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1、Motivation and Addiction,Neuroscience Exploring the Brain Chapter 16,吴鎏桢,WU Liuzhen researcher Neuroscience Research Institute, Peking University,The long-term regulation of feeding behavior by motivation (1)Energy Balance (2)hormonal,hypothalamic regulation of body fat, feeding (3)body fat and food
2、 consumption (4)the hypothalamus and feeding (5)the effects of decreased leptin level on the hypothalamus (6) the effects of elevated leptin level on the hypothalamus (7)the control of feeding by lateral hypothalamic peptides,吴鎏桢,基础,Loading and emptying the bodys energy reserves. (a)After a meal, wh
3、en we are in the prandial state, excess energy is stored as glycogen or as triglycerides.,吴鎏桢,基础,(b) Between meals, when we are in the postabsorptive state, the glycogen and triglycerides are broken down (catabolized) into smaller molecules that can be used as fuel by the cells of the body.,吴鎏桢,基础,E
4、nergy balance and body fat. (a) Normal energy balance leads to normal adiposity. (b) Prolonged positive energy balance leads to obesity, (c) Prolonged negative energy balance leads to starvation.,吴鎏桢,基础,Maintenance of body weight around a set value. Body weight is normally stable. If an animal is fo
5、rce-fed, it will gain weight. The weight is lost, however, as soon as the animal can regulate its own food intake. Similarly, weight lost during a period of starvation is rapidly gained when food is freely available.,吴鎏桢,基础,Ob: obesity Bar Harbor Jackson Labs,吴鎏桢,基础,Regulation of body fat by a circu
6、lating hormone. If a genetically obese ob/ob mouse is surgically fused with a normal mouse so that bloodbome signals are now shared between the animals, the obesity of the ob/ob mouse is greatly moderated.,吴鎏桢,基础,Altered feeding behavior and body weight resulteing from bilateral lesions of the rat h
7、ypothalamus. (a) The lateral hypothalamic syndrome, characterized by anorexia, is caused by lesions of the lateral hypothatamus. (b) The ventromedial hypothalamic syndrome, characterized by obesity, is caused by lesions of the ventromedial hypothalamus.,(LHA),(VMH),吴鎏桢,基础,Hypothalamic nuclei importa
8、nt for the control of feeding. (a) A midsagittal view of the human brain, showing the location of the hypothalamus (b) A coronal section of the human brain, showing, in part, three important nuclei for the control of feeding: the arcuate nucleus, the paraventricular nucleus, and the lateral hypothal
9、amic area,(PVN),(ARC),吴鎏桢,基础,吴鎏桢,基础,吴鎏桢,基础,吴鎏桢,基础,Response to elevated leptin levels. A rise in leptin levels in the blood is detected by neurons in the arcuate nucleus that contain the peptides MSH and CART. These neurons project axons to the lower brain stem and spinal cord, the paraventricular nu
10、clei of the hypothalamus, and the lateral hypothalamic area. Each of these connections contributes to the coordinated humoral, visceromotor, and somatic motor responses to increased leptin levels. (Source: Adapted from Sawchenko, 1998, p. 437.),Anorectic peptides,吴鎏桢,基础,Response to decreased leptin
11、levels. A reduction in blood levels of leptin is detected by neurons in the arcuate nucleus that contain the peptides NPY and AgRP. These arcuate nucleus neurons inhibit the neurons in the paraventricular nuclei that control the release of TSH and ACTH from the pituitary. In addition, they activate
12、the neurons in the lateral hypothalamus that stimulate feeding behavior. Some of the activated lateral hypothalamic neurons contain the peptides melanin concentrating hormone (MCH) and orexin.,orexigenic peptides,吴鎏桢,基础,Competition for activation of the MC4 receptor, One way that MSH, an anor ectic
13、peptide, and AgRP, an orexigenic peptide, exert opposite effects on metabolism and feeding behavior is via an interaction with the MC4 receptor on some hybothalamic neurons, While MSH stimulates the MC4 receptor, AgRP blocks the action of MSH at the receptor.,吴鎏桢,基础,Neurons that stimulate feeding in
14、 the rat lateral hypothalamus. In this phot- omicrograph, neurons containing messe- nger RNA for orexin appear bright on a dark background. Orexin is one of the lateral hypothalamic peptides that stim- ulates feeding behavior As we will see in Chapter 19, the same cells play an important role in the
15、 control of sleep and wakefulness.,Remember that leptin levels rise when body fat is increased and they fall when body fat is decreased A rise in leptin levels increases -MSH and CART in arcuate nucleus neurons. These anorectic peptides act on the brain to inhibit feeding behavior and increase metab
16、olism. A fall in leptin levels increases NPY and AgRP in the arcuate nucleus and MCH and orexin in the lateral hypothalamic area. These orexigenic peptides act on the brain to stimulate feeding behavior and decrease metabolism.,The short-term regulation of feeding behavior by motivation (1)gastric d
17、istension (2)cholecystokinin CCK (3)Insulin Other motivated behaviors (1)drinking (2)temperature regulation,吴鎏桢,基础,Hypothetical model for the short-term regulation of feeding behavior. This graph shows a possible means of regulating food consumption by satiety signals, which rise in response to feed
18、ing. When satiety signals are high, food consumption is inhibited. When the satiety signals fall to zero, the inhibition is eliminated, and food consumption ensues.,Synergistic action of gastric distension and CCK on feeding behavior. Both signals converge onaxons in the vagus nerve that trigger sat
19、iety.,吴鎏桢,基础,Changes in blood insulin levels before, during, and after a meal. (Source: Adapted from Woods and Stricker, 1999, p. 1094),吴鎏桢,基础,吴鎏桢,基础,Mesocorticolimbic dopamine system（MLDS）. Animals are motivated to behave in ways that stimulate the release of dopamine in the basal forebrain area.,(
20、VTA),吴鎏桢,基础,Chang in hypothalamic serotonin levels before and during a meal. The mood elevating effects of eating are believed to be related to the release of serotonin in the brain. (Soure: Adapted from Schwartz et al,1990),吴鎏桢,基础,Pathways triggering volumetric thirst. Hypovolemia is detected in tw
21、o ways, First, angiotensin II, released into the blood-stream in response to decreased blood flow to the kidneys, activates neurons in the subfornical organ. Second, mechanosensory axons in the vagus nerve, detecting a drop in blood pressure, activate neurons in the nucleus of the solitary tract, Th
22、e subfornical organ and nucleus of the solitary tract relay this in formation to the hypothalamus, which orchestrates the coordinated response to reduced blood volume,吴鎏桢,基础,(NTS),(SFO),Hypothalamic response to dehydration. Blood becomes hypertonic when it loses water, Blood hypertonicity is sensed
23、by neurons of the vascular organ of the lamina terminalis (OVLT). The OVLT activates magnocellular neurosecretory cells and cells in the lateral hypothalamus. The neurosecretory cells secrete vasopressin into the blood, and the neurons of the lateral hypothalamus trigger osmometric thirst.,吴鎏桢,基础,Ad
24、dictive drugs on the dopaminergic pathway from vertral tegmental area to the nucleus accumbens (Source: Adapted frm Wise, 1996,p.248,Fig.1.,吴鎏桢,基础,含有神经肽Orexin的大脑侧下丘部的神经元的激发，可能是过食者和药物上瘾者产生强烈欲望的原因。对大鼠所做的 一项研究表明，在一个条件实验中，这些Orexin神经元受到强烈刺激，其受到刺激的程度与试验动物寻找食物或药物 的程度成比例。直接刺激这些Orexin神经元引起寻找药物的行为复发，向大脑中一个主要奖
25、赏中心“腹侧被盖区” （ventral tegmental area）直接施用Orexin，能诱导产生一个类似的复发现象。这些发现显示了大脑中的一些动机和奖 赏机制，并对了解和治疗药物上瘾和食量过度有参考价值。,吴鎏桢,基础,吴鎏桢,基础,吴鎏桢,临床,吴鎏桢,临床,吴鎏桢,临床,吴鎏桢,临床,Addicted Drugs Morphine（吗啡） Heroin（ 海洛因） Codeine （可待因） Cocaine（ 可卡因） Methmphetamin （甲基苯丙胺）(ice) Nitrazepam （硝基安定） Triazolam（三唑仑） Cannabis and Cannabis r
26、esin（大麻与大麻脂）,吴鎏桢,临床,吴鎏桢,临床,吴鎏桢,临床,吴鎏桢,临床,苯丙胺类药品正面,吴鎏桢,临床,苯丙胺类药品背面,吴鎏桢,临床,依赖(dependence) 是指一组认知、行为和生理症状群，使用者尽管明白使用成瘾 物质会带来明显的问题，但还在继续使用，自我用药结果导致了 耐受性增加、戒断症状和强制性觅药行为(compulsive drug seeking behavior)。所谓强制性觅药行为指使用者不顾一切使用药物，是失去自我控制的表现，而不一定是人们常常理解的意志薄弱或道德的问题。传统上，将依赖分为躯体依赖(physical ependence)和心理依赖(psychol
27、ogical dependence)。躯体依赖也称生理依赖，它由于是反 复用药所造成的一种适应状态，主要表现为耐受性增加和戒断症状。心理依赖又称精神依赖，它使吸食者产生一种欣快的感觉，驱使使用者为满足这种感觉反复使用药物。,吴鎏桢,临床,滥用(abuse) 指一种非医疗所需的不良用药方式，由于反复使用药物导 致了明显的不良后果，如不能完成重要的工作、学业，损害了躯 体、心理健康，导致法律上的问题等。 耐受性(tolerance) 指药物使用者必须增加剂量方能获得所需的效果，如仍以 原来的剂量则达不到所追求的效果。,吴鎏桢,临床,戒断综合症（withdrawal syndrome） 指停止使用药
28、物或减少使用药物后或使用拮抗剂后所出现的 特殊的心理生理症状群。不同的药物所致的戒断症状因其药理特 性不同而异，一般表现为所使用药物的药理作用相反的症状。例 如苯丙胺类兴奋剂依赖戒断后出现无力、思睡、情绪抑郁等症状； 而酒精(中枢神经系统抑制剂)依赖戒断后出现兴奋、不眠，甚至癫 痫样发作等表现。,吴鎏桢,临床,谵妄(delirium) 在意识清晰度降低的同时，出现大量的错觉、幻觉，以幻， 视多见视幻觉及视错觉的内容多为生动而鲜明的形象性的情境， 如见到昆虫，猛兽等。有的内容具有恐怖性，患者常产生紧张、 恐惧情绪反应，出现兴奋、思维不连贯、理解困难，有时出现片 断妄想。患者的定向力全部或部分丧失
29、，多数患者表现自我定向 力保存而周围环境定向力丧失。谵妄状态往往昼轻夜重，持续时 间可数 小时至数日，意识恢复后可部分遗忘或全部遗忘。,吴鎏桢,临床,成瘾(addiction) 50年代世界卫生组织专家委员会将药物成瘸定义为：“由于 反复使用某种药物所引起的一种周期性或慢性中毒状态，具有 以下特征：有一种不可抗拒的力量强制性地驱使人们使用该 药，并不择手段去获得它；有加大剂量的趋势；对该药的 效应产生精神依赖，也可产生躯体依赖；对个人和社会都产 生危害。由于“成瘾”这一术语用途太宽泛，世界卫生组织建议 用“依赖”来代替“成瘾”。,吴鎏桢,临床,脱毒(detoxification) 指通过躯体治
30、疗，减轻戒断症状，预防由于突然停止使用成 瘾药物可能引起的躯体戒断症状的过程。可使用相似药物替代的 方法进行脱毒治疗。脱毒治疗一般在封闭的环境下进行。脱毒治 疗仅仅是戒毒治疗最初的一步，脱毒后的心理社会康复、预防复 吸 以及回归社会是一长期、艰巨的过程。,吴鎏桢,临床,幻觉(hallucination) 指没有实现刺激作用于感觉器官时出现的知觉体验，是一种虚 幻的知觉。 幻觉是临床上最常见而且重要的精神病性症状，根据 其所涉及的感官分为幻听、幻视、幻嗅、幻味、幻触、内脏性幻 觉等，药物依赖的幻觉多为幻视和幻听。,吴鎏桢,临床,药物治疗,方法,结果,吴鎏桢,临床,Hypothesis one R
31、ewarding mechanism,吴鎏桢,临床,Hypothesis two Endo-opioids peptides Mechanism,吴鎏桢,临床,吴鎏桢,基础,吴鎏桢,基础,吴鎏桢,基础,边缘系统的概念：脊椎动物前脑由古皮质和旧皮质演化而成的广泛结构。其可分为边缘前脑部分：梨状皮层、内嗅区、眶回、扣带回、胼胝体下回、海马回、杏仁核群、隔区、视前区、下丘脑、海马及乳头体等。和边缘后脑部分：中脑的中央灰质、被盖的中央部、外侧部、和中央灰质腹侧部、脚间核、中央被盖上核等。,内源性阿片肽（endogenous opioid peptides ）: 内吗啡肽（endomorphins） 脑
32、啡肽（enkephalins, EK） 内吗啡肽（-endophin, -EP） 强啡肽（dynorphins,DYN） 孤啡肽（orphanin）非内阿片类，但其发现与之密切,吴鎏桢,临床,吴鎏桢,基础,吴鎏桢,基础,Ill Cyc,Sketch map of dependence in opioids,Endo-opioids peptides,Kindling pharmacology effects,Inordinate physiological function,Psychic emotional abnormality,Go to tolerance and addiction,
33、Withdrawal syndrome,Natural Physiological effects,Keep Physiological function,Psychic emotional balanced,Zero tolerance and addiction,Extrinsic morphine alkaloid,Ill Cyc,吴鎏桢,基础,Opioid receptors,动机的概念：指行为起动前神经高级部位 那种与导致该行为发生有关的思维活动， 是意向、驱动的聚合，它最终导致行为的 出现。,复习参考题： 1，瘦素水平与体内脂肪有什么的关系？ 2，16章讲述的厌食肽和促食肽有哪些？ 其共同受体是什么？ 3，感受高渗渴的神经元在什么位置？ 4，多巴胺奖赏系统与成瘾的关系？ 5，内源性阿片肽有哪些？ 6，本节课介绍了那些成瘾的药物？ 7，请解释动机、成瘾、戒断症状的概念。,Thank you,