1、THE NEUROSCIENCE OF DRUG REWARD ANDADDICTIONNora D.Volkow,Michael Michaelides,and Ruben BalerNational Institute on Drug Abuse,National Institutes of Health,Bethesda,MarylandLVolkowND,MichaelidesM,BalerR.The Neuroscience of Drug Reward and Addic-tion.Physiol Rev 99:21152140,2019.Published September 1
2、1,2019;doi:10.1152/physrev.00014.2018.Drug consumption is driven by a drugs pharmacolog-ical effects,which are experienced as rewarding,and is inuenced by genetic,devel-opmental,and psychosocial factors that mediate drug accessibility,norms,and socialsupport systems or lack thereof.The reinforcing e
3、ffects 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 limb
4、ic 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 drug
5、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,these
6、 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 hunge
7、r.”Treatment interventions intended to reverse theseneuroadaptations show promise as therapeutic approaches for addiction.cannabis;dopamine;glutamate;nucleus accumbens;opioids;substance use disordersI.INTRODUCTION 2115II.DRUG REWARD 2116III.DOPAMINE AND NEUROPLASTICITY 2119IV.NEUROCIRCUITRY OF ADDIC
8、TION 2121V.VULNERABILITY FACTORS 2126VI.CLINICAL IMPLICATIONS 2128VII.CONCLUSIONS 2130I.INTRODUCTIONThere is an inherent need in all sentient beings to seek outpositiveandavoidnegativestimuli,auniversalformulathathasevolvedtomaximizeadaptivetnessandthechancesofsurvival.The extent to which strategies
9、 for attaining oravoiding such stimuli are successful depends on complexinteractions between an organism and its environment thatare orchestrated by the nervous system.Neurobiology em-ploysprocessesrenedduringevolution,suchashomeostasis,sensory perception,associative and nonassociative learning,emot
10、ions,and decision-making,to shape an organisms re-sponsetoenvironmentalstimuliandtomaximizeitsabilitytoharness their predictable features and to adapt to unpredict-able ones.Although types of stimuli vary from one species toanother,therearestrikingsimilaritiesamongdifferentspecies,Neuroscience resea
11、rch 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 actions that are not
12、 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 when there is a str
13、ong 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 of distressing emoti
14、ons,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 also be personalized a
15、nd 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 signicantly reduce substance usedisorder in the individual and in a population.Physiol Rev 99:21
16、152140,2019Published September 11,2019;doi:10.1152/physrev.00014.20182115 0031-9333/19 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.g.,food and sex)and n
17、egative(e.g.,pain and environmental threats)stimuli.This commonrepresentation,whichreectsthecriticalroleofsuchstimuliinboostingtheoddsofsurvival,isoftenreectedattheneurobi-ological level,whereby different species tap into similar brainstructural,neurochemical,and functional strategies to tacklesimil
18、ar problems(77,284).Ingenuity has enabled humans to extract and rene highlyreinforcing stimuli against which naturally occurring rein-forcerscannoteasilycompete.Themostnotableexampleisour ability to purify and deliver drugs(e.g.,high alcoholcontent beverages,cigarettes,syringes for drug injections,a
19、nd 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 environments(e.g.,the ubiquity of legal and illega
20、l drugs,chronic stress,peerpressure)andindividualvulnerabilities(e.g.,preexistingmen-tal illness,chronic pain,genetic predisposition,gender,youngage),inuence drug experimentation as well as the risk andprevalenceofsubstanceusedisorders(SUD).Thelatestexam-ple of the potential consequences of such dru
21、g-promotive en-vironmentsistherisingtideofopioidfatalities,initiallyfueledby 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 esti-mated to have led to over 71,000 opioid overdose fa
22、talities 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 our society.The application of neuroscientic technologies
23、in humansand laboratory animals has led to remarkable advances inour understanding of the neurobiological underpinnings ofdrug reinforcement and addiction.As a result,addiction,whichhasbeenviewedhistoricallyasa“moraldeciency,”is being increasingly regarded as a chronic relapsing disor-der characteri
24、zed by an urge to consume drugs and by theprogressive loss of control over,and escalation in,drugintakedespiterepeated(unsuccessful)attemptstoresistdo-ing it(334).It is also recognized that addiction emerges inthe context of complex biopsychosocial interactions be-tweenthepharmacologicaleffectsofadr
25、ug,individualvul-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 availability of drugs,legal status).Research on the mechanisms underlying themo
26、dulatoryinuenceofadversesocialenvironments,child-hoodexperiences,andgeneticvariabilityisfundamentalforhelping us understand why not everyone who is exposedregularly to a drug becomes addicted(54,231),and whysome addicted individuals can recover while others do not(47,210,287).II.DRUG REWARDDopamine(
27、DA)liesatthecenterofdrugreward(85,182).Every drug with addiction potential increases DA,eitherthrough direct or indirect effects on DA neurons in theventraltegmentalarea(VTA)withtheconsequentreleaseofDA in the nucleus accumbens(NAc)(357)(FIGURE 1).Drugs of abuse increase DA through their initial act
28、ion ondifferent molecular targets and,depending on their phar-macological effects(TABLE 1),also engage additional neu-rotransmitters.Some of these,like the endogenous opioids(BOX1)ortheendogenouscannabinoids(BOX2)(FIGURE2),also contribute to the reinforcing effects of drugsthrough modulation of hedo
29、nic responses or inhibition ofnegative affective states(232).The signicance of non-do-BOX 1.The endogenous opioid systemThe endogenous opioid system modulates the mesolimbic DAsystem(107,328)and is implicated in assigning hedonic val-ues to rewards and in integrating reward related information togui
30、de 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 preferentially through mu(MOR),delta(DOR),and kappa(KOR)opioid receptors,respectively.MORare responsible
31、 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-induced relapse(136).MORin the VTA and NAc,as well as in the basolateral amygdala,areimplicated in o
32、pioids 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.The endogenous cannabinoid systemThe endogenous cannabinoid system(ECS)modulates otherneurotransmitter
33、 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 cognate receptors(CB1R and CB2R)(337).Recent studies corroborate the func-tional importance of the ECS in m
34、odulating 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 lesserextent AEA,released from DA neurons,retrogradely activateCB1R at VTA GABA inputs from GABAergic
35、 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 NAc where medium spiny neurons(MSNs)are modulatedby CB1R expressing GABAergic interneurons,and by CB1Re
36、xpressing glutamate terminals originating from amygdala,hip-pocampus,and prefrontal cortex(3,79,152).VOLKOW ET AL.2116 Physiol Rev VOL 99 OCTOBER 2019 www.prv.orgDownloaded from www.physiology.org/journal/physrev at East Carolina Univ(150.216.068.200)on September 12,2019.paminergicinuencesonrewardpr
37、ocessinghasnotbeenasextensivelyinvestigatedasDAsbutshouldnotbeunderes-timated.In fact,dopamine-decient(DD)mice showedconditioned place preference for cocaine also shown formorphine in naive rats(157),which appeared to be medi-ated by serotonin through a mechanism that involves DAneurons,presumably t
38、hrough their release of glutamate orneuropeptides like cholecystokinin and neurotensin(156).Also,studiesingeneticallyengineeredmicehaveshownthatthe mu opioid receptor(MOR)is not only the main targetfor heroin and other opioid drugs,but is also essential forthe rewarding properties of nonopioid drugs
39、,like alcohol,cocaine,and nicotine(62,153).In turn,repeated dopaminergic stimulation from drug useinducesneuroadaptationsinmultipleneurotransmittersys-tems,including the glutamatergic system,which enhancesneuronal excitability and modulates neuroplasticity(286);the GABAergic system,which inhibits ac
40、tion potentialtransmission(168);andtheopioid,endocannabinoid(232,337,351),cholinergic(78,204),serotonin(36,215),andnoradrenergic(109)systems,whichmodulateaffective,he-donic,and aversive circuits in the brain.Midbrain DA neurons and their projections into the NAcand the dorsal striatum and their GABA
41、ergic outputs areimplicated in motivating and sustaining reinforced behav-iors(includingtowardsfoodanddrugs)butalsoinavoidingaversive stimuli or states(262).DA neurons in the VTAproject to the NAc,which is a central hub of the rewardcircuit and a major driver of goal-directed actions that aresensiti
42、ve 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 recurrent reward signals into habitual actions that be-come increasingly insensitive to actual or updated goalvalues and are selected
43、instead based on prior experiencewith the reinforcement associated with that action.Therepeated reward-associated behavior,over time,can even-tually result in the emergence of habits(103),as the dorsalstriatum gradually takes over from the ventral striatum.Additionally,following repeated drug exposu
44、res,habitsECBECBNAc VTAOpioidpeptidesOpioidpeptidesGABANicotineAlcoholStimulantsBLACTXGlutamateGlutamateMSNAlcoholAlcoholNicotineOpiatesCBsCBsCBsDAGABAOpiatesOpiatesHypothalamusFIGURE 1.Schematic representation of key target sites for various drugs of abuse across the rewardcircuitry.Ventral tegment
45、al 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(NAc).These neurons receive excitatory synaptic inputs from the mPFC(but also from lateral hypothalamusand pedunculopontine te
46、gmental nucleus/dorsolateral tegmental nucleus;not shown).GABAergic neurons inthe VTA target neighboring DAergic neurons as well as projecting to the mPFC and NAc(other inhibitory inputsto these DAergic neurons are likely to arise from extended amygdala output structures;not shown).GABAergicmedium s
47、piny 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 the VTA/SN via D1R-expressingneurons,receive dopaminergic input from the VTA.They also receive excitatory inputs from the mPFC
48、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 shown)(312).Drugs of abuse,despitediverse initial actions,produce some common effects on the VTA and NAc.Stimulants directly i
49、ncreasedopaminergic transmission in the NAc.Opiates increase DA indirectly by inhibiting GABAergic interneurons inthe VTA,disinhibiting them and by stimulating mu opioid receptors(MOR)on NAc neurons(244).Nicotinestimulates DA neuron ring by its effects on ionotropic(nicotinic)acetylcholine receptors
50、(314).Alcohol,among other effects,increases the ring of VTA DA neurons projecting to NAc via their disinhibition throughthe inhibition of GABA neurons(238).Cannabinoids(CBs)disrupt the normal endocannabinoid(ECB)signalingfrom DAergic neurons on nearby glutamatergic(via retrograde suppression of exci
