• Biomolecules & Therapeutics
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• v.31 no.6
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• pp.692-699
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• 2023

The lack of molecular targets hampers the treatment of triple-negative breast cancer (TNBC). In this study, we determined the cytotoxicity of domperidone, a dopamine D2 receptor (DRD2) antagonist in human TNBC BT-549 and CAL-51 cells. Domperidone inhibited cell growth in a dose- and time-dependent manner. The annexin V/propidium iodide staining showed that domperidone induced apoptosis. The domperidone-induced apoptosis was accompanied by the generation of mitochondrial superoxide and the down-regulation of cyclins and CDKs. The apoptotic effect of domperidone on TNBC cells was prevented by pre-treatment with Mito-TEMPO, a mitochondria-specific antioxidant. The prevention of apoptosis with Mito-TEMPO even at concentrations as low as 100 nM, implies that the generation of mitochondrial ROS mediated the domperidone-induced apoptosis. Immunoblot analysis showed that domperidone-induced apoptosis occurred through the down-regulation of the phosphorylation of JAK2 and STAT3. Moreover, domperidone downregulated the levels of D2-like dopamine receptors including DRD2, regardless of their mRNA levels. Our results support further development of DRD2 antagonists as potential therapeutic strategy treating TNBC.

• Biomolecules & Therapeutics
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• v.25 no.6
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• pp.578-585
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• 2017

Recently, there has been a rise in the number of amphetamine derivatives that serve as substitutes for controlled substances (e.g. amphetamine and methamphetamine) on the global illegal drug market. These substances are capable of producing rewarding effects similar to their parent drug. In anticipation of the future rise of new and similar psychoactive substances, we designed and synthesized four novel amphetamine derivatives with N-benzyl, N-benzylamphetamine HCl (NBNA) substituent on the amine region, 1,4-dioxane ring, ethylenedioxy-amphetamine HCl (EDA), methyl, para-methylamphetamine HCl (PMEA), and naphthalene, 2-(aminopropyl) naphthalene HCl (2-APN) substituents on the phenyl site. Then, we evaluated their abuse potential in the conditioned place preference (CPP) test in mice and self-administration (SA) test in rats. We also investigated the psychostimulant properties of the novel drugs using the locomotor sensitization test in mice. Moreover, we performed qRT-PCR analyses to explore the effects of the novel drugs on the expression of D1 and D2 dopamine receptor genes in the striatum. NBNA, but not EDA, PMEA, and 2-APN, induced CPP and SA in rodents. None of the test drugs have produced locomotor sensitization. qRT-PCR analyses demonstrated that NBNA increased the expression of striatal D1 dopamine receptor genes. These data indicate that NBNA yields rewarding effects, suggesting potential for abuse. Continual observation for the rise of related substances is thus strongly encouraged.

• Korean Journal of Biological Psychiatry
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• v.24 no.1
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• pp.32-38
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• 2017

Objectives This study was aimed to investigate the association between amisulpride-induced hyperprolactinemia and the Taq1A polymorphism in the D2 dopamine receptor gene (DRD2) in schizophrenic patients. Methods The plasma concentrations of prolactin were measured before and after treatment with amisulpride in one hundred and twenty-five schizophrenic patients. The effect of the Taq1A variants of the DRD2 on the risk of amisulpride-induced hyperprolactinemia was the main the outcome measure. The genotyping for Taq1A (rs1800497) polymorphism was performed using TaqMan single nucleotide polymorphism (SNP) genotyping assay. Results There was a significant difference between the prolactin level at baseline and the 6th week after treatment with amisulpride in all the subjects. However, there were no significant correlations between ΔProlactin (the difference between prolactin level at baseline and the 6th week after treatment) and the Taq1A genotypes. Conclusions This is the first study to investigate the-correlations between the Taq1A polymorphism and the amisulpride-induced hyperprolactinemia in Korean schizophrenic patients. The current results suggested the further large-scale researches on various SNPs in the DRD2 gene will establish clear goals and provide answers to the unanswered questions described in this study.

• Journal of Life Science
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• v.32 no.1
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• pp.29-35
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• 2022

This study was conducted to analyze the genetic polymorphisms of dopamine receptor D4 (DRD4) in horse breeds and its association with substrate characteristics in Jeju crossbreds (Jeju Horse × Thoroughbred). Polymorphisms in DRD4 are candidate genes associated with temperament in various mammals, including humans. Single nucleotide polymorphism (SNP) G292A in the exon 3 region of the horse DRD4 has a reported association with curiosity and vigilance in thoroughbreds. Sanger sequencing was used to identify polymorphisms of the mutations in DRD4 in three horse breeds. The SNP frequency in Jeju horses was significantly different from the frequency in other breeds. Character evaluation, conducted in the Jeju crossbreds and scored using a temperament test and contact test, revealed a high correlation between each test. Comparison of the polymorphism in the DRD4 of horses and the results of the character evaluation revealed lower scores for all temperaments in horses carrying allele A. Comparison of the SNP of G292A and blood dopamine levels in Jeju crossbreds showed 2.87 times higher levels for the GA type than for the GG type. This study identified an association between DRD4 polymorphism and various test methods for evaluating horse temperament and levels of neurotransmitters. Further research could validate the use of this gene as a genetic marker for character evaluation.

• The Korean Journal of Nuclear Medicine Technology
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• v.14 no.2
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• pp.104-109
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• 2010

Purpose: $[^{18}F]$Fallypride plays an effective radiotracer for the study of dopamine $D_2/D_3$ receptor occupancy, neuropsychiatric disorders and aging in humans. This tracer has the potential for clinical use, but automated labeling efficiency showed low radiochemical yields about 5~20% with relatively long labelling time of fluorine-18. In present study, we describe an improved automatic synthesis of [$^{18}F$]Fallypride using different base concentration for routine clinical use. Materials and Methods: Fully automated synthetic process of [$^{18}F$]Fallypride was perform using the TracerLab $FX_{FN}$ synthesizer under various labeling conditions and tosyl-fallypride was used as a precursor. [$^{18}F$]Fluoride was extracted with various concentration of $K_{2.2.2.}/K_2CO_3$ from $^{18}O$-enriched water trapped on the ion exchange cartridge. After azeotropic drying, the labeling reaction proceeded in $CH_3CN$ at $100^{\circ}C$ for 10 or 30 min. The reaction mixture was purified by reverse phase HPLC and collected organic solution was exchanged by tc-18 Sep-Pak for the clinically available solution. Results: The optimal labeling condition of [$^{18}F$]Fallypride in the automatic production was that 2 mg of tosyl-fallypride in acetonitrile (1 mL) was incubated at $100^{\circ}C$ for 10 min with $K_{2.2.2.}/K_2CO_3$ (11/0.8 mg). [$^{18}F$]Fallypride was obtained with high radiochemical yield about $66{\pm}1.4%$ (decay-corrected, n=28) within $51{\pm}1.2$ min including HPLC purification and solid-phase purification for the final formulation. Conclusion: [$^{18}F$]Fallypride was prepared with a significantly improved radiochemical yield with high specific activity and shorten synthetic time. In addition, this automated procedure provides the high reproducibility with no synthesis failures (n=28).

• BMB Reports
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• v.31 no.3
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• pp.264-268
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• 1998

Dopamine (DA) acts on swimming motor neurons (SMNs) of Polyorchis penicillatus as an inhibitory neurotransmitter by hyperpolarizing their membrane potentials, which results from the activation of voltagesensitive potassium channels mediated through a $D_2-type$ receptor. In addition, DA, and not the hyperpolarized membrane potential, directly decreased the input resistance of SMNs by ca. 50% from 1.42 to 0.68 $G{\Omega}$. It strongly indicates that DA can shunt other excitatory synaptic signals onto SMNs where DA usually elicited much greater responses in their neurites than soma. All these evidences suggest that DA may operate in this primitive nervous system in dual modes as an inhibitory neurotransmitter and neuromodulator as well.

• The Korean Journal of Nuclear Medicine
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• v.35 no.4
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• pp.258-267
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• 2001

Purpose/Methods: Repeated administration of methamphetamine (METH) produces high extracellular levels of dopamine (DA) and subsequent striatal DA terminal damage. The effect of MK-801, a noncompetitive N-methyl-D-aspartate receptor antagonist, on METH-induced changes in DA transporter (DAT) and DA release evoked by an acute METH challenge was evaluated in rodent striatum uslng $[^3H]$]WIN 38,428 ex vivo auto-radiography and in vivo microdialysis. Results: Four injections of METH (10 mg/kg, i.p.), each given 2 h apart, produced 71% decrease in DAT levels in mouse striatum 3 d after administration. Pretreatment with MK-801 (2.5 mg/kg, i.p.) 15 min before each of the four METH injections protected completely against striatal DAT depletions. Four injections of MK-801 alone did not significantly change striatal DAT levels. Striatal DA release evoked by an acute METH challenge (4 mg/kg, i.p.) at 3 d after repeated administration of METH in rats was decreased but significant compared with controls, which was attenuated by repeated pretreatment with MK-801. Also, repeated injections of MK-801 alone attenuated acute METH-induced striatal DA release 3 d after administration. Conclusion: These results suggest that repeated administration of MK-801 may exert a preventive effect against METH-induced DA terminal injury through long-term attenuation of DA release induced by METH and other stimuli.

• Korean Journal of Biological Psychiatry
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• v.20 no.2
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• pp.29-30
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• 2013

First-line therapy of depression is a pharmacological treatment. Many prescribed antidepressants modulate monoamine neurotransmitters including serotonin, norepinephrine and dopamine. Recently, Ketamine, an N-methyl-D-aspartate receptor antagonist, has received attention and has been investigated for clinical trials and neurobiological studies. Here, I introduce ketamine as a rapid-acting antidepressant.

• Biomolecules & Therapeutics
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• v.23 no.3
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• pp.218-224
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• 2015

Endocannabinoids can affect multiple cellular targets, such as cannabinoid (CB) receptors, transient receptor potential cation channel, subfamily V, member 1 (TRPV1) and peroxisome proliferator-activated receptor ${\gamma}$($PPAR{\gamma}$). The stimuli to induce adipocyte differentiation in hBM-MSCs increase the gene transcription of the $CB_1$ receptor, TRPV1 and $PPAR{\gamma}$. In this study, the effects of three endocannabinoids, N-arachidonoyl ethanolamine (AEA), N-arachidonoyl dopamine (NADA) and 2-arachidonoyl glycerol (2-AG), on adipogenesis in hBM-MSCs were evaluated. The adipocyte differentiation was promoted by AEA whereas inhibited by NADA. No change was observed by the treatment of non-cytotoxic concentrations of 2-AG. The difference between AEA and NADA in the regulation of adipogenesis is associated with their effects on $PPAR{\gamma}$ transactivation. AEA can directly activate $PPAR{\gamma}$. The effect of AEA on $PPAR{\gamma}$ in hBM-MSCs may prevail over that on the $CB_1$ receptor mediated signal transduction, giving rise to the AEA-induced promotion of adipogenesis. In contrast, NADA had no effect on the $PPAR{\gamma}$ activity in the $PPAR{\gamma}$ transactivation assay. The inhibitory effect of NADA on adipogenesis in hBM-MSCs was reversed not by capsazepine, a TRPV1 antagonist, but by rimonabant, a $CB_1$ antagonist/inverse agonist. Rimonabant by itself promoted adipogenesis in hBM-MSCs, which may be interpreted as the result of the inverse agonism of the $CB_1$ receptor. This result suggests that the constantly active $CB_1$ receptor may contribute to suppress the adipocyte differentiation of hBM-MSCs. Therefore, the selective $CB_1$ agonists that are unable to affect cellular $PPAR{\gamma}$ activity inhibit adipogenesis in hBM-MSCs.

• Korean Journal of Biological Psychiatry
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• v.5 no.1
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• pp.138-141
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• 1998

Neuroleptic malignant syndrome (NMS) is an uncommon but potentially fatal idiosyncratic reaction to neuroleptics, characterized by muscular rigidity, fever, autonomic dysfunction, and altered consciousness. The major theories to explain NMS is central dopaminergic blockade, but it is unclear. Risperidone is a new antipsychotic drug, a benzisoxazole derivative that blocks dopamine $D_2$ receptor and serotonin type 2 receptor. The comparatively greater serotonin-blocking activity is believed to give risperidone the specific property of not causing any more extrapyramidal side effects than conventional antipsychotics at the optimal dose of 4-8mg/day. It is postulated that risperidone is unlikely to cause NMS. Here, we report a case of risperidone induced neuroleptic malignant syndrome.