• 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.

• 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.

• 동의생리병리학회지
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• 제17권2호
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• pp.529-541
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• 2003

Yukmijihwang-tang has been widely used as an and-aging herbal medicine for hundred years in Asian countries. Numerous studies show that Yukmijihwangtang has anti-oxidative effect both in vivo and in vitro. It has been reported that Moutan Cortex Radicis extract (MCR) was the most effective herb in Yukmijihwang-tang on undifferentiated PC12 cells upon oxidative-stressed with hydrogen peroxide. The purpose of this study is to; 1) evaluate the recovery of neuronal damage by assessing the anti-oxidant effect of MCR on PC12 cells differentiated with nerve growth factor (NGF), 2) identify candidate genes responsible for anti-oxidative effect on differentiated PC12 cells by oligonucleotide chip microarray. PC12 cells, which were differentiated by treating with NGF, were treated without or with hydrogen peroxide in the presence or absence of various concentration of MCR. Cell survival was determined by using MTS assay. Measurement of intracellular reactive oxygen species (ROS) generation was determined using the H2DCFDA assay The viability of cells treated with MCR was significantly recovered from stressed PC12 cell. In addition, wide rage of concentrations of MCR shows dose-dependent inhibitory effect on ROS production in oxidative-stressed cells. Total RNAs of cells without treatment(Control group), only treated with H₂O₂ (stressed group) and treated with both H₂O₂ and of MCR (MCR group) were isolated, and cDNAs was synthesized using oligoT7(dT) primer. The fragmented cRNAs, synthesized from cDNAs, were applied to Affymetrix GeneChip Rat Neurobiology U34 Array. mRNA of Calcium/calmodulin-dependent protein kinase II delta subunit(CaMKII), neuron glucose transporter (GLUT3) and myelin/oligodendrocyte glycoprotein(MOG) were downregulated in Stressed group comparing to Control group. P2X2-5 receptor (P2X2R-5), P2X2-4 receptor (P2X2R-4), c-fos, 25 kDa synaptosomal attachment protein(SNAP-25a) and GLUT3 were downregulated, whereas A2 adenosine receptor (A2AR), cathechol-O-methyltransferase(COMT), glucose transporter 1 (GLUT1), EST223333, heme oxygenase (HO), VGF, UI-R-CO-ja-a-07-0-Ul.s1 and macrophage migration inhibitory factor (MIF) were upregulated in MCA group comparing to Control group. Expression of Putative potassium channel subunit protein (ACK4), P2X2A-5, P2X2A-4, Interferon-gamma inducing factor isoform alpha precursor (IL-18α), EST199031, P2XR, P2X2 purinoceptor isoform e (P2X2R-e), Precursor interleukin 18 (IL-18) were downregulated, whereas MOO, EST223333, GLUT-1, MIF, Neuronatin alpha, UI-R-C0-ja-a-07-0-Ul.s1, A2. adenosine receptor, COMT, neuron-specific enolase (NSE), HO, VGF, A rat novel protein which is expressed with nerve injury (E12625) were upregulated in MCR group comparing to Stressed group. The results suggest that decreased viability and AOS production of PC12 cell by H₂O₂ may be, at lease, mediated by impaired glucose transporter expression. It is implicated that the MCR treatment protect PC12 cell from oxidative stress via following mechanisms; improving glucose transport into the cell, enhancing expression of anti-oxidative genes and protecting from dopamine cytotoxicity by increment of COMT and MIF expression. The list of differentially expressed genes may implicate further insight on the action and mechanism behind the anti-oxidative effects of herbal extract Moutan Cortex Radicis.

• 생물정신의학
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• 제13권3호
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• pp.178-190
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• 2006

목 적: 유전적 요인에 다른 금단 증상의 차이를 파악하는 것은 알코올 의존의 유전적 요인을 파악하는데 도움이 될 수 있으며, 유전적 요인에 따라 개인별 금단 증상을 예측할 수 있다. 본 연구의 목적은 유전자군의 다형성에 따른 금단 증상의 심각도 및 증상의 종류를 파악하는 것이며 이에 따른 치료적 접근을 다양하게 하는 것이다. 방 법: 대상군으로는 19세 이상 65세 이하의 남자 입원 환자 108명을 대상으로 하였고, 유전자 분포 비교를 위하여 76명의 대조군을 두었다. 금단 증상의 평가는 마지막 알코올 섭취로부터 48시간이 지난 시점에서 Clinical Institute Withdrawal Assessment for Alcohol(이하 CIWA-Ar) 척도를 사용하여 평가하였다. 도파민 수송체, 도파민 수용체(DRD2), Catechol-O-Methyltransferase(COMT) 유전자형을 분석하였다. 결 과: 나이, 교육 기간, 유전자 형에서 알코올 의존 군과 대조군 사이의 유의한 차이는 없었다. DRD2 Taq I : 동형 유전자형에서 환청 항목의 점수가, 이형 유전자형에서 CIWA-Ar 총점의 점수가 높았다. 환청 항목의 비교 위험도가 1.34이었다. DAT1 : DAT-9 대립유전자를 가지지 않은 유전자형 집단에서 발한, 불안, CIWA-Ar 총점 항목에서 높은 점수를 보였다. COMT : 유전자 빈도를 보면 이형 유전자형이 동형 유전자형에 비해 CIWA-Ar 총점의 점수가 높았다. 결 론: DRD2, DAT1, COMT 유전자 다형성은 다양한 알코올 금단 증상과 관련이 있으며, 이는 각 유전자와 관련된 신경전달 물질과 연관되어 작용하는 것으로 생각된다. 또한 금단 증상의 심각도와도 밀접한 관련이 있는 것으로 생각되어 알코올 금단 증상을 보이는 환자의 치료에 중요한 역할을 할 것으로 생각된다.

• Biomolecules & Therapeutics
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• 제22권5호
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• pp.406-413
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• 2014

to valproic acid (VPA) during pregnancy produces ASD-like core behavioral phenotypes as well as hyperactivity in offspring both in human and experimental animals, which makes it a plausible model to study ASD-related neurobiological processes. In this study, we examined the effects of two of currently available attention defecit hyperactivity disorder (ADHD) medications, methylphenidate (MPH) and atomoxetine (ATX) targeting dopamine and norepinephrine transporters (DAT and NET), respectively, on hyperactive behavior of prenatally VPA-exposed rat offspring. In the prefrontal cortex of VPA exposed rat offspring, both mRNA and protein expression of DAT was increased as compared with control. VPA function as a histone deacetylase inhibitor (HDACi) and chromatin immunoprecipitation experiments demonstrated that the acetylation of histone bound to DAT gene promoter was increased in VPA-exposed rat offspring suggesting epigenetic mechanism of DAT regulation. Similarly, the expression of NET was increased, possibly via increased histone acetylation in prefrontal cortex of VPA-exposed rat offspring. When we treated the VPA-exposed rat offspring with ATX, a NET selective inhibitor, hyperactivity was reversed to control level. In contrast, MPH that inhibits both DAT and NET, did not produce inhibitory effects against hyperactivity. The results suggest that NET abnormalities may underlie the hyperactive phenotype in VPA animal model of ASD. Profiling the pharmacological responsiveness as well as investigating underlying mechanism in multiple models of ASD and ADHD may provide more insights into the neurobiological correlates regulating the behavioral abnormalities.