• Biomolecules & Therapeutics
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• 제20권2호
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• pp.226-233
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• 2012

Ethanol exposure during gestational period is related to growth retardation, morphological abnormality, and even in neurological abnormalities including attention deficit/hyperactivity disorder (ADHD)-like behaviors on offspring. However, relatively little is known about the effects of maternal ethanol consumption prior to conception on their offspring. In this study, we investigated whether maternal ethanol administration during preconceptional phase produces ADHD-like behaviors in the rat offspring. Sprague-Dawley (SD) female rats were administrated ethanol via intragastric intubation with dosing regimen of 6 g/kg daily for 10 consecutive days and treated female rats then mated with non-treated male SD rats after 8 weeks. Another group subjected to the same procedure as those conducted on ethanol treated group except the saline administration instead of ethanol. Offspring was tested for their ADHD-like behaviors using open field test, Y maze test and impulsivity test that is performed in the aversive electronic foot shock paradigm. Offspring of preconceptional ethanol treated (EtOH) group showed hyperlocomotive activity, attention deficit and impulsivity. And reduction of striatal dopamine transporter (DAT) level was observed by Western blot in the EtOH group, compared to control (Con) group, while the immunohistochemical analysis exhibited increased expression of norepinephrine transporter (NET) in the frontal cortex. These results suggest that maternal ethanol consumption in the preconceptional phase induces ADHD-like behaviors in offspring that might be related to the abnormal expression of DAT and NET in rat.

• 생물정신의학
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• 제10권2호
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• pp.177-185
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• 2003

Object:We investigated the relationship between prolactin response to antipsychotics and clinical courses of psychotic symptoms and DAT gene polymorphisms. Method:Twenty-four acute psychotic inpatients completed the 12-week trial of risperidone. Serum prolactin, BPRS, ESRS and hyperprolactinemia-related symptoms were measured at baseline, 2, 4, 8 and 12 weeks after medication. The DAT gene polymorphisms were analyzed. Results:The serum prolactin was significantly increased over time. According to the prolactin level at 2-week, the subjects were divided into the severe group(serum prolactin>60ng/mL, N=15) and the mild group (serum prolactin<60ng/mL, N=9). The prolactin levels of the mild group didn't increase beyond 60ng/mL throughout 12 weeks. Severe group had slower decrement of BPRS scores than those of mild group. Six females in severe group complained of irregular menstruations, but no female in mild group. Most patients had 10 allele of DAT gene. Conclusion:This study suggests that the magnitude of prolactin elevation at the 2-week of risperidone medication is correlated with severity of hyperprolactinemia throughout treatments. Our results did not show the relationship between prolactin responses and DAT gene polymorphisms.

• Journal of the Korean Academy of Child and Adolescent Psychiatry
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• 제16권2호
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• pp.199-210
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• 2005

연구목표 : 주의력결핍과잉행동장애 (attention deficit hyperactivity disorder : 이하 ADHD)는 역학적 유전연구를 통해 강한 유전적 요인이 작용하는 질환으로 알려져 왔다. 최근에는 이에 근거하여 질환관련 취약유전자를 규명하려는 노력이 시작되었다. 본 연구는 소아정신과에 내원하여 ADHD 진단을 받은 아동과 정상 대조군을 대상으로, 도파민 운반체 유전자 제 1 형 (dopamine transporter gene type 1 ; 이하 DAT1)과 ADHD간의 연합 여부를 규명하는 것을 목적으로 하였다. 연구내용 : 본 연구의 대상이 된 ADHD 아동은 임상적인 면담과 K-SADS-PL을 통한 확진과정을 거쳐 진단되었으며, 모든 ADHD 아동을 대상으로 소아청소년 행동평가척도(Korean Child Behavior Checklist ; K-CBCL), 부모 및 교사용 코너스 척도, 듀폴 ADHD 임상척도 등 다양한 임상척도를 시행하여, 그 심각도를 평가하였다. 이러한 과정을 통해, 최종 진단된 85명의 ADHD 환아와 독립적으로 모집된 100명의 정상대조군을 대상으로 분자유전연구를 시행하였다. 각 대상으로부터 얻은 전혈 1ml로 유전자분석 (genotyping)이 시행되었고, DAT1 variable number of tandem repeat(VNTR)의 다형성을 확인하였다. 이를 통해, ADHD군과 정상군사이의 DAT1 대립유전자의 다형성 빈도차이를 분석하였고, 두 번째로, ADHD군내에서의 다형성 분포 및 유전형에 따른 임상척도, 신경심리변인과의 차이를 규명하였다. 연구결과 : 소아 환자군 및 대조군의 DAT1-VNTR 분석에서는 7, 9, 10, 11 repeat의 4가지 대립유전자가 발견되었다. 먼저 환자-대조군 모델을 적용하여, 각 대립유전자 빈도에 대하여 ADHD 환자군과 대조군 비교를 시행하였다. 그 결과, 9/10 genotype의 빈도가 환자군에서 대조군에 비해 유의하게 높은 빈도로 나타났다(p<0.05). 또한 9 repeat allele 존재여부에 따라 환아군을 나누고, 각 군에서의 주의력장애 진단시스템(attentional deficit diagnostic system ; ADS)의 결과를 비교한 결과, 9 repeat allele를 갖는 군에서 유의하게 높은 오경보 오류(commission error)점수를 보였다. 결론 : 본 연구에서는 첫째, 대조군-환자군 사이에서는 ADHD와 DAT1 9/10 genotype간에 유의한 연관관계를 보여주었다. 그리고 DAT1 9 repeat allele와 ADS결과에 대한 비교 분석에서 높은 충동성 (오경보오류)과 9 repeat allele이 연관되어 있다는 것이 확인되었다. 그러므로 본 연구 결과를 종합할 때, DAT1 9 repeat allele는 한국 아동 ADHD와 연관성이 있으며, 특히 충동성을 가진 ADHD와 유의한 연관관계를 나타낸다고 할 수 있을 것이다. 이러한 연구결과에 대해 향후 보다 큰 규모의 추시가 필요하리라 생각된다.

• Journal of Medicine and Life Science
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• 제18권3호
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• pp.41-48
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• 2021

The prevalence of attention deficit hyperactivity disorder (ADHD), a developmental neuropsychiatric disorder, is high among children and adolescents. The pathogenesis of ADHD is mediated with genetic, biological, and environmental factors. Most therapeutic drugs for ADHD have so far targeted biological causes, primarily by regulating catecholaminergic neurotransmitters. However, ADHD drugs that are clinically treated have various problems in their addictiveness and drug stability; thus, it is recommended that efficacy and safety should be secured through simultaneous prescription of multiple drugs rather than a single drug treatment. Accordingly, it is necessary to develop drugs that newly target pathogenic mechanisms of ADHD. In this study, we attempt to confirm the possibility of developing new drugs by reviewing dopamine-related developmental mechanisms of neurons and their correlation with ADHD. Histone deacetylase inhibitors (HDACi) can regulate the concentration of intracellular dopamine in neurons by expressing vesicular monoamine transporter 2 and inducing the exocytosis of neurotransmitters to the synaptic cleft, thereby promoting the development of neurons and signal transmission. This cellular modulation of HDACi is expected to treat ADHD by regulating endogenous catecholamines such as dopamine. Although studies are still in the preclinical stage, HDAC inhibitors clearly have potential as a therapeutic agent with low addictiveness and high efficacy for ADHD treatment.

• Biomolecules & Therapeutics
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• 제31권4호
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• pp.411-416
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• 2023

Methamphetamine (METH) is a powerful neurotoxic psychostimulant affecting dopamine transporter (DAT) activity and leading to continuous excess extracellular dopamine levels. Despite recent advances in the knowledge on neurobiological mechanisms underlying METH abuse, there are few effective pharmacotherapies to prevent METH abuse leading to brain damage and neuropsychiatric deficits. α-Pinene (APN) is one of the major monoterpenes derived from pine essential oils and has diverse biological properties including anti-nociceptive, anti-anxiolytic, antioxidant, and anti-inflammatory actions. In the present study, we investigated the therapeutic potential of APN in a METH abuse mice model. METH (1 mg/kg/day, i.p.) was injected into C57BL/6 mice for four alternative days, and a conditioned place preference (CPP) test was performed. The METH-administered group exhibited increased sensitivity to place preference and significantly decreased levels of dopamine-related markers such as dopamine 2 receptor (D2R) and tyrosine hydroxylase in the striatum of the mice. Moreover, METH caused apoptotic cell death by induction of inflammation and oxidative stress. Conversely, APN treatment (3 and 10 mg/kg, i.p.) significantly reduced METH-mediated place preference and restored the levels of D2R and tyrosine hydroxylase in the striatum. APN increased the anti-apoptotic Bcl-2 to pro-apoptotic Bax ratio and decreased the expression of inflammatory protein Iba-1. METH-induced lipid peroxidation was effectively mitigated by APN by up-regulation of antioxidant enzymes such as manganese-superoxide dismutase and glutamylcysteine synthase via activation of nuclear factor-erythroid 2-related factor 2. These results suggest that APN may have protective potential and be considered as a promising therapeutic agent for METH-induced drug addiction and neuronal damage.

• 대한임상독성학회지
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• 제1권1호
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• pp.21-26
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• 2003

Methamphetamine (MA) is a major drug of abuse in Korea. Currently preliminary evidence suggests that MA dependence may cause long-term neural damage in human. Repeated exposure to psychostimulants such as methamphetamine results in behavioral sensitization, a paradigm thought to be relevant to drug craving and addiction in human. Sensitization alters neural circuitry involved in normal processes of incentrive, motivation, and reward. However the precise mechanism of this behavioral sensitization has not yet been fully elucidated. Repeated use of high dose MA causes neurotoxicity which is characterized by a long-lasting depletion of striatal dopamine (DA) and tyrosin hydroxylase activity of DA, DA-transporter binding sites in the striatum. The loss of DA transporters correlates with memory problems and lack of motor coordination. DA fuels motivation and pleasure, but it' s also crucial for learning and movement. This selective review provides a summary of studies that assess the neurobiological mechanisms of MA.

• Biomolecules & Therapeutics
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• 제25권2호
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• pp.122-129
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• 2017

A diversity of synthetic cathinones has flooded the recreational drug marketplace worldwide. This variety is often a response to legal control actions for one specific compound (e.g. methcathinone) which has resulted in the emergence of closely related replacement. Based on recent trends, the nitrogen atom is one of the sites in the cathinone molecule being explored by designer type modifications. In this study, we designed and synthesized two new synthetic cathinones, (1) ${\alpha}-piperidinopropiophenone$ (PIPP) and (2) ${\alpha}-piperidinopentiothiophenone$ (PIVT), which have piperidine ring substituent on their nitrogen atom. Thereafter, we evaluated whether these two compounds have an abuse potential through the conditioned place preference (CPP) in mice and self-administration (SA) in rats. We also investigated whether the substances can induce locomotor sensitization in mice following 7 days daily injection and challenge. qRT-PCR analyses were conducted to determine their effects on dopamine-related genes in the striatum. PIPP (10 and 30 mg/kg) induced CPP in mice, but not PIVT. However, both synthetic cathinones were not self-administered by the rats and did not induce locomotor sensitization in mice. qRT-PCR analyses showed that PIPP, but not PIVT, reduced dopamine transporter gene expression in the striatum. These data indicate that PIPP, but not PIVT, has rewarding effects, which may be attributed to its ability to affect dopamine transporter gene expression. Altogether, this study suggests that PIPP may have abuse potential. Careful monitoring of this type of cathinone and related drugs are advocated.

• 대한핵의학회지
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• 제35권4호
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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.

• 대한방사성의약품학회지
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• 제9권1호
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• pp.3-8
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• 2023

Parkinson's disease is a neurodegenerative disease caused by damage to brain neurons related to dopamine. Non-clinical animal models mainly used in Parkinson's disease research include drug-induced models of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 6-hydroxydopamine, and genetically modified transgenic animal models. Parkinson's diagnosis can be made using brain imaging of the substantia nigra-striatal dopamine system and using a radiotracer that specifically binds to the dopamine transporter. In this study, ¹⁸F-N-(3-fluoropropyl)-2β-carboxymethoxy-3β-(4-iodophenyl) nortropane was used to confirm the image evaluation cutoff between normal and parkinson's disease models, and to confirm model persistence over time. In addition, the efficacy of single or combined administration of clinically used therapeutic drugs in parkinson's animal models was evaluated. Image analysis was performed using the PMOD software. Converted to standardized uptake value, and analyzed by standardized uptake value ratio by dividing the average value of left striatum by the average value of right striatum obtained by applying positron emission tomography images to the atlas magnetic resonance template. The image cutoff of the normal and the parkinson's disease model was calculated as SUVR=0.829, and it was confirmed that it was maintained during the test period. In the three-drug combination administration group, the right and left striatum showed a high symmetry of more than 0.942 on average and recovered significantly. Images using ¹⁸F-N-(3-fluoropropyl)-2β-carboxymethoxy-3β-(4-iodophenyl) nortropane are thought to be able to diagnose and evaluate treatment efficacy of non-clinical Parkinson's disease.

• Nuclear Medicine and Molecular Imaging
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• 제41권4호
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• pp.272-279
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• 2007

목적: 본 연구는 $^{123}I-FP-CIT$ SPECT을 사용하여 파킨슨증을 구성하는 각 질환군별 차이를 평가하는 것이었다 방법: 본태성진전(64.9$\pm$8.4세, 남:녀 =20:59), 알츠하이머병(69.2$\pm$10.0세, 남:녀=4.4), 파킨슨병(66.4$\pm$9.5세, 남:녀=45:82), 레이소체치매(74.6$\pm$8.4세, 남:녀 =1:8), 그리고 다계통위축증(59.7$\pm$6.7세, 남:녀 = 8:6)을 진단받은 환자 237명과 정상군 18명(60.4$\pm$10.2세, 남:녀=9:9)의 $^{123}I-FP-CIT$ SPECT 영상을 분석하였다. 도파민운반체의 표준뇌지도로 검사자의 영상을 공간정규화한 후, 관심영역을 이용하여 미상핵, 피각의 특이영역 계수와 후두엽의 비특이 영역계수를 측정하여 결합잠재능(binding potential; BP)를 계산하였다. 선조체의 특이영역 계수 및 BP는 미상핵과 피각의계수를 가중평균(weighted mean)하여 구하였다. 그리고 피각과 미상핵의 BP간 비(BP ratio of putamen to caudate;PCR)와 선조체, 미상핵, 그리고 피각의 좌우 비대칭 비(asymmetric index; ASI)를 구하였다. 경과 영상을 시행한 파킨슨병(59.3$\pm$11.2세, 남 녀 = 2:3)에서는 연간 BP 감소를 구하였다. 결과 정상군의 BP는 본태성진전이나 알츠하이머병과는 차이가 없었고, 파킨슨병, 다계통위축증, 그리고 레이소체치매보다는 유의하게 높은 값이었다(p<0.005). 정상군의 PCR은 파킨슨병보다는 통계적으로 높았고, ASI는 낮았다(p<0.005), 파킨슨병은 다경색위축증보다 유의하게 PCR값과 피각 및 선조체의 BP는 낮았으며, ASI는 높았다(p<0.05). 그러나 본태성진전과 알츠하이머병 그리고 파킨슨병과 레이소체치매 간에는 모든 변수에서 유의한 차이를 보이지 않았다. 결론: 도파민 운반체 방사성추적자인 $^{123}I-FP-CIT$와 SPECT 영상을 이용하여 파킨슨증에서 질환군에 따른 차이를 평가 할 수 있었다. $^{123}I-FP-CIT$ SPECT를 이용한 도파민 운반체 영상은 파킨슨증의 감별에 유용할 것이다.