摘要
研究背景
注意缺陷多动障碍(attention-deficit/hyperactivity disorder,ADHD)是儿童时期最常见的神经行为发育障碍性疾病。主要表现为与患儿年龄不相称的注意力易分散、注意广度缩小、不分场合的过度活动、情绪冲动并常伴有认知障碍、品行障碍和学习困难等。ADHD的发病率较高,国外报道学龄儿童的患病率为3%-5%,男孩患病率高于女孩,二者的比例为4:1-9:1。由于其症状多在学龄期出现,因此数十年来ADHD被认为是一种局限于儿童、青少年的行为问题。但是到20世纪80年代初,相继有许多学者对ADHD进行了追踪研究,结果发现10%-60%的ADHD患者到青春期后,其症状尤其是社会功能并未缓解,只是ADHD的临床表现形式发生了变化,而且出现了更多的共患病和社会问题,对患者的学业、家庭和社会生活等方面产生了明显不良的影响。因此,ADHD已经越来越引起人们更广泛地关注。
中枢兴奋药在临床上已经成为治疗ADHD的一线用药,最常用的是盐酸哌甲酯(利他林)。然而在临床上大约有20%-30%的患者使用MPH治疗效果差甚至无效,不能达到症状的控制。还有一部分患者因不能耐受MPH的副作用(睡眠障碍、食欲降低、头痛、抽搐等)而减少药量甚至停药,也不能达到临床控制。另外由于中枢兴奋药物远期疗效的局限性和潜在的滥用危险,一些家庭拒绝中枢兴奋药物的治疗。因此进一步深入研究ADHD的发病机制,寻求新的药物靶点是至关重要的,也是这一领域的研究热点。
由于在人体研究许多因素受限,动物模型可以客观观察评价ADHD的症状,可以直接从脑组织采集标本,监测在不同行为状态,症状的缓解或恶化时期相应的脑组织结构、功能以及各种神经递质生化的改变;可以妥善地控制遗传和环境因素,因而实验可取得较好的重复性和反应的一致性;与疾病有关的直接病因和影响因素可以在动物身上再现,从而了解其在该病发病过程中的作用。因此,建立理想的动物模型对于研究ADHD的病因和发病机理有重要价值。
幼年自发性高血压大鼠(spontaneously hypertensive rat,SHR)有很多特点类似ADHD患者的临床表现,如在新奇环境中活动过度、在固定间歇/消退强化实验中反应过度、操作任务完成困难等,而且研究表明其纹状体和伏隔核的多巴胺受体的密度是增高的,这与ADHD患者多巴胺失调假说是相一致的。虽然有研究者置疑,SHR作为自发性高血压模型,高血压会产生一定的混杂效应,但更多学者认为,SHR大鼠在4周龄即表现多动,高血压在12周龄才出现,因此多动并非是高血压所致。而且有人专门从效标效度、结构效度和预测效度三个方面对SHR进行论证,结果表明幼年SHR是迄今最理想的ADHD动物模型。
尽管ADHD的病因和发病机制还不十分明确,但是大量的实验研究表明ADHD的发病可能与投射到额叶和前额叶皮层的儿茶酚胺通路功能障碍有关。在遗传学水平上,通过对家系和孪生子的研究发现ADHD具有很强的遗传倾向,初步研究认为ADHD与D1R的多态性有关。探讨ADHD与多巴胺能系统之间的关系更进一步的研究是基于几个间接的多巴胺能激动剂对ADHD治疗的有效性,学者们提出了ADHD发病地多巴胺失调假说。在脑内多巴胺通过激活D1和D2两个不同的受体家族来介导其作用。多巴胺D1受体(D1R)在前额叶皮层和纹状体有很高的表达,而且其对额叶纹状体通路介导的活动和认知功能有着重要的调节作用,而ADHD患者则表现为这两个功能的缺陷。那么D1R在ADHD发病中起着怎样的作用,D1R激动剂又会对ADHD产生怎样的影响机制又是怎样的呢?
目的
利用Wista-Kyoto大鼠(WKY)作为对照组初步观察幼年SHR大鼠对注意缺陷多动障碍临床特征的再现性,以评估其作为ADHD模型的有效性。观察完全选择性多巴胺D1受体激动剂SKF-81297对幼年SHR/WKY大鼠活动及其认知的影响并通过研究其对脑内多巴胺D1受体表达、早期反应基因及神经元可塑性相关因子的影响初步探讨SKF-81297介导幼年SHR大鼠行为学变化的分子生物学机制,为ADHD的治疗寻找可能的药物靶点。
方法
1.观察幼年SHR/WKY大鼠对注意缺陷多动障碍临床特征的再现性。应用动物行为学原理,采用开场试验、Lat迷宫、morris水迷宫、Y迷宫试验方法,初步观察动物自主活动、非选择性注意、视觉—空间学习记忆及工作记忆等方面的行为特征。所有行为检测均用摄像机连续拍摄后离线分析。
2.研究完全选择性D1R激动剂SKF-81297对幼年SHR/WKY大鼠活动水平及空间学习记忆的影响。5周龄雄性SHR大鼠和WKY大鼠随机分为SHR对照组、SHR药物组、WKY对照组以及WKY药物组。药物组各24只,对照组各6只。药物组随机分为A(低剂量组)、B(中剂量组)、C(高剂量组)三组,每组8只,每天腹腔注射SKF-81297(0.5mg/kg,5mg/kg,10mg/kg),对照组注射同等体积的生理盐水。在连续用药2周后用开场试验和morris水迷宫检测其活动水平及视觉-空间学习和记忆的变化。
3.探讨完全选择性多巴胺D1受体激动剂SKF-81297对SHR/WKY大鼠前额叶皮层中多巴胺D1受体、早期反应蛋白及神经元可塑性相关因子的影响。将5周龄的SHR和WKY大鼠按照上述剂量用药2周后。一部分大鼠断头取脑用实时定量RT-PCR检测其D1RmRNA、BDNFmRNA、ARCmRNA的表达,用western-blot检测其早期反应基因蛋白及calcyon蛋白的定量表达,其余大鼠及相应对照组过量麻醉后灌注固定,用于免疫组织化学检测早期反应基因蛋白及calcyon蛋白在前额叶皮层中的定性表达情况。
结果
1.(1)开场实验中SHR大鼠穿越格子数及直立次数均较对照组WKY大鼠显著增多,提示SHR大鼠较对照组WKY大鼠活动明显增多;(2)Lat迷宫中SHR大鼠在0-5分钟、15-20分钟、25-30分钟各个时间段SHR大鼠穿越角落的频数均较WKY大鼠显著增加,提示SHR大鼠不但在新奇环境中,而且在熟悉环境中的自发活动水平也较WKY大鼠显著增加;在Lat迷宫的30分钟及上述三个时间段内SHR大鼠的直立或者两前足斜搭在墙上的频率数均显著高于WKY大鼠,提示SHR大鼠的非选择性注意水平也高于对照WKY大鼠;(3)morris水迷宫试验结果显示,SHR大鼠和WKY大鼠的学习能力并无显著差异,记忆测试时SHR大鼠在目的象限停留的时间停留的时间与WKY组相比缩短,说明SHR大鼠存在空间记忆力的缺陷(4)Y迷宫中SHR大鼠在训练阶段和保持阶段的错误次数均明显高于WKY大鼠,说明SHR大鼠存在明显的工作记忆的缺陷。
2.SKF-81297对幼年SHR大鼠活动水平及空间学习记忆的影响。
2.1对活动水平的影响:在连续用药14天后,低剂量组(0.5mg/kg)SHR与WKY大鼠在测试的5-20min时段均表现为活动水平的明显增加,而且刻板行为也是明显增加的,而仅在测试的25-40min表现为直立次数的增加。中等剂量组(5mg/kg)仅在测试25-40min表现了活动水平的增加,同时明显增加了两类大鼠的刻板行为。而在观察的三个时段都明显增加了SHR大鼠的直立次数,仅在5-20min减少了WKY大鼠的直立次数。在高剂量组对SHR/WKY大鼠的活动水平产生了双时相的影响即表现为开始阶段的抑制和随后的兴奋。在抑制阶段,没有增加动物的刻板行为,而兴奋阶段同时引起了动物刻板行为的明显增加。而在测试的5-20min和25-40min时段明显降低了SHR大鼠的直立次数,而在WKY大鼠则仅表现为25-40min直立次数的减少。
2.2对空间学习记忆的影响:在连续用药14天后,在morris水迷宫4天的定向航行试验中,各组大鼠找到平台的潜伏期与对照组相比没有明显差异,说明SKF-81297对动物的空间学习能力没有明显的影响。第5天的探索试验,与对照组相比较SHR/WKY大鼠在目标象限停留的时间均明显增长,说明SKF-81297明显改善了大鼠的空间记忆水平。
3.SKF-81297对SHR/WKY大鼠前额叶皮质多巴胺D1受体、早期反应基因及神经元重塑因子的影响
3.1免疫组化及Western-blot的试验结果表明,SKF-81297在各个剂量都不同程度的增加了SHR/WKY大鼠的c-fos、fosB及calcyon的表达。
3.2实时定量PCR结果显示,在SHR/WKY大鼠的额叶皮层D1RmRNA和GDNFmRNA的表达呈剂量依赖性的增高,而SKF-81297对arcmRNA的表达则没有明显的影响。
结论
1.SHR大鼠在多动、注意力障碍、学习认知障碍等方面很好的再现了ADHD的行为特征;利用开场实验、Lat迷宫、morris水迷宫以及Y迷宫多种行为学方法组合可以简单有效的从多动、注意障碍、学习记忆等方面对SHR大鼠ADHD模型有效性加以评估,为下一步的研究莫定基础。
2.SKF-81297不同的剂量以及观察的不同时间都对SHR/WKY大鼠的活动水平产生了一定的影响;SKF-81297可以明显改善SHR/WKY大鼠的空间记忆能力,并且在中等剂量时改善效果最明显,初步说明了适当的多巴胺D1受体的激活对动物的认知功能有着重要的作用。
3.SKF-81297不同程度的提高了SHR/WKY大鼠前额叶皮质中多巴胺D1受体、BDNF、calcyon以及c-fos、fosB的表达,说明SKF-81297在调整前额叶的功能中发挥着重要的作用,而多巴胺D1受体、神经元可塑性相关因子BDNF以及多巴胺D1受体调节蛋白calcyon参与了这一调节的过程,从而最终介导了SHR/WKY大鼠行为的一系列变化。
Background
Attention-Deficit Hyperactivity Disorder (ADHD) is one of the most common chronic neurobehavioural disease encountered in child development. It is characterized by symptoms of developmentally inappropriate inattention, distractibility ,excessive motor activity and impulsivity ofen accompany with behavioural problems and cognitive deficits. It affects 3%-5% of the school-aged population worldwide. The disorder occurs more frequently in males than females, with male-to female ratios ranging from 4:1 to 9:1 on setting. ADHD is most ofen diagnosed during childhood and therefore, over the last decade, it was regarded as a disease which is belong to children. But follw up studies have indicated that 10%-60% of patients continue to suffer from ADHD during late adolescence and adulthood. These children are at risk for developing mood, anxiety, and drug abuse disorder as adult . So ADHD would lead to a series of negative consequences for their academic and personal lives. As a result, more and more attention focus on the ADHD.
Although stimulants are the drugs of choice in the treatment of ADHD. Methylphenidate is the first drug for the treatment of ADHD. However, the clinical response to methylphenidate may be absent or insufficient in about 20-30 % drug-treated children while the occurrence of adverse effects with methylphenidate (sleep disturbances, loss of appetite, tics increase...) may sometimes require a dose reduction or even the discontinuation of the treatment. Consequently, there is a need for alternatives to stimulant medication. So it is very important to further explore the mechanism of ADHD for finding a new action point to treatment of ADHD.
Many studies don't attempt in the man because many reasons, animal model is a good choice , it can observe, evaluate the symptom of ADHD and specimen may be collected from the brain of animal model to better explore the structure, function, and the change of transmitter under the different state of behaviour or different period of disease. In the animal experiment, we can better control the inheritance and environment factor, thus it is possible to repeated and conformity of response. The etiopathogenisis and influential factor of disease can be reappearance in an animal model, so we can also explore the action in the invasion course of disease. As a result, it is important for an ideal animal model to investigate the etiological factor and pathogenesy of disease.
The spontaneously hypertensive rat (SHR) is commonly used as a rodent model of attention deficit hyperactivity disorder(ADHD), as it displays a characteristic pattern of behaviour including increased impulsivity, hyperactivity,and an inability to sustain attention. In addition, D1R densities are elevated in the striatum and nucleus accumbens of SHR which is consistent with the hypothesis that D1R neurotransmission may be altered in ADHD. Hypertension is a confounding factor in the SHR model of ADHD. However, SHR do not develop hypertension until they are adults, from 10 to 12 weeks of age, whereas hyperactivity is observed at 3 to 4 weeks of age before they enter puberty . A series of studies that addressed the criterion validity, constitution validity and predictive validity have been finished. It is suggest that SHR is the best validated animal of ADHD.
The aetiology of ADHD is not well understood, but there is converging evidence implicating the catecholamine dysfuction frontal-striatal circuitry . At the genetic level, ADHD is highly heritable and the genetic component as demonstrated by family and twin studies and preliminary evidence supports an association between ADHD and polymorphisms in D1R. Specifically, dysregulation of dopamine (DA) has been hypothesized in ADHD based on the potent efficacy of indirect dopaminergic agonists. In brain, DA effects are mediated through activation of two distinct receptor families, referred to as the D1 and the D2 classes .The DAD1 receptors (D1R), which are expressed highly in the striatum and prefrontal cortex (PFC), may be particularly relevant for ADHD. These receptors are crucial modulators of the motor and cognitive functions mediated by the frontal-striatal circuitry , functions which are impaired in patients with ADHD. So what is the action of D1R in ADHD ,What is the effect of D1R agonists to ADHD and How isit?
Objective
To evaluate juvenile spontaneously hypertensive rats (SHR) as an animal model of a developmental disorder, which is diagnosed according to attention deficit/hyperactivity disorder (ADHD). We observe the effects of treatment with a highly selective dopamine D1 receptor agonist SKF-81297 on locomotion and cognition (spatial learning and working memory) of SHR. We also explore the role of D1R in cause of ADHD, by evaluating the effect of SKF-81297 on on D1R expression, IEG and neuron plasticity fator in the PFC of an animal model of ADHD.
Methods
1. To characterize behavioural alterations, we studied motor activity, as well as attention and cognitive behaviours in juvenile SHR by using open-field environment test, lat maze, morris water maze and Y-maze. All the behavior in the tests were monitored by a CCD video camera and analyzed off-line.
2. The effects of treatment with SKF-81297 on locomotor, spatial learning and memory. Thirty male 4 weeks old SHRs and thirty male 4 week-old WKY rats as the control group were randomly divided into SKF-81297 and saline control groups respectively. There are twenty-four SHRs and WKYs in group of SKF-81297. The SKF-81297 groups were injected i.p. with SKF-81297 (0.5 mg/kg, 5 mg/kg, 10mg/kg) once daily for 14 days. The control groups were treated by saline according to control principle. We evaluate the motor activity by using open-field environment test on the time after 14day administration of SKF-81297. Spatial learning and memory were test by morris water maze from day 9 to 14 during the treatment.
3. After 2-weeks treatment with SKF-81297 SHRs and WKYs rats and the controls were divided into two parts. One part was sacrificed by decapitation and the brain was removed on an ice-cold stage. These brains were used in the study of quantitative real-time detection PCR and western blot to observe the effect on immediately early gene(IEG) , dopamine-related receptor(DlR) and protein( calcyon) and neuron plasticity factor (GDNF、arc). The other part that was used in the study of immunohistochemistry.
Results
1. Ambulatory and rearing activities in the open-field environment were significantly higher in SHR than in their Wistar-Kyoto (WKY) controls;The behavior in a Lat maze during three consecutive 10-min was monitored, frequency of running across the corners and the rearing activities which is useda sa nin dexo fno n-selectivea tention,w eres ignificantlyh igherin SHR than in WKY during either the 30 minutes or the three consecutive 10-min; In the morris water maze test, there are no significant difference of in the time to find the platform between the SHR and WKY groups. In contrast, on the morris water maze there was siginificant difference in the time spend in objective quadrant between 2 groups. In Y maze test, control rats learned the left-right alternative memory model. Total errors in SHRs group significantly increased compared to WKY rats in both training sessions and retention sessions. So the SHRs had deficits in working memoty.
2. The effects of SKF-81297 in activity and spatial learing and memory.
2.1 The effects of SKF-81297 in activity . After the 14 days the administration of SKF-81297, SHR rats were more behaviourally active than WKY rats after injection with vehicle in all course of test. The 0.5 mg/kg dose of SKF-81297 increased locomotion behaviour and the stereotyped behavior in both SHR and WKY rats and stimulate the rearing in 25-40min. The 5 mg/kg dose increase locomotion behaviour only in 25-40min in SHR and WKY rats, at the same time the stereotyped behavior have a significant increase. The rearing behaviour of SHR rats were raise in the test session,however, the rearing behaviour have been reduced in 5-20min in WKY rats. The 10 mg/kg dose of SKF-81297 produced a biphasic effect on locomotion, which was characterized by an initial decrease followed by later stimulation. The latter stimulatory effect was more pronounced in SHR than in WKY rats when compared to their respective vehicle-injected groups. The rearing behaviour of SHR rats were reduced in 5-20min and 25-40min, however, the rearing behaviour of SHR rats were only reduce in 25-40min.
2.2 The effects of SKF-81297 in spatial learing and memory. After the 14 days the administration of SKF-81297, in morris water maze, the SKF-81297 group spent more time in the target quadrant at all dose levels compared with control rats( P<0.05)but the time in finding the platform has no significant difference at all dose levels (P>0.05).
3. The effect of SKF-81297 on D1R expression, immediately early gene andneuron plasticity fator in the PFC of SHR/WKY rats.
3.1 SKF-81297 increase the expression the c-fos,fosB,and calcyon in the PFC of SHR rats by immunohistochemistry and western-blot.
3.2 DIRmRNA and BDNFmRNA in the PFC of SHR/WKY rats were raised by the
SKF-81297 dose-dependent in the real-time PCR, no change in expression ofarcmRNA.
Conclusion
1. Our findings reveal that juvenile SHR manifest behaviours resembling a developmental disorder of ADHD, such as hyperactivity, attention deficit, and disorder of cognition. Using the open-field experiment, Lat maze, morris water maze and Y-maze, we can evaluate the hyperactivity , attention deficit, learing and memory in the animal model of ADHD. It is important to supply the evidence to further study.
2. The activity of SHR/WKY rats were effect by different dose of SKF-81297 and the time of test.The SKF-81297 improve the spatial memory of SHR/WKY rats, and have a most significant improvement in the medium dosage . These evidences suggests the activation of the appropriate suitable dopamine receptor is very important to obtain the good cogtion function.
3. D1R, BDNF,calcyon and c-fos,fosB have been increased in the different degree by SKF-81297. It is suggest that SKF-81297 is very important to regulate the function of PFC,the course were medicated by D1R, BDNF,calcyon, as a result, the behaviour of SHR/WKY have differently change.
引文
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[2] Biederman, J. Attention-deficit/hyperactivity disorder: a selective overview. Biol Psychiatry 2005; 57:1215-20.
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[6] Dai H, Kaneko K, Kato H. Selective cognitive dysfunction in mice lacking histamine H1 and H2 receptors. Neuroscience Research 2007; 57:306-13.
[7] Berridge CW, Devilbiss DM, Andrzejewski ME, Arnsten AFT, Kelley AE, Schmeichel B, et al. Methylphenidate preferentially increases catecholamine neurotransmission within the prefrontal cortex at low doses that enhance cognitive function. Biol Psychiatry 2006;60:1111 -20.
[8] Craig W, Berridge, David M, et al. Methylphenidate Preferentially Increases Catecholamine Neurotransmission within the Prefrontal Cortex at Low Doses that Enhance Cognitive Function. Biol Psychiatry 2006;60:1111-20.
[9] Dalley JW, Cardinal RN, Robbins TW. Prefrontal executive and cognitive functions in rodents: neural and neurochemical substrates. Neurosci. Biobehav. Rev 2004;28:771-784.
[10] Arnsten AF, Steere JC, Hunt RD. The contribution of alpha-2 noradrenergic mechanisms of prefrontal cortical cognitive function: potential significance for attention deficit hyperactivity disorder.Arch.Gen.Psychiatry 1996;53:448-55.
[11]Franowicz JS,Kessler LE,Borja CM,Kobilka BK,Limbird LE,Arnsten AF.Mutation of the alpha2A-adrenoceptor impairs working memory performance and annuls cognitive enhancement by guanfacine.J Neurosci 2002;22:8771-7.
[12]Arnsten AFT.Fundamentals of Attention-Deficit/Hyperactivity Disorder:circuits and pathways.J Clin Psychiatry 2006;67(suppl 8):7-12.
[13]Pliszka SR,McCracken JT,Maas JW.Catecholamines in attention deficit hyperactivity disorder:current perspectives.J..Am.Acad.Child Adolesc.Psychiatry 1996;35:264-72.
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[17]Prediger RD,Pamplona FA,Fernandes D,Takahashi RN.Caffeine improves spatial learning deficits in an animal model of attention deficit hyperactivity disorder(ADHD-the spontaneously hypertensive rat(SHR).Int J Neuropsychopharmacol 2005;8(4):583-94.
[18]Bymaster FP,Katner JS,Nelson DL,Hemrick-Luecke SK,Threlkeld PG,Heiligenstein JH,et al.Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat:a potential mechanism for efficacy in attention deficit/hyperactivity disorder.Neuropsychopharmacology 2002;27:699-711.
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[23] Leurs R, Bakker RA, Timmerman H, De Esch UP. The histamine H3 receptor from gene cloning to H3 receptor drugs. Nat. Med 2005;4:107-20.
[24] Homer WE , Johnson DE, Schmidt AW, Rollema H. Methylphenidate and atomoxetine increase histamine release in rat prefrontal cortex. Eur J Pharmacol 2007;558:96-7.
[25] Roof RL and Stein DG Gender differences in Morris water maze performance depend on task parameters. Physiol Behav 1999;68:81-6.
[26] Li XM, Perry KW, Wong DT, Bymaster FP. Olanzapine increases in vivo dopamine and norepinephrine release in rat prefrontal cortex, nucleus accumbens and striatum. Psychopharmacol 1998;136:153-61.
[27] Paxinos G, Watson C. The Rat Brain in Stereotaxic Coordinates. Academic Press, New York; 1997.
[28] Westerink BHC, Cremers TIFH, De Vries JB, Liefers H, Tran N, De Boer P. Evidence for activation of histamine H3 autoreceptors during handling stress in the prefrontal cortex of the rat. Synase 2002;43: 238-43.
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[36] Doreulee N, Yanovsky Y, Flagmever I, Stevens DR, Hass HL and Brown RE. Histamine H3 receptors depress synaptic transmission in the corticostriatal pathway. Neuropharmacology 2001;40:106-13.
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