• Korean Journal of Biological Psychiatry
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• v.8 no.1
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• pp.116-122
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• 2001

Objectives : Schizophrenia manifests a variety of interindividual differences in therapeutic response to antipsychotics. This might be attributable to dopamine and serotonin receptors that a important target for various antipsychotics, and the $D_3$ receptor(DRD3) alleles they carry. The purpose of our study was to investigate whether the plasma levels of homovanillic acid(HVA) and 5-hydroxyindoleacetic acid(HIAA), and the polymorphism of DRD3 can be held as a predictor of treatment response in chronic schizophrenic patients. Methods : Therapeutic response for 116 korean schizophrenia patient treated during 48 weeks were assessed by PANSS used as the clinical symptom rating scales. The levels of concentration of HVA and 5-HIAA were examined by HPLC at baseline and at 48 weeks. We classified the polymorphism of DRD3 receptor using amplifying by polymerase chain reaction(PCR). Results : Neither concentrations of HVA and 5-HIAA nor genotype of dopamine 3 receptor were not significantly associated with the therapeutic response. But, the patients who has A1 alleles of DRD3 gene showed poor therapeutic responses. Conclusion : A1 allele of DRD3 gene is associated with poor prognosis of chronic schizophrenia.

• Korean Journal of Biological Psychiatry
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• v.4 no.2
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• pp.225-233
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• 1997

The authors attempted to examine the allelic association between the A1 allele of Dopamine $D_2$ receptor and schizophrenia, alcoholism, drug addiction in Koreans. Schizophrenic patients(n=31), alcoholism(n=65), drug addiction(n=18) and controls(n=52) were examined by case-control study for distribution of the TaqI polymorphism of the dopamine $D_2$ receptor gene in Korean population to minimize the effect of racial differencies in gene frequencies. In schizophrenics, the numbers of schizophrenics with A1A1, A1A2, A2A2 were 9(29.0%), 15(48.4%) and 7(22.6%) respectively and in alcoholics with A1A1, A1A2, A2A2 were 14(21.5%), 36(55.4%) and 15(23.1%) respectively and in drug addiction with A1A1, A1A2, A2A2 were 2(11.1%), 10(55.6%) and 6(33.3%) respectively and in controls with A1A1, A1A2, A2A2 were 4(7.6%), 24(46.2%) and 24(46.2%) respectively. The prevalence of the A1 allele in schizophrenics, alcoholics, drug addiction and controls were 77%, 76.9%, 67% and 53.8% respectively. And the frequency of the A1 allele in schizophrenics, alcoholics, drug addiction and controls were 0.53, 0.49 0.39 and 0.31 respectively. There was significant difference in the frequency of the A1 allele between schizophrenics, alcoholics and controls. We also classified our alcoholic population. For classification by severity, we used the median MAST score 30 in our samples. There was also significant difference in the frequency of the A1 allele between less severe group(0.42) and more severe group(0.57). This data suggest that the A1 allele is associated with schizophrenia and alcoholism in Koreans. Furthermore the prevalence of the A1 allele increassed in more severely affected alcoholics. The authors conclude that our data support an allelic association between the A1 allele at dopamine $D_2$ receptor and schizophrenia, alcoholism. These results suggest the A1 allele of the $DRD_2$ gene is associated with a number of behavior disorders in which it may act as a modifying gene rather than as the primary etiological agent.

• Korean Journal of Biological Psychiatry
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• v.9 no.1
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• pp.15-24
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• 2002

Even though alcoholism is a multi-factorial psychiatric disorder, it is reasonable to suppose that genetic factors play a substantial role in the manifestation of this disorder. Because alcohol is the reinforcing substance which manifests its effects through activation of the mesolimbic dopaminergic reward pathway of the brain, the gene encoding dopamine receptor subtypes can be a major natural candidate gene. Since 1990, many association studies have identified strong evidence implicating the dopamine D2 receptor(DRD2) gene in alcoholism, specifically TaqI A minor(A1) allele. Association studies have also been conducted on other dopamine receptor(DRD3 & DRD4) polymorphisms but the results have yet to be confirmed. Through a number of other approaches, each dopamine receptor gene has been investigated in association with different phenotypes in alcoholism, but further researches will be needed. In conclusion, studies in the past decade have shown that the TaqI A1 allele of the DRD2 gene is associated with alcoholism in various subject groups. Other dopamine receptor genes have since been added to the list but yet to be identified. Thus, the knowledge of these genes and their functional significance will enhance the understanding of the underlying biological mechanisms of alcoholism. Furthermore, it could lead to more helpful prevention and treatment approaches to alcoholism.

• The Korean Journal of Pharmacology
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• v.30 no.1
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• pp.87-100
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• 1994

It has been known for some time that dopamine-containing cells are existed in sympathetic ganglia, i.e., small, intensely fluorescent cells. However, its role and mechanism of action as a peripheral neurotransmitter are poorly understood so far. In the present study, an attempt was made to examine the effect of apomorphine, which is known to be a selective agonist of dopaminergic $D_2$. receptor on secretion of catecholamines (CA) from the isolated perfused rat adrenal gland. The perfusion of a low concentration of 10uM apomorphine into an adrenal vein for 20 min produced significant reduction in CA secretion induced by 5.32 mM ACh, 56 mM KCl, 100 uM DMPP and 100 uM McN-A-343. Increasing apomorphine concentration to 30 uM led to more markedly decreased CA secretion as compared to the case of 10 uM apomorphine and also did inhibit clearly CA release by $10^{-5}M$ Bay-K-8644. Furthermore, in adrenal glands preloaded with a higher dose of 100 uM apomorphine, CA releases evoked by ACh, excess $K^+$, DMPP and McN-A-343 were almost abolished by the drug. The perfusion of $3.3{\pm}10^{-5}M$ metoclopramide, which is well-known as a selective dopaminergic $D_2$ antagonist, produced significantly inhibitory effect of CA release by ACh, DMPP and McN-A-343 but did not affect that by excess $K^+$. However, preloading of 30uM apomorphine in the presence of metoclopramide did not modify the CA secretory effect of excess $K+$ and DMPP. These experimental results demonstrate that apomorphine causes dose-dependent inhibition of CA secretion by cholinergic receptor stimulation and also by membrane depolarization from the isolated perfused rat adrenal gland, suggesting that these effects appear to be exerted by inhibiting influx of extracellular calcium into the rat adrenal medullary chromaffin cells through activation of inhibitory dopaminergic receptors.

• Korean Journal of Biological Psychiatry
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• v.7 no.2
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• pp.152-158
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• 2000

Background : No association between schizophrenia and dopamine D4 receptor polymorphisms have been reported. Despite these results, it is premature to exclude the association. It has been suggested that the susceptibility to develop schizophrenia could result from variation at a number loci which may interact or coact with each other. Therefore, we investigated a possible association of combinations of exon III 48bp polymorphism[D4E3] and exon I 12bp polymorphism of the DRD4 gene [D4E1] with schizophrenia. Methods : 207 unrelated Korean schizophrenic patients and 191 healthy controls were recruited. DRD4 genotype was established using the polymerase chain reaction. Statistical analysis consisted of ${\chi}^2$ tests for Hardy-Weinberg proportions and genotypic and allelic frequencies in the patients and control groups. Results : There were no statistically significant differences in the each polymorphisms between schizophrenics and controls. And all genotype frequencies were within Hardy-Weinberg expectations. When the combinations of the polymorphism in schizophrenia and controls were compared, however, there were significant differences at $A1A2^*2/4$ in the distributions of the combinations of D4E1 and D4E3(p<0.01). Conclusions : These findings suggest that the certain combination of D4E1 and D4E3($A1A2^*2/4$) has the protective role to a susceptibility for schizophrenia.

• Journal of Life Science
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• v.15 no.1 s.68
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• pp.55-60
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• 2005

The murine dopamine receptor regulating factor (DRRF) gene is transcribed from a TATA-less promoter that has several putative Sp1 binding sites. The present investigation identifies functional transcription factors that modulate the expression of this gene, In the $D_2-expressing$ NB41A3 cells, Spl potently activates transcription from the DRRF promoter in pCAT-DRRF-1153/+17, but DRRF effectively inhibits it. Deletion of the 31 bp fragment between -1153 and -1122 decreased transcription down to about $60\%$. This fragment contains a functional API binding site. In addition, deletion of the 129 bp region between -901 and -772 further decreased transcription. The latter region has a functional AP2 binding site. Using a DRRF_AP1 (bases -1153 to -1121) probe, a specific retarded band was observed, and the unlabeled AP1 consensus competitor could effectively compete away this retarded band. In addition, using a DRRF_AP2 (bases -873 to -846), a specific retarded band was observed, and the unlabeled AP2 consensus competitor could effectively compete away this retarded band. The present observations suggest that Spl and DRRF regulate the DRRF promoter and that both API and AP2 also modulate this gene.

• The Korean Journal of Nuclear Medicine
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• v.39 no.6
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• pp.413-420
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• 2005

Purpose: Neuroreceptor PET studies require 60-120 minutes to complete and head motion of the subject during the PET scan increases the uncertainty in measured activity. In this study, we investigated the effects of the data-driven head mutton correction on the evaluation of endogenous dopamine release (DAR) in the striatum during the motor task which might have caused significant head motion artifact. Materials and Methods: $[^{11}C]raclopride$ PET scans on 4 normal volunteers acquired with bolus plus constant infusion protocol were retrospectively analyzed. Following the 50 min resting period, the participants played a video game with a monetary reward for 40 min. Dynamic frames acquired during the equilibrium condition (pre-task: 30-50 min, task: 70-90 min, post-task: 110-120 min) were realigned to the first frame in pre-task condition. Intra-condition registrations between the frames were performed, and average image for each condition was created and registered to the pre-task image (inter-condition registration). Pre-task PET image was then co-registered to own MRI of each participant and transformation parameters were reapplied to the others. Volumes of interest (VOI) for dorsal putamen (PU) and caudate (CA), ventral striatum (VS), and cerebellum were defined on the MRI. Binding potential (BP) was measured and DAR was calculated as the percent change of BP during and after the task. SPM analyses on the BP parametric images were also performed to explore the regional difference in the effects of head motion on BP and DAR estimation. Results: Changes in position and orientation of the striatum during the PET scans were observed before the head motion correction. BP values at pre-task condition were not changed significantly after the intra-condition registration. However, the BP values during and after the task and DAR were significantly changed after the correction. SPM analysis also showed that the extent and significance of the BP differences were significantly changed by the head motion correction and such changes were prominent in periphery of the striatum. Conclusion: The results suggest that misalignment of MRI-based VOI and the striatum in PET images and incorrect DAR estimation due to the head motion during the PET activation study were significant, but could be remedied by the data-driven head motion correction.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1993.04a
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• pp.93-93
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• 1993

도파민 D 수용체 및 5-HT 수용체 차단기전을 지닌 새로운 항정신분열증 약물인 risperidone은 활성형 대사물로 9-OH risperidone을 체내에서 생성하는 바, 이 대사과정의 유전적 다형성의 여부 즉 hydroxylation 과정에 CYPIID6의 관여 여부를 검토코자 하였다. Metoprolol 100 mg 경구투여로 CYPIID6의 대사능의 표현형을 결정한 12명의 정상 피험자(11명: extensive metabolizer, 1명: poor metabolizer)를 대상으로 하였으며, 피험자는 risperidone 1 또는 2 mg 경구투여후 혈중 risperidone 및 9-OH risperidone 농도를 경시적으로 radioimmunoassay법으로 측정하였다. 이들 피험자중 6명의 extensive metabolizer는 quinidine 600 mg/day의 용량 투여로 CYPIID6의 활성도를 완전 억제시킨 후 risperidone 1 mg 경구투여에 따른 약동학적 성상을 재검토하여 risperidone hydroxylation에 CYPIID6의 관여 여부를 검토하였다. 1) 1명의 poor metabolizer는 extensive metabolizer에 비해 현저히 긴 risperidone 반감기를 보였다. 2) 12명의 피험자에서 관찰된 metoprolol metabolic ratio는 risperidone 혈장 반감기 및 log(risperidone AUC/9-OH-risperidone AUC)와 유의한 상관성을 나타내었다. 3) Quinidine 투여는 risperidone의 반감기의 유의한 증가와 9OH risperidone AUC의 현저한 감소를 보였으나, 9-hydroxylation 대사과정이 완전히 억제되지는 않았다.

• Korean Journal of Biological Psychiatry
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• v.20 no.3
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• pp.91-96
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• 2013

Objectives The aim of this study is to evaluate the association between rs6280 and rs905568 genetic polymorphism of DRD3 gene and the treatment response of amisulpride. Methods After six weeks treatment of amisulpride, 125 schizophrenia patients were interviewed based on the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impression-Severity (CGI-S). The genotyping for rs6280 and rs905568 was performed using TaqMan single nucleotide polymorphism (SNP) genotyping assay. Results There was no significant difference in the frequency of genotype and allele of rs6280 between the responders and non-responders based on the total, positive, and general score of PANSS and CGI-S score. However, there was a significant association between this SNP and treatment response in the negative score of PANSS (${\chi}^2=5.23$, p = 0.022). There was no significant association between rs905568 and the response in positive, negative, general, and total PANSS score and CGI-S score. Conclusions This is the first positive association study between DRD3 gene and the treatment response of negative symptoms to amisulpride in Korean schizophrenia patients. A larger scale research on more SNP of the DRD3 gene will make a progress in the study of pharmacogenetics on the treatment response of the amisulpride.

• Korean Journal of Biological Psychiatry
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• v.18 no.3
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• pp.119-125
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• 2011

Objective It has been suggested that the dopamine D2 receptor gene (DRD2) is associated with pathological gambling (PG). We investigated the association of the DRD2 Taq1A polymorphism and the temperament in PG using Cloninger's temperament and characteristic inventory (TCI). Methods 104 PG patients and 114 control subjects were recruited. Tests for DRD2 Taq1A polymorphism were conducted in both PG patients and controls. PG patients were requested to complete the TCI. Results There were no significant differences in frequencies of the genotype (${\chi}^2$ = 0.77, p = 0.681), allele (${\chi}^2$ = 0.52, p = 0.469), and allele (A1) carrier (${\chi}^2$ = 0.15, p = 0.695) between the PG patients and the control group. When we compared the TCI profile in the PG patients according to genotypes, there were significant differences in harm-avoidance (HA, p = 0.033), and self-directedness (SD, p = 0.012) among genotypes. These difference were more evident between A1 allele carriers and non-carriers (HA, p = 0.009 and SD, p = 0.004). Conclusion Present results suggest Taq1A polymorphism may not play an important role in the susceptibility to pathological gambling in our population. However, Taq1A polymorphism might be associated with some temperament in Korean PG patients.