Lack of allelic association of dopamine D4 receptor gene polymorphisms with Parkinson's disease in a Chinese population.

Parkinson's disease (PD) is a neurodegenerative disease caused by a multitude of environmental, neurochemical, and genetic factors. The gene for human dopamine D4 receptor (DRD4) has been considered as a plausible candidate for the pathogenesis of PD. Different dopamine D4 receptor allelic forms have variable affinity toward certain neuroleptics such as clozapine, suggesting a role for dopamine D4 receptors in neurologic disorders. To test the hypothesis that the DRD4 polymorphism is associated with the susceptibility to Parkinson's disease, we have examined differences in allele frequencies of different DRD4 polymorphisms in 101 Chinese patients with PD and in 105 age-matched control subjects in Hong Kong. The DRD4 gene was analyzed by a non-radioactive polymerase chain reaction-based Southern hybridization with chemiluminescence detection. The number of polymorphic 48 base pair tandem repeats in exon 3 was identified in each study subject. The DRD4 alleles with high frequencies in the control subjects are 4-repeat allele (72.4%), 2-repeat allele (21.4%), and 7-repeat allele (3.8%) which accounted for over 97% of the total alleles in the elderly Chinese population. The most prevalent genotype in the control subjects is the 4/4 (47.6%), followed by 4/2 (38.6), 4/7 (7.6%), and 2/2 (3.0%). None of the variable number tandem repeat polymorphism showed evidence for genetic association with Parkinson's disease.     

Sex differences in clinical and genetic determinants of levodopa peak-dose dyskinesias in Parkinson disease: an exploratory study

BACKGROUND: Several factors, both clinical and genetic, may account for the risk of developing levodopa-induced peak-dose dyskinesias (PDD) in patients with Parkinson disease, but it is unclear how these factors interact for modulating the individual susceptibility for PDD. OBJECTIVE: To examine clinical and genetic risk factors for determining individual susceptibility of PDD in patients with Parkinson disease. DESIGN: Cohort study. SETTING: Referral center for Parkinson disease in Calabria, southern Italy.Patients Two hundred fifty patients with Parkinson disease were screened for the presence or absence of PDD following a short-term levodopa administration, and 215 subjects were available for further evaluations, including genotypic analysis of the CA dinucleotide short tandem repeat (CAn-STR) polymorphism located in the dopamine receptor D2 gene (DRD2). RESULTS: One hundred five patients (48.8%) exhibited PDD following short-term levodopa administration, and 110 patients (51.2%) did not. Multivariate logistic regression analysis showed that independent predictors for the occurrence of PDD were female sex, earlier age at onset of Parkinson disease, longer duration of treatment, and higher dose of levodopa. Genetic factors related to the DRD2 CAn-STR polymorphism were not independent predictors for PDD in the total population, but they had a strong protective effect on the appearance of PDD when the multivariate analysis was performed in men (odds ratio, 0.34 [95% confidence interval, 0.14-0.84]). In women, a genetic protective effect on PDD was not evident. CONCLUSIONS: Risk factors for PDD, both clinical and genetic, act in different ways for men and women. Genetic factors related to the DRD2 polymorphic status have a protective effect on PDD development in men but not in women. A female sex-related effect for the risk of PDD may be so strong that it overcomes any protective effect due to genetic factors.     

Genotype and smoking history affect risk of levodopa-induced dyskinesias in Parkinson's disease.

Parkinson's disease (PD) patients vary widely in their response to levodopa treatment, and this variation may be partially genetic in origin. We determined whether particular dopamine and opioid receptor polymorphisms were associated with risk of earlier onset of dyskinesia side effects during levodopa therapy. Smoking status was also examined. The 92 subjects were recruited from the movement disorders clinic of a neurology practice associated with a medical school. All were adult-onset PD patients who had been taking levodopa at least 5 years and/or had developed levodopa-induced dyskinesia. Carrying the G-allele of the A118G single nucleotide coding region polymorphism of the mu opioid receptor, as well as a history of never smoking, were independently associated with increased risk of earlier onset of dyskinesia (P=0.05 and 0.02, respectively). One genotype of the D2 dopamine receptor intronic dinucleotide repeat polymorphism (14 repeats/15 repeats, with frequency of 6%) was also associated with earlier dyskinesia (P=0.003). History of smoking has previously been associated with reduced risk of developing PD. Our results suggest that smoking history may also influence the response to levodopa, with contribution comparable to those of individual genes including the mu opioid receptor and D2 dopamine receptor.     

The dopamine D2 receptor gene is a susceptibility locus for Parkinson's disease.

The dopamine D2 receptor (DRD2) gene has been proposed as a candidate gene underlying several psychiatric and neurologic disorders. The aim of the present study was to examine if selected polymorphisms in the DRD2 gene are associated with Parkinson's disease (PD). We determined the allelic frequencies for four polymorphisms located in the DRD2 gene in a sample of 135 patients with PD and 202 normal control subjects. No significant difference was observed in the allelic frequencies between patients with PD and control subjects with regard to the -141C Ins/Del and the Ser311/Cys311 variants. On the contrary, the A1 allele of the TaqIA polymorphism and the B1 allele of the TaqIB polymorphism were more frequent in patients with PD than in control subjects (control subjects: TaqIA A1 = 14.6%, TaqIB B1 = 10.6%; patients with PD: TaqIA A1 = 20.7%, TaqIB B1 = 17.4%). Patients carrying the A1 allele or the B allele had an increased risk of developing PD (TaqIA, odds ratio: 1.71, 95% confidence intervals: 1.08-2.73; TaqIB, odds ratio: 1.83, 95% confidence intervals: 1.12-3.02). The TaqIA and TaqIB polymorphisms were in strong linkage disequilibrium, suggesting that these two polymorphisms convey the same information about the risk of presenting with PD. Genetic variation in the DRD2 gene may influence the risk of developing PD, thus confirming that the DRD2 gene is a susceptibility locus for PD.     

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

The density of striatal dopamine D2 receptors has been shown to vary considerably among healthy subjects. This 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 [11C]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 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.     

Sequence Variants in SLC6A3, DRD2, and BDNF Genes and Time to Levodopa-Induced Dyskinesias in Parkinson’s Disease

Levodopa-induced dyskinesias (LID) present a common but elusive complication of levodopa therapy in Parkinson’s disease (PD). In order to identify genetic factors associated with LID, 352 (213 males) levodopa-treated Israeli PD patients were genotyped for 34 polymorphisms within three candidate genes affecting dopaminergic activity and synaptic plasticity: dopamine transporter gene (DAT1 or SLC6A3) [14 single nucleotide polymorphisms (SNPs) and 40-bp variable number tandem repeat (VNTR)], DRD2 [11 SNPs and dinucleotide CA short tandem repeat (STR)], and BDNF (7 SNPs). A comparison of patients with and without LID was performed by applying a time-oriented approach, with survival analyses evaluating LID development hazard rate over time [Cox proportional hazards and accelerated failure time (AFT) lognormal models]. Overall, 192 (54.5 %) participants developed LID, with a mean latency of 5.0 (±4.5) years. After adjusting for gender, age at PD onset, duration of symptoms prior to levodopa exposure, and multiple testing correction, one SNP in SLC6A3 (with 81 % genotyping success) was significantly associated with LID latency: the C allele of the rs393795 extended the time to LID onset, time ratio?=?4.96 (95 % CI, 2.3–10.9; p?=?4.1?×?10^?5). This finding should be validated in larger, ethnically diverse PD populations, and the biological mechanism should be explored.     

Association study of dopamine D2, D3 receptor gene polymorphisms with motor fluctuations in PD.

The authors investigated the association between dopamine receptor D2, D3 gene polymorphisms, and the risk of developing motor fluctuations in PD. DRD3 BalI and MspI polymorphisms were not associated with risk of developing motor fluctuations. However, the genotypic distribution of DRD2 TaqIA polymorphism was significantly different in motor fluctuators and nonmotor fluctuators. These findings suggest that DRD2 TaqIA polymorphism may be associated with an increased risk for developing motor fluctuations in PD.     

Allelic association between the DRD2 TaqI A polymorphism and Parkinson's disease.

Genes encoding proteins involved in dopaminergic transmission have been of special interest during the evaluation of candidate genes for Parkinson's disease (PD). The dopamine D2 receptor gene (DRD2) is located on chromosome 11 q22-q23, and several polymorphisms of the gene have been described. The DRD2 gene has a TaqI A restriction fragment length polymorphism that is located in the untranslated region, approximately 10 kilobases from the 3' end of the gene. This polymorphism creates the two alleles A1 (variant) and A2. In this study, we investigated the hypothesis that a TaqI repeat fragment length polymorphism in the dopamine D2 receptor gene may be associated with PD. DNA from 72 patients with PD, classified as definite, probable, or atypical PD, and from 81 controls was genotyped by polymerase chain reaction and gel electrophoresis for the presence of the TaqI A1 polymorphism. The controls were matched for age, race, and geographic origin. There were significant differences in allelic distribution between the overall PD group and control groups (chi2 = 5.009, p = 0.025). When only patients with definite PD were considered an even more significant association was found (chi2 = 8.2121, p = 0.004). Among the overall PD group, the odds ratio for having the variant allele A1 was found to be 2.2 (95% confidence interval, [1.1; 4.4]), whereas it was calculated to be 3.0 (95% confidence interval, [1.4; 6.4]) when only patients with definite PD were considered. The current study showed that there is a statistically significant association between the DRD2 variant allele A1 and PD. This association is most pronounced in patients with definite PD and becomes nonsignificant when the clinical picture is classified as atypical PD.     

Dopamine D4 receptor gene polymorphism and personality traits in healthy volunteers

An association between long alleles of a variable number tandem repeat (VNTR) polymorphism in the dopamine receptor D4 gene and the extraversion related personality traits Excitement and Novelty Seeking has been reported in healthy subjects. In an attempt to replicate the previous findings, 256 healthy Caucasian volunteers were analysed for a potential relationship between the dopamine receptor D4 exon III VNTR polymorphism and Extraversion as assessed by the Revised Neo Personality Inventory (NEO PI-R). The present study did not yield evidence for an association between Extraversion and the dopamine receptor D4 polymorphism. Received: 8 June 1999 / Accepted: 4 April 2000     

Genetic variation analysis in parkinson disease patients with and without hallucinations: case-control study

BACKGROUND: Visual hallucinations in Parkinson disease (PD) occur in approximately one third of patients treated long-term with dopaminergic medications. In Alzheimer disease, hallucinations and psychosis have been linked to increased representations of B2/B2 homozyogotes for the dopamine receptor gene DRD1 and 1/1 or 2/2 homozygotes for DRD3. In addition, a previous study of PD patients with and without hallucinations did not show differences in D2 and D3 polymorphisms, although careful case-control matching was not performed. Another study linked the apolipoprotein E4 (APOE4) allele to hallucinations in PD. OBJECTIVE: To determine whether the frequency of dopamine receptor genetic variants and APOE alleles in patients with PD with and without chronic visual hallucinations resembles the pattern previously documented in patients with Alzheimer disease. METHODS: We conducted a case-control study of 44 patients with PD and chronic hallucinations and 44 patients with PD who had never hallucinated. Cases and controls were matched for current age and medications. DNA was isolated from blood samples and assayed for DRD1, DRD2, DRD3, DRD4, and APOE polymorphisms. Receptor polymorphisms were genotyped by polymerase chain reaction. Genotypes in hallucinators and nonhallucinators were compared using Mantel-Haenszel tests stratified by pair, and allele frequencies were compared using Wilcoxon signed rank tests within pairs. RESULTS: Neither D1 receptor genotypes (P =.37) nor allele frequencies (P =.38) differed, and there was no predominance of B2/B2 homozygotes in the hallucinators. For D3, there was a higher frequency of allele 2 (P =.047), but there was no significant difference between frequencies of homozygotes vs heterozygotes (P =.39) as reported in Alzheimer disease. D4 receptor distribution of long and short alleles did not differ between the 2 patient groups, and there were too few C alleles (3 of 86) to compare D2 allele genotypes or frequencies. For APOE, 12 cases and 12 controls carried E4 alleles (P>.99). CONCLUSIONS: With careful case-control matching, visual hallucinations in PD are not associated with the pattern seen for patients with Alzheimer disease and visual hallucinations. Furthermore, there was no association between hallucinations and APOE. Similar methods using larger sample sizes might be adapted to test whether specific dopaminergic receptor genetic variants are associated with visual hallucinations in PD. Based on our data, the DRD3 allele 2 may merit further study.     

Dopamine transporter gene polymorphism, spect imaging, and levodopa response in patients with Parkinson disease

OBJECTIVES: To assess the potential association between dopamine transporter (DAT) genotype, single photon emission CT (SPECT) measures using [123I]-N-omega-fluoropropyl-2beta-carbomethoxy-3beta-(4-iodophenyl)nortropane ([123I]-FP-CIT) of striatal dopaminergic function, and oral levodopa response pattern in a cohort of patients with Parkinson disease. METHODS: Thirty-six patients at different disease stages enrolled in the study. Each patient was examined by [123I]-FP-CIT SPECT and a standardized oral levodopa test on 2 separate days in a randomized order within 3 weeks. The main outcome variables were the specific-to-nonspecific tracer uptake ratio in the contralateral putamen for SPECT analysis; latency, duration, and magnitude of the motor effect; and presence of dyskinesias for the levodopa test. The variable number of tandem repeat (VNTR) polymorphisms of the gene coding for DAT were detected for each patient by standard methods. RESULTS: Contralateral putamen [123I]-FP-CIT uptake ratios were similar in the patients carrying the 9-copy allele (n=20) of the DAT VNTR compared with 10-repeat homozygotes (n=16). No significant difference was found in levodopa main outcome variables and dyskinesia incidence between the two groups of patients stratified by DAT VNTR polymorphism. CONCLUSIONS: The study did not identify clinically relevant in vivo DAT neurochemical function phenotypes or levodopa response patterns associated with the DAT polymorphism.     

Anatomy and function of dopamine receptors: understanding the pathophysiology of fluctuations in Parkinson's disease

The principal dopamine (DA) receptors mediating the antiparkinson effects of levodopa are D1 and D2, which are anatomically and functionally segregated. We hypothesize that DA receptor-mediated effects are critical for the development of treatment-related fluctuations in Parkinson's disease (PD). We suggest that two sequential processes occur to permit the emergence of the so-called short duration response and dyskinesias: (1) functional uncoupling of D1 and D2 receptor-mediated effects with shift to the left of the dose-response curve; and, (2) sensitization of the D1-mediated striatal output due to repetitive, primarily D1 receptor stimulation by DA. These mechanisms result in excessive, pathological inhibition of basal ganglia output neurons in the GPi producing dyskinesias and the short duration response.     

Association of VNTR polymorphisms in the MAOA promoter and DRD4 exon 3 with heroin dependence in male Chinese addicts

Objective. To explore the involvement of variable number tandem repeat (VNTR) polymorphisms in the monoamine oxidase A (MAOA) promoter and exon 3 of the dopamine D4 receptor (DRD4) gene in heroin addiction modulate the vulnerability of individuals to heroin addiction. Methods. Eight hundred and ninety-four male heroin addicts without other psychiatric disorders, were recruited as subjects. Another community 180 males were selected randomly as controls. Results. The geno-distribution of the DRD4 exon 3 VNTR polymorphism in controls was in Hardy–Weinberg equilibrium (HWEχ²=0.925), but the distribution in heroin addicts was not (HWEχ²=28.35). The long-repeat alleles of the DRD4 exon 3 VNTR polymorphism were found more frequently in the heroin addicts (P=0.019). However, the long-repeat alleles of the MAOA promoter VNTR polymorphism were not (P=0.828). No interaction between these two VNTR polymorphisms was found by using multiple logistic regression analysis (P=0.261). Conclusion. The long-repeat allelic variants (>4-repeats) and 2-repeat allele of the DRD4 exon 3 VNTR polymorphism might be risk alleles for individual vulnerability to heroin addiction in Chinese men, but the MAOA promoter VNTR polymorphism does not mean that the partial dominant inherited mode might involved in the genetics of heroin dependence.     

Genetic polymorphisms in Parkinson disease subjects with and without hallucinations: an analysis of the cholecystokinin system

BACKGROUND: Hallucinations in patients with Parkinson disease (PD), occurring in about one third of those receiving long-term dopaminergic therapy, contribute to morbidity and mortality. In matched Chinese PD subjects with and without hallucinations, the presence of the -45 C/T locus in the cholecystokinin (CCK) gene, particularly when combined with the CCK receptor, CCKAR (cholecystokinin A receptor), C polymorphism, was associated with increased hallucination risk. Because CCK gene polymorphisms vary across ethnic groups, the presence of similar associations in white PD subjects merits investigation. OBJECTIVE: To determine whether polymorphisms of CCK and CCK receptor genes are associated with hallucinations in white PD subjects. DESIGN: Case-control study of PD subjects with and without chronic hallucinations matched for age and dopaminergic medication. Genomic DNA was analyzed for CCK, CCKAR, and CCKBR (cholecystokinin B receptor) polymorphisms by polymerase chain reaction. Genotype distributions and allele frequencies were compared between groups and in matched pairs. RESULTS: Comparing matched pairs, we found more frequent representation of the CCK T allele in hallucinating PD subjects, although this finding was not statistically significant (P =.06). Of 5 cases with both CCK T and CCKAR C alleles, 4 were hallucinators. Cases and controls did not differ in CCKAR or CCKBR polymorphisms. CONCLUSIONS: Our study supports a previous association of hallucinations in PD subjects with the CCK T allele and the combined CCK T and CCKAR C allele, suggesting that the CCK system may influence the development of hallucinations in PD subjects. The lower representation of the T allele in our white sample limited our statistical power. Further assessment of the T allele as a risk factor for hallucinations would include longitudinal study of nonhallucinators to detect the evolution of hallucinations relative to T allele frequency.     

Early combination of bromocriptine and levodopa in the treatment of Parkinson's disease: a 5-year follow-up

Compared with levodopa, long-term bromocriptine treatment of parkinsonian patients for 5 years resulted in fewer fluctuations of disability and peak-dose dyskinesias, but also less improvement in parkinsonian disability. Combination of low-dose bromocriptine and levodopa resulted in a therapeutic response equal to that of levodopa alone but with fewer end-of-dose disturbances and peak-dose dyskinesias. I believe that treatment should begin promptly with a low dose of levodopa, combined with a dopamine agonist such as bromocriptine.     

A genetic association study of migraine with dopamine receptor 4, dopamine transporter and dopamine-beta-hydroxylase genes

We assessed the role of some dopamine metabolism genes in the genetic susceptibility to migraine. We performed an association study using three functional polymorphisms: a 48-base-pair (bp) tandem repeat in the D4 dopamine receptor gene (DRD4), a 40-bp tandem repeat in the dopamine transporter gene (DAT) and a dinucleotide repeat in the dopamine beta-hydroxylase (DBH) gene. Allelic and genotypic frequencies for each polymorphism were assayed in two migraine populations (93 individuals with migraine with aura (MA) and 101 with migraine without aura (MO)) and were compared with those in a control group (117 individuals). No significant differences were found between control and migraine groups for DAT and DBH polymorphisms. Instead, the distribution of alleles for the DRD4 gene in the MO group was significantly different from those in both MA and control groups, with the shortest and longest alleles being less frequent in MO. Our data indicate that MO, but not MA, shows significant genetic association with DRD4. Received: 11 July 2002 / Accepted in revised form: 2 December 2002 Correspondence to M. Mochi     

Variations in the monoamine oxidase B (MAOB) gene are associated with Parkinson's disease.

The monoamine oxidase B gene (MAOB; Xp15.21-4) is a candidate gene for Parkinson's disease (PD) given its role in dopamine metabolism and its possible role in the activation of neurotoxins. The association of MAOB polymorphisms (a [GT] repeat allelic variation in intron 2 and an A-G transition in intron 13) with Parkinson's disease (PD) was studied in an Australian cohort of 204 (male:female ratio 1.60) people with PD and 285 (male:female ratio 1.64) age- and gender-matched control subjects. Genomic DNA was extracted from venous blood and polymerase chain reaction was used to amplify the appropriate regions of the MAOB gene. The length of each (GT) repeat sequence was determined by 5% polyacrylamide denaturing gel electrophoresis and a DNA fragment analyzer, while the G-A genotype was determined using 2% agarose gel electrophoresis. The G-A polymorphism showed no association with PD (odds ratio [OR] = 0.80; p = 0.51; 95% confidence interval [CI] = 0.42-1.53). There was a significant difference in allele frequencies of the (GT) repeat allelic variation between patients and control subjects (chi2 = 20.09; p<0.01). After statistical adjustment for potential confounders using a logistic regression analysis, the (GT) repeat alleles > or =188 base pairs in the intron 2 marker of the MAOB gene were significantly associated with PD (OR = 4.60; p<0.00005; 95% CI = 1.97-10.77). The 186 base pair allele was also significantly associated with PD (OR = 1.85; p = 0.048; 95% CI = 1.01-3.42). The GT repeat in intron 2 of the MAOB gene is a powerful marker for PD in this large Australian cohort.     

Cervical dystonia is associated with a polymorphism in the dopamine (D5) receptor gene

The objective was to assess whether polymorphisms in the dopamine receptor and transporter genes are associated with development of primary cervical dystonia. A case-control allelic association study is described of 100 patients with cervical dystonia and 100 controls using polymorphisms within D1-5 receptor and dopamine transporter genes. No significant association was found between patient and control allele frequencies for polymorphisms in genes for the D1 to 4 receptors and dopamine transporter. Significant associations, however, were found for alleles 2 and 6 of the D5 receptor microsatellite. Carriage of allele 2 was associated with cervical dystonia, whereas allele 6 was overrepresented in the control group, implying a possible protective effect. The association with allele 6 remained significant after Bonferroni correction. In conclusion, the finding of a significant association with an allele in the D5 receptor gene in patients with cervical dystonia may indicate a pathogenic role of this gene (or neighbouring genes). Further studies are required to confirm this finding and to assess whether these alleles are part of distinct haplotypes associated with other polymorphisms imparting a functional effect on the D5 receptor.     

Pergolide in the treatment of patients with early and advanced Parkinson's disease

Introduced on the market in 1989, pergolide, a D1/D2 dopamine receptor agonist, is still widely prescribed for the treatment of patients with early and advanced Parkinson's disease (PD). Initially, pergolide was introduced as an adjunct therapy to levodopa treatment in patients exhibiting fluctuating motor responses and dyskinesias. Results of recent randomized controlled clinical trials in de novo patients with PD show that pergolide is able to improve parkinsonian symptoms when used as monotherapy. Moreover, preliminary results of a long-term monotherapy study in early PD suggest that pergolide is as effective as levodopa, and that a significant delay in the time of the onset of levodopa-induced motor complications can be obtained. A number of randomized studies have shown that pergolide is more effective than bromocriptine as adjunct therapy to levodopa in patients with advanced PD; the greater benefit found with pergolide could be ascribed to its action on both D1 and D2 dopamine receptors. However, controlled comparative studies with new dopamine agonists, such as ropinirole, cabergoline, and pramipexole, have not been performed yet. Interestingly, few open studies in patients with complicated PD have shown that high doses of pergolide (> 6 mg/d) are able to improve motor fluctuations and dyskinesias through a dramatic reduction of levodopa dosage. The side-effect profile of pergolide is similar to that of other dopamine agonists, and complications such as sleep attack and serosal fibrosis have been rarely reported.     

Gene variants of brain dopamine pathways and smoking-induced dopamine release in the ventral caudate/nucleus accumbens

CONTEXT: Preclinical studies demonstrate that nicotine administration leads to dopamine release in the ventral striatum. However, human studies reveal considerable interindividual variability in the extent of smoking-induced dopamine release. OBJECTIVE: To determine whether common gene variants of the brain dopamine pathway explain this observed phenotypic variability in humans. DESIGN: Blood samples were drawn to determine gene variants of dopamine system components, and positron emission tomography scanning with the radiotracer raclopride labeled with radioactive carbon (11C) was performed to measure smoking-induced dopamine release. SETTING: Academic brain imaging center. PARTICIPANTS: Forty-five tobacco-dependent smokers. INTERVENTIONS: Subjects either smoked a cigarette (n = 35) or did not smoke (n = 10) during positron emission tomography scanning. MAIN OUTCOME MEASURES: Gene variants of dopamine system components (the dopamine transporter variable nucleotide tandem repeat, D2 receptor Taq A1/A2, D4 receptor variable nucleotide tandem repeat, and catechol-O-methyltransferase Val158Met polymorphisms) and change in [11C]raclopride binding potential in the ventral caudate/nucleus accumbens on positron emission tomography scans. RESULTS: For subjects who smoked during scanning, those with at least one 9 allele of the dopamine transporter variable nucleotide tandem repeat, fewer than 7 repeats of the D4 variable nucleotide tandem repeat, and the Val/Val catechol-O-methyltransferase genotype had greater decreases in binding potential (an indirect measure of dopamine release) with smoking than those with the alternate genotypes. An overall decrease in ventral caudate/nucleus accumbens binding potential in those who smoked compared with those who did not smoke was also found but was smaller in magnitude than previously reported. CONCLUSIONS: Smokers with genes associated with low resting dopamine tone have greater smoking-induced (phasic) dopamine release than those with alternate genotypes. These findings suggest that dopamine system genotype variabilities explain a significant proportion of the interindividual variability in smoking-induced dopamine release and indicate that smoking-induced dopamine release has a genetic predisposition.