動機與成癮幻燈片

MotivationandAddictionNeuroscienceExploringtheBrain

Chapter16

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

JacksonLabs

吳鎏楨基礎(chǔ)Regulationofbodyfatbyacirculatinghormone.Ifageneticallyobeseob/obmouseissurgicallyfusedwithanormalmousesothatbloodbomesignalsarenowsharedbetweentheanimals,theobesityoftheob/obmouseisgreatlymoderated.吳鎏楨基礎(chǔ)Alteredfeedingbehaviorandbodyweightresulteingfrombilaterallesionsoftherathypothalamus.(a)Thelateralhypothalamicsyndrome,characterizedbyanorexia,iscausedbylesionsofthelateralhypothatamus.(b)Theventromedialhypothalamicsyndrome,characterizedbyobesity,iscausedbylesionsoftheventromedialhypothalamus.(LHA)(VMH)吳鎏楨基礎(chǔ)Hypothalamicnucleiimportantforthecontroloffeeding.(a)Amidsagittalviewofthehumanbrain,showingthelocationofthehypothalamus(b)Acoronalsectionofthehumanbrain,showing,inpart,threeimportantnucleiforthecontroloffeeding:thearcuatenucleus,theparaventricularnucleus,andthelateralhypothalamicarea(PVN)(ARC)吳鎏楨基礎(chǔ)吳鎏楨基礎(chǔ)吳鎏楨基礎(chǔ)吳鎏楨基礎(chǔ)Responsetoelevatedleptinlevels.AriseinleptinlevelsinthebloodisdetectedbyneuronsinthearcuatenucleusthatcontainthepeptidesαMSHandCART.Theseneuronsprojectaxonstothelowerbrainstemandspinalcord,theparaventricularnucleiofthehypothalamus,andthelateralhypothalamicarea.Eachoftheseconnectionscontributestothecoordinatedhumoral,visceromotor,andsomaticmotorresponsestoincreasedleptinlevels.(Source:AdaptedfromSawchenko,1998,p.437.)Anorecticpeptides吳鎏楨基礎(chǔ)Responsetodecreasedleptinlevels.AreductioninbloodlevelsofleptinisdetectedbyneuronsinthearcuatenucleusthatcontainthepeptidesNPYandAgRP.ThesearcuatenucleusneuronsinhibittheneuronsintheparaventricularnucleithatcontrolthereleaseofTSHandACTHfromthepituitary.Inaddition,theyactivatetheneuronsinthelateralhypothalamusthatstimulatefeedingbehavior.Someoftheactivatedlateralhypothalamicneuronscontainthepeptidesmelaninconcentratinghormone(MCH)andorexin.orexigenicpeptides吳鎏楨基礎(chǔ)CompetitionforactivationoftheMC4receptor,OnewaythatαMSH,ananorecticpeptide,andAgRP,anorexigenicpeptide,exertoppositeeffectsonmetabolismandfeedingbehaviorisviaaninteractionwiththeMC4receptoronsomehybothalamicneurons,WhileαMSHstimulatestheMC4receptor,AgRPblockstheactionofαMSHatthereceptor.吳鎏楨基礎(chǔ)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吳鎏楨基礎(chǔ)Hypotheticalmodelfortheshort-termregulationoffeedingbehavior.Thisgraphshowsapossiblemeansofregulatingfoodconsumptionbysatietysignals,whichriseinresponsetofeeding.Whensatietysignalsarehigh,foodconsumptionisinhibited.Whenthesatietysignalsfalltozero,theinhibitioniseliminated,andfoodconsumptionensues.SynergisticactionofgastricdistensionandCCKonfeedingbehavior.Bothsignalsconvergeonaxonsinthevagusnervethattriggersatiety.吳鎏楨基礎(chǔ)Changesinbloodinsulinlevelsbefore,during,andafterameal.(Source:AdaptedfromWoodsandStricker,1999,p.1094)吳鎏楨基礎(chǔ)吳鎏楨基礎(chǔ)Mesocorticolimbicdopaminesystem（MLDS）.Animalsaremotivatedtobehaveinwaysthatstimulatethereleaseofdopamineinthebasalforebrainarea.(VTA)吳鎏楨基礎(chǔ)Changinhypothalamicserotoninlevelsbeforeandduringameal.Themoodelevatingeffectsofeatingarebelievedtoberelatedtothereleaseofserotonininthebrain.(Soure:AdaptedfromSchwartzetal,1990)吳鎏楨基礎(chǔ)Pathwaystriggeringvolumetricthirst.Hypovolemiaisdetectedintwoways,First,angiotensinII,releasedintotheblood-streaminresponsetodecreasedbloodflowtothekidneys,activatesneuronsinthesubfornicalorgan.Second,mechanosensoryaxonsinthevagusnerve,detectingadropinbloodpressure,activateneuronsinthenucleusofthesolitarytract,Thesubfornicalorganandnucleusofthesolitarytractrelaythisinformationtothehypothalamus,whichorchestratesthecoordinatedresponsetoreducedbloodvolume,吳鎏楨基礎(chǔ)(NTS)(SFO)Hypothalamicresponsetodehydration.Bloodbecomeshypertonicwhenitloseswater,Bloodhypertonicityissensedbyneuronsofthevascularorganofthelaminaterminalis(OVLT).TheOVLTactivatesmagnocellularneurosecretorycellsandcellsinthelateralhypothalamus.Theneurosecretorycellssecretevasopressinintotheblood,andtheneuronsofthelateralhypothalamustriggerosmometricthirst.吳鎏楨基礎(chǔ)Addictivedrugsonthedopaminergicpathwayfromvertraltegmentalareatothenucleusaccumbens(Source:AdaptedfrmWise,1996,p.248,Fig.1.吳鎏楨基礎(chǔ)含有神經(jīng)肽Orexin的大腦側(cè)下丘部的神經(jīng)元的激發(fā)，可能是過食者和藥物上癮者產(chǎn)生強烈欲望的原因。對大鼠所做的一項研究表明，在一個條件實驗中，這些Orexin神經(jīng)元受到強烈刺激，其受到刺激的程度與試驗動物尋找食物或藥物的程度成比例。直接刺激這些Orexin神經(jīng)元引起尋找藥物的行為復(fù)發(fā)，向大腦中一個主要獎賞中心“腹側(cè)被蓋區(qū)”（ventral

tegmental

area）直接施用Orexin，能誘導(dǎo)產(chǎn)生一個類似的復(fù)發(fā)現(xiàn)象。這些發(fā)現(xiàn)顯示了大腦中的一些動機和獎賞機制，并對了解和治療藥物上癮和食量過度有參考價值。吳鎏楨基礎(chǔ)吳鎏楨基礎(chǔ)吳鎏楨臨床吳鎏楨臨床吳鎏楨臨床吳鎏楨臨床AddictedDrugsMorphine（嗎啡）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（三唑侖）CannabisandCannabisresin（大麻與大麻脂）吳鎏楨臨床吳鎏楨臨床吳鎏楨臨床吳鎏楨臨床苯丙胺類藥品正面吳鎏楨臨床苯丙胺類藥品背面吳鎏楨臨床

依賴(dependence)

是指一組認(rèn)知、行為和生理癥狀群，使用者盡管明白使用成癮物質(zhì)會帶來明顯的問題，但還在繼續(xù)使用，自我用藥結(jié)果導(dǎo)致了耐受性增加、戒斷癥狀和強制性覓藥行為(compulsivedrugseekingbehavior)。所謂強制性覓藥行為指使用者不顧一切使用藥物，是失去自我控制的表現(xiàn)，而不一定是人們常常理解的意志薄弱或道德的問題。傳統(tǒng)上，將依賴分為軀體依賴(physicalependence)和心理依賴(psychologicaldependence)。軀體依賴也稱生理依賴，它由于是反復(fù)用藥所造成的一種適應(yīng)狀態(tài)，主要表現(xiàn)為耐受性增加和戒斷癥狀。心理依賴又稱精神依賴，它使吸食者產(chǎn)生一種欣快的感覺，驅(qū)使使用者為滿足這種感覺反復(fù)使用藥物。

吳鎏楨臨床濫用(abuse)

指一種非醫(yī)療所需的不良用藥方式，由于反復(fù)使用藥物導(dǎo)致了明顯的不良后果，如不能完成重要的工作、學(xué)業(yè)，損害了軀體、心理健康，導(dǎo)致法律上的問題等。

耐受性(tolerance)

指藥物使用者必須增加劑量方能獲得所需的效果，如仍以原來的劑量則達不到所追求的效果。吳鎏楨臨床

戒斷綜合癥（withdrawalsyndrome） 指停止使用藥物或減少使用藥物后或使用拮抗劑后所出現(xiàn)的特殊的心理生理癥狀群。不同的藥物所致的戒斷癥狀因其藥理特性不同而異，一般表現(xiàn)為所使用藥物的藥理作用相反的癥狀。例如苯丙胺類興奮劑依賴戒斷后出現(xiàn)無力、思睡、情緒抑郁等癥狀；而酒精(中樞神經(jīng)系統(tǒng)抑制劑)依賴戒斷后出現(xiàn)興奮、不眠，甚至癲癇樣發(fā)作等表現(xiàn)。吳鎏楨臨床

譫妄(delirium)

在意識清晰度降低的同時，出現(xiàn)大量的錯覺、幻覺，以幻，視多見視幻覺及視錯覺的內(nèi)容多為生動而鮮明的形象性的情境，如見到昆蟲，猛獸等。有的內(nèi)容具有恐怖性，患者常產(chǎn)生緊張、恐懼情緒反應(yīng)，出現(xiàn)興奮、思維不連貫、理解困難，有時出現(xiàn)片斷妄想。患者的定向力全部或部分喪失，多數(shù)患者表現(xiàn)自我定向力保存而周圍環(huán)境定向力喪失。譫妄狀態(tài)往往晝輕夜重，持續(xù)時間可數(shù)小時至數(shù)日，意識恢復(fù)后可部分遺忘或全部遺忘。吳鎏楨臨床成癮(addiction)50年代世界衛(wèi)生組織專家委員會將藥物成瘸定義為：“由于反復(fù)使用某種藥物所引起的一種周期性或慢性中毒狀態(tài)，具有以下特征：①有一種不可抗拒的力量強制性地驅(qū)使人們使用該藥，并不擇手段去獲得它；②有加大劑量的趨勢；③對該藥的效應(yīng)產(chǎn)生精神依賴，也可產(chǎn)生軀體依賴；④對個人和社會都產(chǎn)生危害。由于“成癮”這一術(shù)語用途太寬泛，世界衛(wèi)生組織建議用“依賴”來代替“成癮”。吳鎏楨臨床脫毒(detoxification)

指通過軀體治療，減輕戒斷癥狀，預(yù)防由于突然停止使用成癮藥物可能引起的軀體戒斷癥狀的過程?？墒褂孟嗨扑幬锾娲姆椒ㄟM行脫毒治療。脫毒治療一般在封閉的環(huán)境下進行。脫毒治療僅僅是戒毒治療最初的一步，脫毒后的心理社會康復(fù)、預(yù)防復(fù)吸以及回歸社會是一長期、艱巨的過程。吳鎏楨臨床幻覺(hallucination)

指沒有實現(xiàn)刺激作用于感覺器官時出現(xiàn)的知覺體驗，是一種虛幻的知覺?；糜X是臨床上最常見而且重要的精神病性癥狀，根據(jù)其所涉及的感官分為幻聽、幻視、幻嗅、幻味、幻觸、內(nèi)臟性幻覺等，藥物依賴的幻覺多為幻視和幻聽。吳鎏楨臨床藥物治療新的成癮物代替舊的成癮物最終不能接受仍有依賴潛力副作用極大1，替代療法2，阻斷預(yù)防療法3，BPN療法4，其它藥物療法方法結(jié)果吳鎏楨臨床HypothesisoneRewardingmechanism吳鎏楨臨床HypothesistwoEndo-opioidspeptidesMechanism吳鎏楨臨床吳鎏楨基礎(chǔ)吳鎏楨基礎(chǔ)吳鎏楨基礎(chǔ)邊緣系統(tǒng)的概念：脊椎動物前腦由古皮質(zhì)和舊皮