(21)--毒品滥用对神经系统的影响.pdf

《(21)--毒品滥用对神经系统的影响.pdf》由会员分享，可在线阅读，更多相关《(21)--毒品滥用对神经系统的影响.pdf（26页珍藏版）》请在淘文阁 - 分享文档赚钱的网站上搜索。

1、THE NEUROSCIENCE OF DRUG REWARD ANDADDICTIONNora D.Volkow,Michael Michaelides,and Ruben BalerNational Institute on Drug Abuse,National Institutes of Health,Bethesda,MarylandLVolkow ND,Michaelides M,Baler R.The Neuroscience of Drug Reward and Addic-tion.Physiol Rev 99:21152140,2019.Published Septembe

2、r 11,2019;doi:10.1152/physrev.00014.2018.Drug consumption is driven by a drugs pharmacolog-ical effects,which are experienced as rewarding,and is influenced by genetic,devel-opmental,and psychosocial factors that mediate drug accessibility,norms,and socialsupport systems or lack thereof.The reinforc

3、ing effects of drugs mostly depend on dopaminesignaling in the nucleus accumbens,and chronic drug exposure triggers glutamatergic-mediatedneuroadaptations in dopamine striato-thalamo-cortical(predominantly in prefrontal cortical regionsincluding orbitofrontal cortex and anterior cingulate cortex)and

4、 limbic pathways(amygdala andhippocampus)that,in vulnerable individuals,can result in addiction.In parallel,changes in theextended amygdala result in negative emotional states that perpetuate drug taking as an attemptto temporarily alleviate them.Counterintuitively,in the addicted person,the actual

5、drug consump-tion is associated with an attenuated dopamine increase in brain reward regions,which mightcontribute to drug-taking behavior to compensate for the difference between the magnitude of theexpected reward triggered by the conditioning to drug cues and the actual experience of it.Combined,

6、these effects result in an enhanced motivation to“seek the drug”(energized by dopa-mine increases triggered by drug cues)and an impaired prefrontal top-down self-regulation thatfavors compulsive drug-taking against the backdrop of negative emotionality and an enhancedinteroceptive awareness of“drug

7、hunger.”Treatment interventions intended to reverse theseneuroadaptations show promise as therapeutic approaches for addiction.cannabis;dopamine;glutamate;nucleus accumbens;opioids;substance use disordersI.INTRODUCTION2115II.DRUG REWARD2116III.DOPAMINE AND NEUROPLASTICITY2119IV.NEUROCIRCUITRY OF ADD

8、ICTION2121V.VULNERABILITY FACTORS2126VI.CLINICAL IMPLICATIONS2128VII.CONCLUSIONS2130I.INTRODUCTIONThere is an inherent need in all sentient beings to seek outpositiveandavoidnegativestimuli,auniversalformulathathas evolved to maximize adaptive fitness and the chances ofsurvival.The extent to which s

9、trategies for attaining oravoiding such stimuli are successful depends on complexinteractions between an organism and its environment thatare orchestrated by the nervous system.Neurobiology em-ploysprocessesrefinedduringevolution,suchashomeostasis,sensory perception,associative and nonassociative le

10、arning,emotions,and decision-making,to shape an organisms re-sponse to environmental stimuli and to maximize its ability toharness their predictable features and to adapt to unpredict-able ones.Although types of stimuli vary from one species toanother,therearestrikingsimilaritiesamongdifferentspecie

11、s,Neuroscience research has revealed that addiction is achronic,relapsing disease of the brain triggered by repeatedexposure to drugs in those who are vulnerable because ofgenetics and developmental or adverse social exposures.Asa result,the reward circuits capacity to respond to rewardand motivate

12、actions that are not drug related is decreased,the sensitivity of the emotional circuits to stress is enhanced,and the capacity to self-regulate is impaired.The result iscompulsive drug seeking and drug taking despite severeharms and an inability to control the strong urges to con-sume the drug,even

13、 when there is a strong desire to quit.The changes in the brain responsible for these maladaptivebehaviors can persist for months or even years after drugdiscontinuation but are amenable to treatment.Treatmentshould be aimed at improving self-regulation;helping to con-trol craving and the emergence

14、of distressing emotions,including depression and anxiety;and improving the sensitiv-ity to alternative reinforcers.Addiction is a chronic disease,so its treatment should follow a sustained model of interven-tion,the intensity of which should be adjusted to the stage ofthe disease.Treatment should al

15、so be personalized and cal-ibrated to the severity of the addiction,the presence ofcomorbidities,and the individuals support systems.Cru-cially,addiction can be prevented,and both universal as wellas tailored strategies can significantly reduce substance usedisorder in the individual and in a popula

16、tion.Physiol Rev 99:21152140,2019Published September 11,2019;doi:10.1152/physrev.00014.201821150031-9333/19 Copyright 2019 the American Physiological SocietyDownloaded from www.physiology.org/journal/physrev at East Carolina Univ(150.216.068.200)on September 12,2019.in their responses to positive(e.

17、g.,food and sex)and negative(e.g.,pain and environmental threats)stimuli.This commonrepresentation,whichreflectsthecriticalroleofsuchstimuliinboosting the odds of survival,is often reflected at the neurobi-ological level,whereby different species tap into similar brainstructural,neurochemical,and fu

18、nctional strategies to tacklesimilar problems(77,284).Ingenuity has enabled humans to extract and refine highlyreinforcing stimuli against which naturally occurring rein-forcers cannot easily compete.The most notable example isour ability to purify and deliver drugs(e.g.,high alcoholcontent beverage

19、s,cigarettes,syringes for drug injections,and more recently vaping devices)along with advances inchemistry that ushered new psychoactive compounds ofunprecedented potency(e.g.,synthetic opioids,cannabi-noids,and stimulants).Access to these highly reinforcingdrugs,when combined with promotive environ

20、ments(e.g.,the ubiquity of legal and illegal drugs,chronic stress,peerpressure)and individual vulnerabilities(e.g.,preexisting men-tal illness,chronic pain,genetic predisposition,gender,youngage),influence drug experimentation as well as the risk andprevalenceofsubstanceusedisorders(SUD).Thelatestex

21、am-ple of the potential consequences of such drug-promotive en-vironments is the rising tide of opioid fatalities,initially fueledby misuse of prescription opioid analgesics,then by heroin,and now exacerbated by the misuse of very potent syntheticopioids such as fentanyl.The current opioid epidemic

22、esti-mated to have led to over 71,000 opioid overdose fatalities in2017(57)andwithnosignsofabatingin2018(2),combinedwith the high background mortality rate from alcohol(88,000 annual deaths)(56,310)and tobacco(?480,000annual deaths)(58)use,highlights the devastating impact ofdrugs and addiction in o

23、ur society.The application of neuroscientific technologies in humansand laboratory animals has led to remarkable advances inour understanding of the neurobiological underpinnings ofdrug reinforcement and addiction.As a result,addiction,which has been viewed historically as a“moral deficiency,”is bei

24、ng increasingly regarded as a chronic relapsing disor-der characterized by an urge to consume drugs and by theprogressive loss of control over,and escalation in,drugintake despite repeated(unsuccessful)attempts to resist do-ing it(334).It is also recognized that addiction emerges inthe context of co

25、mplex biopsychosocial interactions be-tween the pharmacological effects of a drug,individual vul-nerabilities(e.g.,genetics/epigenetics,developmental stage,existing pathology),inadequate social connectivity,andother sociocultural factors(e.g.,normative behaviors re-garding drug use,affordability and

26、 availability of drugs,legal status).Research on the mechanisms underlying themodulatory influence of adverse social environments,child-hoodexperiences,andgeneticvariabilityisfundamentalforhelping us understand why not everyone who is exposedregularly to a drug becomes addicted(54,231),and whysome a

27、ddicted individuals can recover while others do not(47,210,287).II.DRUG REWARDDopamine(DA)lies at the center of drug reward(85,182).Every drug with addiction potential increases DA,eitherthrough direct or indirect effects on DA neurons in theventraltegmentalarea(VTA)withtheconsequentreleaseofDA in t

28、he nucleus accumbens(NAc)(357)(FIGURE 1).Drugs of abuse increase DA through their initial action ondifferent molecular targets and,depending on their phar-macological effects(TABLE 1),also engage additional neu-rotransmitters.Some of these,like the endogenous opioids(BOX 1)or the endogenous cannabin

29、oids(BOX 2)(FIGURE2),also contribute to the reinforcing effects of drugsthrough modulation of hedonic responses or inhibition ofnegative affective states(232).The significance of non-do-BOX 1.The endogenous opioid systemThe endogenous opioid system modulates the mesolimbic DAsystem(107,328)and is im

30、plicated in assigning hedonic val-ues to rewards and in integrating reward?related information toguide decision?making and execution of goal?directed behaviors(193).It consists of endogenous opioid peptides and their cog-nate receptors,namely,?-endorphins,enkephalins,and dynor-phins,which signal pre

31、ferentially through mu(MOR),delta(DOR),and kappa(KOR)opioid receptors,respectively.MORare responsible for the rewarding effects of opioids and foranalgesia,DOR are implicated in analgesia and anxiolysis,whileKOR are implicated in the dysphorigenic responses associatedwith addiction(194)and in stress

32、-induced relapse(136).MORin the VTA and NAc,as well as in the basolateral amygdala,areimplicated in opioids rewarding effects(FIGURES 1 AND 2).The opioid system also modulates mood,with stimulation ofMOR and KOR having predominantly antidepressant and dys-phorigenic effects,respectively(250).BOX 2.T

33、he endogenous cannabinoid systemThe endogenous cannabinoid system(ECS)modulates otherneurotransmitter systems including GABA,glutamate,and DAin key areas along the mesolimbic circuitry(209,348).TheECS consists of endogenous cannabinoids anandamide(AEA)and 2-arachidonoylglycerol(2-AG)and their cognat

34、e receptors(CB1R and CB2R)(337).Recent studies corroborate the func-tional importance of the ECS in modulating reward circuitry(252).For example,activation of CB1R in cortical glutamater-gic afferents inhibited DA release in the NAc and blunted re-ward-driven behaviors(225).In the VTA,2-AG,and to a

35、lesserextent AEA,released from DA neurons,retrogradely activateCB1R at VTA GABA inputs from GABAergic interneurons(FIG-URE 2),or from pallidum or rostromedial tegmental nucleiterminals(252,271).2-AG also activates CB1Rs at VTA glu-tamate inputs arising from cortex(252).Cannabinoids also actin the NA

36、c where medium spiny neurons(MSNs)are modulatedby CB1R expressing GABAergic interneurons,and by CB1Rexpressing glutamate terminals originating from amygdala,hip-pocampus,and prefrontal cortex(3,79,152).VOLKOW ET AL.2116Physiol RevVOL 99OCTOBER 2019www.prv.orgDownloaded from www.physiology.org/journa

37、l/physrev at East Carolina Univ(150.216.068.200)on September 12,2019.paminergic influences on reward processing has not been asextensively investigated as DAs but should not be underes-timated.In fact,dopamine-deficient(DD)mice showedconditioned place preference for cocaine also shown formorphine in

38、 naive rats(157),which appeared to be medi-ated by serotonin through a mechanism that involves DAneurons,presumably through their release of glutamate orneuropeptides like cholecystokinin and neurotensin(156).Also,studiesingeneticallyengineeredmicehaveshownthatthe mu opioid receptor(MOR)is not only

39、the main targetfor heroin and other opioid drugs,but is also essential forthe rewarding properties of nonopioid drugs,like alcohol,cocaine,and nicotine(62,153).In turn,repeated dopaminergic stimulation from drug useinduces neuroadaptations in multiple neurotransmitter sys-tems,including the glutamat

40、ergic system,which enhancesneuronal excitability and modulates neuroplasticity(286);the GABAergic system,which inhibits action potentialtransmission(168);and the opioid,endocannabinoid(232,337,351),cholinergic(78,204),serotonin(36,215),andnoradrenergic(109)systems,which modulate affective,he-donic,a

41、nd aversive circuits in the brain.Midbrain DA neurons and their projections into the NAcand the dorsal striatum and their GABAergic outputs areimplicated in motivating and sustaining reinforced behav-iors(includingtowardsfoodanddrugs)butalsoinavoidingaversive stimuli or states(262).DA neurons in the

42、 VTAproject to the NAc,which is a central hub of the rewardcircuit and a major driver of goal-directed actions that aresensitive to the current salience(estimated value)of an as-sociated goal(281).Meanwhile,DA neurons in the sub-stantia nigra(SN)project to the dorsal striatum and trans-late recurren

43、t reward signals into habitual actions that be-come increasingly insensitive to actual or updated goalvalues and are selected instead based on prior experiencewith the reinforcement associated with that action.Therepeated reward-associated behavior,over time,can even-tually result in the emergence o

44、f habits(103),as the dorsalstriatum gradually takes over from the ventral striatum.Additionally,following repeated drug exposures,habitsECBECBNAcVTAOpioidpeptidesOpioidpeptidesGABANicotineAlcoholStimulantsBLACTXGlutamateGlutamateMSNAlcoholAlcoholNicotineOpiatesCBsCBsCBsDAGABAOpiatesOpiatesHypothalam

45、usFIGURE 1.Schematic representation of key target sites for various drugs of abuse across the rewardcircuitry.Ventral tegmental area(VTA)dopamine(DA)ergic neurons project to forebrain targets such as thebasolateral amygdala(BLA),medial prefrontal area of the cortex(CTX)or mPFC,and nucleus accumbens(

46、NAc).These neurons receive excitatory synaptic inputs from the mPFC(but also from lateral hypothalamusand pedunculopontine tegmental nucleus/dorsolateral tegmental nucleus;not shown).GABAergic neurons inthe VTA target neighboring DAergic neurons as well as projecting to the mPFC and NAc(other inhibi

47、tory inputsto these DAergic neurons are likely to arise from extended amygdala output structures;not shown).GABAergicmedium spiny neurons(MSNs)in the NAc,which project to either the globus pallidus externus/ventral pallidum(VP)predominantly via D2R-expressing but also D1R-expressing neurons or to th

48、e VTA/SN via D1R-expressingneurons,receive dopaminergic input from the VTA.They also receive excitatory inputs from the mPFC and thebasolateral amygdala(BLA)(but also from the hippocampus and thalamus).The activity of MSNs is modulatedby both cholinergic and fast-spiking GABAergic interneurons(not s

49、hown)(312).Drugs of abuse,despitediverse initial actions,produce some common effects on the VTA and NAc.Stimulants directly increasedopaminergic transmission in the NAc.Opiates increase DA indirectly by inhibiting GABAergic interneurons inthe VTA,disinhibiting them and by stimulating mu opioid recep

50、tors(MOR)on NAc neurons(244).Nicotinestimulates DA neuron firing by its effects on ionotropic(nicotinic)acetylcholine receptors(314).Alcohol,among other effects,increases the firing of VTA DA neurons projecting to NAc via their disinhibition throughthe inhibition of GABA neurons(238).Cannabinoids(CB