• Animal cells and systems
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• v.12 no.2
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• pp.77-83
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• 2008

The canine fearfulness is a behavioral trait known to have a genetic basis. This research analyzed genetic effects of the dopamine D4 receptor polymorphism on this behavior by postulating a mixed model of inheritance. Genotyping for the three different repeat polymorphism found in the third exon of the receptor gene was carried out for the population of the Korean native dogs. Four hundred fifty eight dogs with known pedigree were genotyped, and 264 individuals were tested for their fear responses to an experimenter, in which four different behavioral paradigms were adopted. Since the results assessed by principal factor analysis revealed a major factor explaining 69% of the total phenotypic variance, the subsequent analyses were conducted for this quantity. Analyses of the factor scores by estimating their posterior means indicated that there is a fixed effect exerted by the three different repeat polymorphism found in the D4 receptor as well as sex, in addition to unidentified polygenic effects. The phenotypic contribution of the D4 genotype was roughly estimated to be about 2%, which is a fraction of the total genetic effects responsible for more than 20% of the total phenotypic variance.

• The Korean Journal of Physiology and Pharmacology
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• v.9 no.5
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• pp.263-268
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• 2005

Striatum has important roles in motor control, habitual learning and memory. It receives glutamatergic inputs from neocortex and thalamus, and dopaminergic inputs from substantia nigra. We examined effects of dopamine (DA) on the corticostriatal synaptic transmission using in vitro extracellular recording technique in rat brain corticostriatal slices. Synaptic responses were elicited by stimulation of cortical glutamatergic inputs on the corpus callosum and recorded in the dorsal striatum. Corticostriatal population spike (PS) amplitudes were decreased ($39.4{\pm}7.9$%) by the application of $100{\mu}M$ DA. We applied receptor subtype specific agonists and antagonists and characterized the modulation of corticostriatal synaptic transmission by different DA receptor subtypes. $D_2$ receptor agonist (quinpirole), antagonist (sulpiride), and $D_1$ receptor antagonist (SKF 83566), but not $D_1$ receptor agonist (SKF 38393), induced significantly the reduction of striatal PS. Pretreatment neither with SKF 83566 nor sulpiride significantly affected corticostriatal synaptic inhibition by DA. However, the inhibition of DA was completely blocked by pretreatment with mixed solution of both SKF 83566 and sulpiride. These results suggest that DA inhibits corticostriatal synaptic transmission through both $D_1$ and $D_2$ receptors in concert with each other.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.23
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• pp.10339-10343
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• 2015

Breast cancer is the most common cancer among females worldwide and a most prevalent malignancy in Iranian women. Chronic stress may make an important contribution to cancer, especially in the breast. Numerous studies showed roles of neurotransmitters in the occurrence and progression of cancers which are mediated by their various types of receptors. This study was conducted to evaluate alterations in the expression profile of dopamine receptor genes in peripheral blood mononuclear cells (PBMC) as stress factors in breast cancer patients and the human breast cancer cell line (MCF-7). Peripheral blood samples were obtained from 30 patients and 30 healthy individuals. Total mRNA was extracted from PBMC and MCF-7 cells and RT-PCR was performed to confirm the presence of five dopamine receptors (DRD1-DRD5). Expression changes of dopamine receptor genes were evaluated by real time PCR. We observed that DRD2-DRD4 in PBMCs of breast cancer patients were increased compared to healthy individuals. In addition, all dopamine receptor subtypes but DRD1 were expressed in MCF-7 cells. Therefore, alterations of these receptors as stress factors should be assessed for selecting appropriate drugs such as D2-like agonists for treatment of breast cancer after performing complimentary tests. Determining the expression profile of dopamine receptor genes thus seems promising.

• Journal of Life Science
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• v.11 no.1
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• pp.1-7
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• 2001

The caffeine intake cause a local or wide ranges of convulsion and it is associated with release of dopamine (DA) receptors into the brain striatum. However, the effect of caffeine addiction on expression of DA receptors gene in the rat caudate-putamen (CPu), nucleus accumbens (NAc), and olfactory tubercle (OTu) has not been elucidated. In this study, we examined the influence of caffeine addiction on DA D $_1$and D$_2$receptor mRNAs after the treatment of caffeine for four weeks. Using the specific antisense ribo-probes for DA D$_1$and D$_2$receptor cDNAs, in situ hybridization was performed on the CPu, NAc, and OTu of the adult male Sprague Dawely rats. In caffeine-treated group, DA D$_1$and D$_2$receptor mRNAs were highly increased in CPu, NAc, and OTu. The expression density of DA D$_1$receptor mRNAs were 2.52${\pm}$1.40 (CPu), 2.78${\pm}$1.69 (NAc), and 3.91${\pm}$1.28 (OTu) in control group and 7.76${\pm}$2.09 (CPu), 4.2 ${\pm}$1.85 (NAc), and 8.21${\pm}$1.72 (OTu) in caffeine-treated group. The expression density of DA D$_2$receptor mRNA was 2.32${\pm}$1.52 (CPu), 2.63${\pm}$2.11 (NAc), and 3.61${\pm}$1.43 (OTu) in control group, and 6.41${\pm}$1.82 (CPu), 6.89${\pm}$1.32 (NAc), and 6.82${\pm}$1.18 (OTu) in caffeine-treated group. DA D$_1$receptor mRNA was higher expressed than DA D$_2$ receptor mRNA in CPu and NAc. These results suggest that caffeine reacts as a upregulator of the expression of DA D$_1$and D$_2$receptor mRNA among the neurotransmitters.

• Biomolecules & Therapeutics
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• v.29 no.4
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• pp.392-398
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• 2021

In this study, we determined the effect of 24 different synthetic 4-benzylpiperidine carboxamides on the reuptake of serotonin, norepinephrine, and dopamine (DA), and characterized their structure-activity relationship. The compounds with a two-carbon linker inhibited DA reuptake with much higher potency than those with a three-carbon linker. Among the aromatic ring substituents, biphenyl and diphenyl groups played a critical role in determining the selectivity of the 4-benzylpiperidine carboxamides toward the serotonin transporter (SERT) and dopamine transporter (DAT), respectively. Compounds with a 2-naphthyl ring were found to exhibit a higher degree of inhibition on the norepinephrine transporter (NET) and SERT than those with a 1-naphthyl ring. A docking simulation using a triple reuptake inhibitor 8k and a serotonin/norepinephrine reuptake inhibitor 7j showed that the regions spanning transmembrane domain (TM)1, TM3, and TM6 form the ligand binding pocket. The compound 8k bound tightly to the binding pocket of all three monoamine reuptake transporters; however, 7j showed poor docking with DAT. Co-expression of DAT with the dopamine D₂ receptor (D₂R) significantly inhibited DA-induced endocytosis of D₂R probably by reuptaking DA into the cells. Pretreatment of the cells with 8f, which is one of the compounds with good inhibitory activity on DAT, blocked DAT-induced inhibition of D₂R endocytosis. In summary, this study identified critical structural features contributing to the selectivity of a molecule for each of the monoamine transporters, critical residues on the compounds that bound to the transporters, and the functional role of a DA reuptake inhibitor in regulating D₂R function.

• Journal of the Korean Academy of Child and Adolescent Psychiatry
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• v.12 no.2
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• pp.179-191
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• 2001

Objectives：This study evaluated the association between behavioral characteristics and polymorphisms in DAT1, DRD2, DRD3, and DRD4 genes. Methods：The subjects were 114 neonates, who were born by normal spontaneous vaginal delivery and had no physical problems. The behavioral characteristics were evaluated using Neonatal Behavioral Assessment Scale(NBAS) at $17.8{\pm}7.0$ hours after their birth to minimize environmental influences, and cord blood was used to analyze the gene polymorphisms. Results：In comparison to DAT1 gene 10/10 genotype group(N=93), other genotype group(N=19) showed significantly high NBAS scores on social-interaction, state organization, and state regulation. DRD2 gene Ser311/Cys311, TaqI A, and TaqI B polymorphisms showed no significant differences on NBAS scores when they were grouped by genotypes. DRD3 gene polymorphism and DRD4 gene promotor polymorphism showed no significant difference on NBAS scores when they were grouped by genotypes. In comparison to the short repeats(N=102), long repeats(N=10) in DRD4 gene showed significantly high habituation score of NBAS. Conclusion：These results suggest that the genetic effects of the neonatal behavioral characteristics may be mediated via DAT1 and DRD4 genes.

• Toxicological Research
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• v.30 no.4
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• pp.267-276
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• 2014

Exposures to lead (Pb) are associated with neurological problems including psychiatric disorders and impaired learning and memory. Pb can be absorbed by iron transporters, which are up-regulated in hereditary hemochromatosis, an iron overload disorder in which increased iron deposition in various parenchymal organs promote metal-induced oxidative damage. While dysfunction in HFE (High Fe) gene is the major cause of hemochromatosis, the transport and toxicity of Pb in Hfe-related hemochromatosis are largely unknown. To elucidate the relationship between HFE gene dysfunction and Pb absorption, H67D knock-in Hfe-mutant and wild-type mice were given drinking water containing Pb 1.6 mg/ml ad libitum for 6 weeks and examined for behavioral phenotypes using the nestlet-shredding and marble-burying tests. Latency to nestlet-shredding in Pb-treated wild-type mice was prolonged compared with non-exposed wild-types (p < 0.001), whereas Pb exposure did not alter shredding latency in Hfe-mutant mice. In the marble-burying test, Hfe-mutant mice showed an increased number of marbles buried compared with wild-type mice (p = 0.002), indicating more repetitive behavior upon Hfe mutation. Importantly, Pb-exposed wild-type mice buried more marbles than non-exposed wild-types, whereas the number of marbles buried by Hfe-mutant mice did not change whether or not exposed to Pb. These results suggest that Hfe mutation could normalize Pb-induced behavioral alteration. To explore the mechanism of repetitive behavior caused by Pb, western blot analysis was conducted for proteins involved in brain dopamine metabolism. The levels of tyrosine hydroxylase and dopamine transporter increased upon Pb exposure in both genotypes, whereas Hfe-mutant mice displayed down-regulation of the dopamine transporter and dopamine D1 receptor with D2 receptor elevated. Taken together, our data support the idea that both Pb exposure and Hfe mutation increase repetitive behavior in mice and further suggest that these behavioral changes could be associated with altered dopaminergic neurotransmission, providing a therapeutic basis for psychiatric disorders caused by Pb toxicity.

• 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.

• Bulletin of the Korean Chemical Society
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• v.34 no.11
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• pp.3467-3470
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• 2013

• Journal of Animal Science and Technology
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• v.64 no.4
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• pp.792-799
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• 2022

Dopamine (DA) is known to be a key modulator of animal behaviors. Thus, the plasma concentration of DA might be used as a biomarker for the behavioral characteristics of horses. The behavioral characteristics of horses vary depending on the breed, age, and sex. Moreover, the DA receptor genotypes are also related to horse behaviors. Thus, the aim of this study was to investigate the DA concentration variations of horse plasma by breed, age, sex, or genotype of its receptor. The horses were divided by breed into Thoroughbred (n = 13), Pony (n = 9), Warmblood (n = 4), and Haflinger (n = 5). The age variable was divided into three different groups: post-pubertal (2-5 years, n = 6), adult (6-13 years, n = 19), and aged horses (15-24 years, n = 6). The sex variable was divided into geldings (n = 8) and mares (n = 23). Approximately 10 mL of blood was collected, and an ELISA kit was used to measure the plasma concentration of DA. Polymerase chain reaction analysis was performed to identify the genetic variation in the DA D4 receptor gene (DRD4). SPSS statistical software was used for statistical analysis. The DA concentrations in geldings were significantly lower than those in mares. There was no significant difference in DA concentrations among breed and age groups. Horses with the GG and GA genotypes had significantly higher plasma concentrations of DA compared to horses with the AA genotype for the G292A gene. Briefly, the plasma concentration of DA varied depending on the sex and genotype of G292A. These factors should be considered when the concentration of DA is used as a biomarker for the behavioral characteristics of horses. In conclusion, the DA concentration or DRD4 genotype of horse plasma has the potential to be used as a biomarker that can predict the behavioral characteristics of horses.