 9) during a 2-week treatment period. Taq1 A genotypes were determined by PCR method. Plasma prolactin concentration was measured by radioimmunoassay. Plasma concentration of bromperidol was measured by HPLC method. The subjects were divided into four subgroups by gender and the genotypes, i.e., 10 males and 11 females with the A1 allele, 6 males and 5 females with no A1 allele. The females with the A1 allele had the highest Delta prolactin (the change from the pretreatment concentration)/bromperidol concentration ratio among the other groups (P < 0.05). The present study thus suggests that female patients with the A1 allele show greater prolactin response to bromperidol, who may have a high risk for adverse effects associated with neuroleptic-induced hyperprolactinemia.

Adult↗
PubMed1995

Occurrence of the Cys311 DRD2 variant in a pedigree multiply affected with panic disorder.

Following the detection of the rare DRD2 codon 311 variant (Ser-->Cys) in an affected member from a large, multiply affected panic disorder family, we investigated the occurrence of this variant in other family members. The variant occurred in both affected and unaffected individuals. Further screening in panic disorder sib pairs unrelated to this family failed to detect the Cys311 variant. Our data suggests that this variant has no pathogenic role in panic disorder.

Base Sequence↗
PubMed1998

A global survey of haplotype frequencies and linkage disequilibrium at the DRD2 locus.

A four-site haplotype system at the dopamine D2 receptor locus (DRD2) has been studied in a global sample of 28 distinct populations. The haplotype system spans about 25 kb, encompassing the coding region of the gene. The four individual markers include three TaqI restriction site polymorphisms (RSPs) -- TaqI "A", "B", and "D" sites -- and one dinucleotide short tandem repeat polymorphism (STRP). All four of the marker systems are polymorphic in all regions of the world and in most individual populations. The haplotype system shows the highest average heterozygosity in Africa, a slightly lower average heterozygosity in Europe, and the lowest average heterozygosities in East Asia and the Americas. Across all populations, 20 of the 48 possible haplotypes reached a frequency of at least 5% in at least one population sample. However, no single population had more than six haplotypes reaching that frequency. In general, African populations had more haplotypes present in each population and more haplotypes occurring at a frequency of at least 5% in that population. Permutation tests for significance of overall disequilibrium (all sites considered simultaneously) were highly significant (P<0.001) in all 28 populations. Except for three African samples, the pairwise disequilibrium between the outermost RSP markers, TaqI "B" and "A", was highly significant with D' values greater than 0.8; in two of those exceptions the RSP marker was not polymorphic. Except for those same two African populations, the 16-repeat allele at the STRP also showed highly significant disequilibrium with the TaqI "B" site in all populations, with D' values usually greater than 0.7. Only four haplotypes account for more than 70% of all chromosomes in virtually all non-African populations, and two of those haplotypes account for more than 70% of all chromosomes in most East Asian and Amerindian populations. A new measure of the amount of overall disequilibrium shows least disequilibrium in African populations, somewhat more in European populations, and the greatest amount in East Asian and Amerindian populations. This pattern seems best explained by random genetic drift with low levels of recombination, a low mutation rate at the STRP, and essentially no recurrent mutation at the RSP sites, all in conjunction with an "Out of Africa" model for recent human evolution.

Alleles↗
PubMed1996

Dopamine D2 receptor (DRD2) gene and susceptibility to posttraumatic stress disorder: a study and replication.

Subjects on an addiction treatment unit who had been exposed to severe combat conditions in Vietnam were screened for posttraumatic stress disorder (PTSD). Of 24 with PTSD, 58.3% carried the D2A1 allele. Of the remaining eight who did not meet PTSD criteria, 12.5% carried the D2A1 allele (p = 0.04). In a replication study of 13 with PTSD, 61.5% carried the D2A1 allele. Of the remaining 11 who did not meet criteria for PTSD, 0% carried the D2A1 allele (p = 0.002). For the combined group 59.5% of those with PTSD carried the D2A1 allele versus 5.3% of those who did not have PTSD (p = 0.0001). These results suggest that a DRD2 variant in linkage disequilibrium with the D2A1 allele confers an increased risk to PTSD, and the absence of the variant confers a relative resistance to PTSD.

Adult↗