跳到主要內容

臺灣博碩士論文加值系統

(3.231.230.177) 您好!臺灣時間:2021/08/04 01:42
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果 :::

詳目顯示

: 
twitterline
研究生:葉冠毅
研究生(外文):Yeh, KuanYi
論文名稱:運用99mTc-TRODAT-1單光子電腦斷層照影探討過動大鼠多巴胺轉運體的變化
論文名稱(外文):Investigating Brain Dopamine Transporter in ADHD Rat Model Using 99mTc-TRODAT-1/SPECT
指導教授:馬國興馬國興引用關係
指導教授(外文):Ma, KuoHsing
口試委員:劉江川馬國興黃文盛
口試委員(外文):Liu, JiangChuanMa, KuoHsingHuang, WenSheng
口試日期:101/05/25
學位類別:碩士
校院名稱:國防醫學院
系所名稱:生物及解剖學研究所
學門:生命科學學門
學類:生物訊息學類
論文種類:學術論文
論文出版年:2012
畢業學年度:100
語文別:中文
論文頁數:42
中文關鍵詞:過動症多巴胺轉運體單光子電腦斷層
外文關鍵詞:ADHDDATSPECT99mTc-TRODAT-1
相關次數:
  • 被引用被引用:0
  • 點閱點閱:220
  • 評分評分:
  • 下載下載:6
  • 收藏至我的研究室書目清單書目收藏:0
注意力不足過動症最主要有三項臨床上神經心理症狀,包括:活動力 過剩、注意力不集中以及衝動,因此在臨床上的治療變得十分複雜。過去 研究顯示,腦內單胺類神經傳導物質失調,可能是造成過動症的主要原 因,特別是多巴胺轉運體在紋狀體的異常表現。本研究主要目的是要在大 鼠身上建立一個99mTc-TRODAT-1/SPECT活體照影技術,並且利用此照影 模式探討過動大鼠腦內多巴胺轉運體的變化。曾經有文獻指出核醫藥物 99mTc-TRODAT-1因為難以穿越血腦障壁,不易在大鼠腦內成影,因此, 在實驗中我們將會以不傷害腦組織為前提,利用甘露糖醇誘導血腦障壁暫 時開啓。結果顯示在經過甘露糖醇前處理的狀態下99mTc-TRODAT-1與多 巴胺轉運體的特異性結合比率有顯著性的提高。另外,本實驗參考先前文 獻利用新生鼠經6-OHDA注射之動物模式來模擬過動鼠。行為測試結果顯 示,在出生後三天經過6-OHDA注射的仔鼠,在四週齡時確實會表現出過 動及注意力不集中等症狀。在照影結果部分,經過新生6-OHDA注射大鼠 99mTc-TRODAT-1與多巴胺轉運體的特異性結合比率明顯低於正常大鼠。 在本實驗中,我們成功在大鼠身上建立了99mTc-TRODAT-1/SPECT活體照 影技術,並且發現,在經過新生6-OHDA注射的大鼠,其腦內多巴胺轉運 體表現明顯降低。本研究結果利用活體照影技術,對新生後6-OHDA注射 之過動大鼠模型與過動行為提出了一個新的觀點。
Attention-Deficit/Hyperactivity Disorder (ADHD) is characterized by excessive inattention, hyperactivity, and impulsivity. Those symptoms were complicated for clinical therapy. While the levels of monoamine metabolite excreted in ADHD are often correlated, dopamine transporter/ dopaminergic abnormalities have been frequently found in striatum. The purposes of this study are to establish in vivo imaging techniques in rats, and then using the neuroimaging method to investigate the relationship between the dopamine transporter and ADHD. 99mTc-TRODAT-1/SPECT were used to imaging the ADHD rat. Previous data indicated that 99mTc- TRODAT-1 hardly penetrate rat blood brain barrier(BBB) and resulting in poorly striatial uptakes. We used mannitol to induce a temporary BBB disruption without causing brain damage to observe the 99mTc-TRODAT-1 uptakes in rat brains. That will address the possible pathophysiology and validity of 99mTc-TRODAT-1/SPECT imaging techniques in rats. Our data showed the 99mTc-TRODAT-1 SURs of the normal rats that pretreat mannitol is higher than those without mannitol. To establish ADHD model, the 6-OHDA was injected into the brain of neonatal rats(P3). The results of behavior test showed the 6-OHDA lesioned rat had higher activity than normal. In image results, the 99mTc-TRODAT-1 uptake in striatum of 6-OHDA lesioned rat was markly lower than those of control. Our results suggest that 99mTc-TRODAT-1 with mannitol may be a useful method in evaluating the change of DAT in rat and the expression of DAT are decreased in striatum of 6-OHDA lesioned rat. Our study provide useful information in developing the new drug, and have better methods of monitoring its therapeutic responses.
壹、緒言‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧1
一、注意力不足過動症理論概述‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧1
二、多巴胺神經系統簡介‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧5
三、多巴胺轉運體與注意力不足過動症之關係‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧8
四、核子醫學照影‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧11
五、血腦障壁簡介‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧13
六、目的‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧15
貳、材料與方法‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧16
一、實驗分組及實驗流程‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧16
二、注意力不足過動症動物模式建立‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧16
三、開放空間動物行為觀察‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧17
四、單光子電腦斷層照影‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧18
參、結果‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧20
一、比較正常大鼠及以6-OHDA注射新生大鼠在開放空間活動量‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧20
二、比較99mTc-TRODAT-1給與甘露糖醇前處理後鼠腦照影活性‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧23
三、比較99mTc-TRODAT-1在正常大鼠及新生6-OHDA注射大鼠腦部照影活性‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧26
肆、討論‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧29
一、新生6-OHDA注射大鼠與注意力不足過動症之關係‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧29
二、多巴胺轉運體與注意力不足過動症之關係 ‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧31
三、造成新生6-OHDA注射大鼠過動的可能原因‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧32
四、未來研究方向‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧33
伍、結論‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧34
陸、參考文獻‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧35
Abbott, N. J., L. Ronnback, et al. (2006). "Astrocyte-endothelial interactions at the blood-brain barrier." Nat Rev Neurosci 7(1): 41-53.
Arnsten, A. F. (2000). "Genetics of childhood disorders: XVIII. ADHD, Part. 2: Norepinephrine has a critical modulatory influence on prefrontal cortical function." J Am Acad Child Adolesc Psychiatry 39(9): 1201-1203.
Arnsten, A. F. (2001). "Modulation of prefrontal cortical-striatal circuits: relevance to therapeutic treatments for Tourette syndrome and attention-deficit hyperactivity disorder." Adv Neurol 85: 333-341.
Aspide, R., U. A. Gironi Carnevale, et al. (1998). "Non-selective attention and nitric oxide in putative animal models of Attention-Deficit Hyperactivity Disorder." Behav Brain Res 95(1): 123-133.
Bannon, M. J., S. K. Michelhaugh, et al. (2001). "The human dopamine transporter gene: gene organization, transcriptional regulation, and potential involvement in neuropsychiatric disorders." Eur Neuropsychopharmacol 11(6): 449-455.
Baumgardner, T. L., H. S. Singer, et al. (1996). "Corpus callosum morphology in children with Tourette syndrome and attention deficit hyperactivity disorder." Neurology 47(2): 477-482.
Berger, T. W., S. Kaul, et al. (1985). "Hyperinnervation of the striatum by dorsal raphe afferents after dopamine-depleting brain lesions in neonatal rats." Brain Res 336(2): 354-358.
Biederman, J. (2005). "Attention-deficit/hyperactivity disorder: a selective overview." Biol Psychiatry 57(11): 1215-1220.
Carlson, C. L. and M. Mann (2002). "Sluggish cognitive tempo predicts a different pattern of impairment in the attention deficit hyperactivity disorder, predominantly inattentive type." J Clin Child Adolesc Psychol 31(1): 123-129.
Castellanos, F. X., J. N. Giedd, et al. (2001). "Quantitative brain magnetic resonance imaging in girls with attention-deficit/hyperactivity disorder." Arch Gen Psychiatry 58(3): 289-295.
Castellanos, F. X. and R. Tannock (2002). "Neuroscience of attention-deficit/hyperactivity disorder: the search for endophenotypes." Nat Rev Neurosci 3(8): 617-628.
Cheon, K. A., Y. H. Ryu, et al. (2003). "Dopamine transporter density in the basal ganglia assessed with [123I]IPT SPET in children with attention deficit hyperactivity disorder." Eur J Nucl Med Mol Imaging 30(2): 306-311.
Cook, E. H., Jr., M. A. Stein, et al. (1995). "Association of attention-deficit disorder and the dopamine transporter gene." Am J Hum Genet 56(4): 993-998.
Davids, E., K. Zhang, et al. (2002). "Effects of norepinephrine and serotonin transporter inhibitors on hyperactivity induced by neonatal 6-hydroxydopamine lesioning in rats." J Pharmacol Exp Ther 301(3): 1097-1102.
Davids, E., K. Zhang, et al. (2002). "Stereoselective effects of methylphenidate on motor hyperactivity in juvenile rats induced by neonatal 6-hydroxydopamine lesioning." Psychopharmacology (Berl) 160(1): 92-98.
Davids, E., K. Zhang, et al. (2003). "Animal models of attention-deficit hyperactivity disorder." Brain Res Brain Res Rev 42(1): 1-21.
Dougherty, D. D., A. A. Bonab, et al. (1999). "Dopamine transporter density in patients with attention deficit hyperactivity disorder." Lancet 354(9196): 2132-2133.
Faraone, S. V., J. Biederman, et al. (2006). "The age-dependent decline of attention deficit hyperactivity disorder: a meta-analysis of follow-up studies." Psychol Med 36(2): 159-165.
Fisher, S. E., C. Francks, et al. (2002). "A genomewide scan for loci involved in attention-deficit/hyperactivity disorder." Am J Hum Genet 70(5): 1183-1196.
Frankle, W. G., M. Slifstein, et al. (2005). "Neuroreceptor imaging in psychiatry: theory and applications." Int Rev Neurobiol 67: 385-440.
Grillner, P. and N. B. Mercuri (2002). "Intrinsic membrane properties and synaptic inputs regulating the firing activity of the dopamine neurons." Behav Brain Res 130(1-2): 149-169.
Halmoy, A., O. B. Fasmer, et al. (2009). "Occupational outcome in adult ADHD: impact of symptom profile, comorbid psychiatric problems, and treatment: a cross-sectional study of 414 clinically diagnosed adult ADHD patients." J Atten Disord 13(2): 175-187.
Krause, K. H., S. H. Dresel, et al. (2000). "Increased striatal dopamine transporter in adult patients with attention deficit hyperactivity disorder: effects of methylphenidate as measured by single photon emission computed tomography." Neurosci Lett 285(2): 107-110.
Kung, H. F., H. J. Kim, et al. (1996). "Imaging of dopamine transporters in humans with technetium-99m TRODAT-1." Eur J Nucl Med 23(11): 1527-1530.
LaHoste, G. J., J. M. Swanson, et al. (1996). "Dopamine D4 receptor gene polymorphism is associated with attention deficit hyperactivity disorder." Mol Psychiatry 1(2): 121-124.
Lou, H. C. (1996). "Etiology and pathogenesis of attention-deficit hyperactivity disorder (ADHD): significance of prematurity and perinatal hypoxic-haemodynamic encephalopathy." Acta Paediatr 85(11): 1266-1271.
Ludolph, A. G., J. Kassubek, et al. (2008). "Dopaminergic dysfunction in attention deficit hyperactivity disorder (ADHD), differences between pharmacologically treated and never treated young adults: a 3,4-dihdroxy-6-[18F]fluorophenyl-l-alanine PET study." Neuroimage 41(3): 718-727.
Luthman, J., A. Fredriksson, et al. (1989). "Effects of d-amphetamine and methylphenidate on hyperactivity produced by neonatal 6-hydroxydopamine treatment." Psychopharmacology (Berl) 99(4): 550-557.
Ma, K. H., W. S. Huang, et al. (2009). "Validation of 4-[18F]-ADAM as a SERT imaging agent using micro-PET and autoradiography." Neuroimage 45(3): 687-693.
Milberger, S., J. Biederman, et al. (1997). "ADHD is associated with early initiation of cigarette smoking in children and adolescents." J Am Acad Child Adolesc Psychiatry 36(1): 37-44.
Moll, G. H., S. Hause, et al. (2001). "Early methylphenidate administration to young rats causes a persistent reduction in the density of striatal dopamine transporters." J Child Adolesc Psychopharmacol 11(1): 15-24.
Nigg, J. T., M. Nikolas, et al. (2010). "Confirmation and extension of association of blood lead with attention-deficit/hyperactivity disorder (ADHD) and ADHD symptom domains at population-typical exposure levels." J Child Psychol Psychiatry 51(1): 58-65.
Oades, R. D. (2008). "Dopamine-serotonin interactions in attention-deficit hyperactivity disorder (ADHD)." Prog Brain Res 172: 543-565.
Ouellet-Morin, I., K. G. Wigg, et al. (2008). "Association of the dopamine transporter gene and ADHD symptoms in a Canadian population-based sample of same-age twins." Am J Med Genet B Neuropsychiatr Genet 147B(8): 1442-1449.
Paxinos, G. and C. Watson (2007). The Rat Brainin Stereotaxic Coordinates, Sixth edition. Burlington, MA, Elsevier Inc. .
Qian, Y., G. Lei, et al. (2010). "Deficits in fine motor skills in a genetic animal model of ADHD." Behav Brain Funct 6: 51.
Roessner, V., T. Sagvolden, et al. (2010). "Methylphenidate normalizes elevated dopamine transporter densities in an animal model of the attention-deficit/hyperactivity disorder combined type, but not to the same extent in one of the attention-deficit/hyperactivity disorder inattentive type." Neuroscience 167(4): 1183-1191.
S.A., F. (2001). A review of rodent models of ADHD.
Sagvolden, T., V. A. Russell, et al. (2005). "Rodent models of attention-deficit/hyperactivity disorder." Biol Psychiatry 57(11): 1239-1247.
Streissguth, A. P., F. L. Booksteina, et al. (1995). "Attention: Prenatal alcohol and continuities of vigilance and attentional problems from 4 through 14 years." Development and Psychopathology 7(03): 419-446.
van Dyck, C. H., D. M. Quinlan, et al. (2002). "Unaltered dopamine transporter availability in adult attention deficit hyperactivity disorder." Am J Psychiatry 159(2): 309-312.
Vanbilloen, H. P., D. Kieffer, et al. (2005). "Development and biological evaluation of 99mTc-BAT-tropane esters." Nucl Med Biol 32(6): 607-612.
Vandenbergh, D. J., A. M. Persico, et al. (1992). "Human dopamine transporter gene (DAT1) maps to chromosome 5p15.3 and displays a VNTR." Genomics 14(4): 1104-1106.
Waldman, I. D., D. C. Rowe, et al. (1998). "Association and linkage of the dopamine transporter gene and attention-deficit hyperactivity disorder in children: heterogeneity owing to diagnostic subtype and severity." Am J Hum Genet 63(6): 1767-1776.
Wang, M., J. Etu, et al. (2007). "Enhanced disruption of the blood brain barrier by intracarotid mannitol injection during transient cerebral hypoperfusion in rabbits." J Neurosurg Anesthesiol 19(4): 249-256.
Yeh, C. B., S. S. Gau, et al. (2008). "Psychometric properties of the Chinese version of the adult ADHD Self-report Scale." Int J Methods Psychiatr Res 17(1): 45-54.
Zappitelli, M., T. Pinto, et al. (2001). "Pre-, peri-, and postnatal trauma in subjects with attention-deficit hyperactivity disorder." Can J Psychiatry 46(6): 542-548.
Zhang, K., E. Davids, et al. (2002). "Effects of dopamine D4 receptor-selective antagonists on motor hyperactivity in rats with neonatal 6-hydroxydopamine lesions." Psychopharmacology (Berl) 161(1): 100-106.
Zhang, K., F. I. Tarazi, et al. (2001). "Role of dopamine D(4) receptors in motor hyperactivity induced by neonatal 6-hydroxydopamine lesions in rats." Neuropsychopharmacology 25(5): 624-632.
Zhang, K., F. I. Tarazi, et al. (2002). "Plasticity of dopamine D4 receptors in rat forebrain: temporal association with motor hyperactivity following neonatal 6-hydroxydopamine lesioning." Neuropsychopharmacology 26(5): 625-633.

QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top