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標題: | Orexin系統在ADHD動物模式之注意力、衝動性、活動力及社交行為中所扮演之角色 Role of the orexin system in attention, impulsivity, locomotor activity and social interaction in SHR ─ an ADHD animal model |
作者: | Chi-Hsiang Chang 張騏翔 |
指導教授: | 邱麗珠 |
關鍵字: | 注意力,衝動,社交行為,注意力不足過動症,自發性高血壓大鼠,食慾素, attention,impulsivity,social interaction,ADHD,SHR,orexin, |
出版年 : | 2011 |
學位: | 碩士 |
摘要: | 注意力不足過動症(Attention-deficit hyperactivity disorder; ADHD)是一種在兒童期常見的認知行為失調,主要症狀為注意力不集中(inattention)、衝動(impulsivity)和過動(hyperactivity)。此病在全世界之盛行率約5%~10%,其中大約有60%的病人,其症狀會持續到成年之後。目前ADHD的動物模式種類仍有限,但自發性高血壓大鼠 (Spontaneous Hypertension Rats, SHR),已被證實是一良好之ADHD動物模式。本實驗使用SHR大鼠測試其在五洞鼻觸注意力測試儀(5-Choice Serial Reaction Time Task;5-CSRTT)、開放空間(open field)、社交行為實驗(social interaction)中之表現,並比較其對照組WKY大鼠在這些試驗中之表現
Orexins(食慾素,或稱下視丘素Hypocretins)為一種胜肽類激素,包含Orexin A和B(Hypocretin-1和2)。Orexin受體為一G蛋白偶合受體,可分為OX1和OX2兩種,其內生性致效劑為食慾素(Orexins)。最近的研究指出Orexin系統的活化可投射到基底前腦,而造成該腦區內膽鹼系統的活化以及乙烯膽鹼(acetylcholine)的釋放。普遍認為基底前腦(basal forebrain)的膽鹼系統(cholinergic system)在注意力的表現中扮演著重要角色。 因此在本研究中,藉由給予OX1受體之選擇性拮抗劑SB-334867 (5mg/kg)以及OX2受體之拮抗劑TCS-OX2-29 (10mg/kg),並以大鼠五洞鼻觸注意力測試儀(5-CSRTT)、開放空間(open field) 社交行為實驗(social interaction)等實驗來探討orexin在SHR與WKY大鼠之注意力、衝動性、活動力以及社交行為中的角色, 實驗發現: (1) SHR大鼠在5-CSRTT中表現較多錯誤率以及衝動行為。腹腔注射SB-334867 (5mg/kg) 會造成SHR以及WKY大鼠的注意力表現產生缺失,顯示此藥物引起之降低注意力之作用不具物種專一性;此外腹腔給予TCS-OX2-29 (10mg/kg) 也能夠造成一定程度之注意力缺損。 (2) SHR大鼠在開放空間中表現出過動行為。在給予SB-334867之後穿越格線(crossing)與後腿直立(rearing)之次數明顯減少;此外給予TCS-OX2-29之後後腿直立之次數明顯減少,但並不影響穿越格線之次數。 (3) SHR大鼠在社交行為實驗中表現社交行為缺損和具有攻擊性。腹腔注射SB-334867會降低WKY大鼠的社交行為時間,但不影響SHR大鼠之社交行為。 因此在本文中實驗證實不只OX1受體的拮抗能造成注意力的缺損,OX2受體可能也在注意力的機制中扮演重要的角色。此外,給予Orexin的拮抗劑可以造成活動力的減低以及社交行為的缺損,也說明了orexin系統在這些行為上具有一定程度之重要性。 Attention-deficit/hyperactivity disorder (ADHD) characterized with three main symptoms, inattention, impulsivity and hyperactivity, is a behavioral disorder affecting 5%-10% of children worldwide and remains in the adulthood in 60% of them. An ideal animal model for ADHD is lacking but spontaneous hypertension rats (SHR) has been proposed to be one. In this study, we evaluated the performance of SHR and their strain control, Wistar Kyoto rats (WKY), in the 5-choice serial reaction time task (5-CSRTT), open field test and social interaction. Orexins, consisting of orexin A and B (also named hypocretin 1or 2), are endogenous peptide agonists of a couple of G protein-coupled receptors, OX1 and OX2. Orexin neurons have been reported to project to the basal forebrain. Activation of the cholinergic system in the basal forebrain is believed to play an important role in the attention process. Therefore, in this study, we also investigated the role of endogenous orexins in attention, impulsivity, locomotor activity and social interaction in SHR and WKY by examining effects of the selective OX1 and OX2 antagonists, SB-334867 and TCS-OX2-29, respectively, on the performance of 5-CSRTT, open-field and social interaction. (1) In the 5-CSRTT, as compared with WKY, SHR displayed higher incorrect response rate and impulsivity, but had the same correct response rate. Systemic SB-334867 (5 mg/kg., i.p) significantly increased the correct latency and omission, decreased correct response in both SHR and WKY. TCS-OX2-29 (10 mg/kg., i.p) slightly decreased the correct response rate in SHR and increased the correct latency in WKY. (2) SHR also had more exploring acitivty and higher locomotor activity in the open field test than WKY. Systemic SB-334867 decreased the number of crossing and rearing in SHR. TCS-OX2-29 decreased the number of rearing. (3) In the social interaction test, SHR displayed less social exploration but had more aggressive behaviors in social interaction test than WKY. The duration of social interaction of WKY were decreased in both SB-334867 and TCS-OX2-29 treatment groups. These results suggest that endogenous orexins play a role in the performance of attention, social ability and locomotor activity in both strains and this effect is mainly mediated by OX1 receptors and also involves OX2 receptors. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/22632 |
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