动机与成瘾幻灯片

MotivationandAddictionNeuroscienceExploringtheBrain

Chapter16

Thelong-termregulationoffeedingbehaviorbymotivation(1)EnergyBalance(2)hormonal,hypothalamicregulationofbodyfat,feeding(3)bodyfatandfoodconsumption(4)thehypothalamusandfeeding(5)theeffectsofdecreasedleptinlevelonthehypothalamus(6)theeffectsofelevatedleptinlevelonthehypothalamus(7)thecontroloffeedingbylateralhypothalamicpeptides吴鎏桢基础Loadingandemptyingthebody'senergyreserves.(a)Afterameal,whenweareintheprandialstate,excessenergyisstoredasglycogenorastriglycerides.吴鎏桢基础(b)Betweenmeals,whenweareinthepostabsorptivestate,theglycogenandtriglyceridesarebrokendown(catabolized)intosmallermoleculesthatcanbeusedasfuelbythecellsofthebody.吴鎏桢基础Energybalanceandbodyfat.(a)Normalenergybalanceleadstonormaladiposity.(b)Prolongedpositiveenergybalanceleadstoobesity,(c)Prolongednegativeenergybalanceleadstostarvation.吴鎏桢基础Ob:obesityBarHarbor

JacksonLabs

吴鎏桢基础Regulationofbodyfatbyacirculatinghormone.Ifageneticallyobeseob/obmouseissurgicallyfusedwithanormalmousesothatbloodbomesignalsarenowsharedbetweentheanimals,theobesityoftheob/obmouseisgreatlymoderated.吴鎏桢基础Alteredfeedingbehaviorandbodyweightresulteingfrombilaterallesionsoftherathypothalamus.(a)Thelateralhypothalamicsyndrome,characterizedbyanorexia,iscausedbylesionsofthelateralhypothatamus.(b)Theventromedialhypothalamicsyndrome,characterizedbyobesity,iscausedbylesionsoftheventromedialhypothalamus.(LHA)(VMH)吴鎏桢基础Hypothalamicnucleiimportantforthecontroloffeeding.(a)Amidsagittalviewofthehumanbrain,showingthelocationofthehypothalamus(b)Acoronalsectionofthehumanbrain,showing,inpart,threeimportantnucleiforthecontroloffeeding:thearcuatenucleus,theparaventricularnucleus,andthelateralhypothalamicarea(PVN)(ARC)吴鎏桢基础吴鎏桢基础吴鎏桢基础吴鎏桢基础Responsetoelevatedleptinlevels.AriseinleptinlevelsinthebloodisdetectedbyneuronsinthearcuatenucleusthatcontainthepeptidesαMSHandCART.Theseneuronsprojectaxonstothelowerbrainstemandspinalcord,theparaventricularnucleiofthehypothalamus,andthelateralhypothalamicarea.Eachoftheseconnectionscontributestothecoordinatedhumoral,visceromotor,andsomaticmotorresponsestoincreasedleptinlevels.(Source:AdaptedfromSawchenko,1998,p.437.)Anorecticpeptides吴鎏桢基础Responsetodecreasedleptinlevels.AreductioninbloodlevelsofleptinisdetectedbyneuronsinthearcuatenucleusthatcontainthepeptidesNPYandAgRP.ThesearcuatenucleusneuronsinhibittheneuronsintheparaventricularnucleithatcontrolthereleaseofTSHandACTHfromthepituitary.Inaddition,theyactivatetheneuronsinthelateralhypothalamusthatstimulatefeedingbehavior.Someoftheactivatedlateralhypothalamicneuronscontainthepeptidesmelaninconcentratinghormone(MCH)andorexin.orexigenicpeptides吴鎏桢基础CompetitionforactivationoftheMC4receptor,OnewaythatαMSH,ananorecticpeptide,andAgRP,anorexigenicpeptide,exertoppositeeffectsonmetabolismandfeedingbehaviorisviaaninteractionwiththeMC4receptoronsomehybothalamicneurons,WhileαMSHstimulatestheMC4receptor,AgRPblockstheactionofαMSHatthereceptor.吴鎏桢基础Neuronsthatstimulatefeedingintheratlateralhypothalamus.Inthisphot-omicrograph,neuronscontainingmesse-ngerRNAfororexinappearbrightonadarkbackground.Orexinisoneofthelateralhypothalamicpeptidesthatstim-ulatesfeedingbehaviorAswewillseeinChapter19,thesamecellsplayanimportantroleinthecontrolofsleepandwakefulness.RememberthatleptinlevelsrisewhenbodyfatisincreasedandtheyfallwhenbodyfatisdecreasedAriseinleptinlevelsincreasesα-MSHandCARTinarcuatenucleusneurons.Theseanorecticpeptidesactonthebraintoinhibitfeedingbehaviorandincreasemetabolism.AfallinleptinlevelsincreasesNPYandAgRPinthearcuatenucleusandMCHandorexininthelateralhypothalamicarea.Theseorexigenicpeptidesactonthebraintostimulatefeedingbehavioranddecreasemetabolism.Theshort-termregulationoffeedingbehaviorbymotivation(1)gastricdistension(2)cholecystokininCCK(3)InsulinOthermotivatedbehaviors(1)drinking(2)temperatureregulation吴鎏桢基础Hypotheticalmodelfortheshort-termregulationoffeedingbehavior.Thisgraphshowsapossiblemeansofregulatingfoodconsumptionbysatietysignals,whichriseinresponsetofeeding.Whensatietysignalsarehigh,foodconsumptionisinhibited.Whenthesatietysignalsfalltozero,theinhibitioniseliminated,andfoodconsumptionensues.SynergisticactionofgastricdistensionandCCKonfeedingbehavior.Bothsignalsconvergeonaxonsinthevagusnervethattriggersatiety.吴鎏桢基础Changesinbloodinsulinlevelsbefore,during,andafterameal.(Source:AdaptedfromWoodsandStricker,1999,p.1094)吴鎏桢基础吴鎏桢基础Mesocorticolimbicdopaminesystem（MLDS）.Animalsaremotivatedtobehaveinwaysthatstimulatethereleaseofdopamineinthebasalforebrainarea.(VTA)吴鎏桢基础Changinhypothalamicserotoninlevelsbeforeandduringameal.Themoodelevatingeffectsofeatingarebelievedtoberelatedtothereleaseofserotonininthebrain.(Soure:AdaptedfromSchwartzetal,1990)吴鎏桢基础Pathwaystriggeringvolumetricthirst.Hypovolemiaisdetectedintwoways,First,angiotensinII,releasedintotheblood-streaminresponsetodecreasedbloodflowtothekidneys,activatesneuronsinthesubfornicalorgan.Second,mechanosensoryaxonsinthevagusnerve,detectingadropinbloodpressure,activateneuronsinthenucleusofthesolitarytract,Thesubfornicalorganandnucleusofthesolitarytractrelaythisinformationtothehypothalamus,whichorchestratesthecoordinatedresponsetoreducedbloodvolume,吴鎏桢基础(NTS)(SFO)Hypothalamicresponsetodehydration.Bloodbecomeshypertonicwhenitloseswater,Bloodhypertonicityissensedbyneuronsofthevascularorganofthelaminaterminalis(OVLT).TheOVLTactivatesmagnocellularneurosecretorycellsandcellsinthelateralhypothalamus.Theneurosecretorycellssecretevasopressinintotheblood,andtheneuronsofthelateralhypothalamustriggerosmometricthirst.吴鎏桢基础Addictivedrugsonthedopaminergicpathwayfromvertraltegmentalareatothenucleusaccumbens(Source:AdaptedfrmWise,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AddictedDrugsMorphine（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）CannabisandCannabisresin（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(compulsivedrugseekingbehavior)。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(physicalependence)和心理依赖(psychologicaldependence)。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（withdrawalsyndrome） 指停止使用药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，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：①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；②有加大剂量的趋势；③对该药的效应产生精神依赖，也可产生躯体依赖；④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新的成瘾物代替旧的成瘾物最终不能接受仍有依赖潜力副作用极大1，替代疗法2，阻断预防疗法3，BPN疗法4，其它药物疗法方法结果吴鎏桢临床HypothesisoneRewardingmechanism吴鎏桢临床HypothesistwoEndo-opioidspeptidesMechanism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