Addiction - Wikipedia

Addiction is a neuropsychological disorder characterized by a persistent and intense urge to engage in certain behaviors, often usage of a drug, ... Addiction FromWikipedia,thefreeencyclopedia Jumptonavigation Jumptosearch Diseaseresultingincompulsiveengagementinrewardingstimulidespiteadverseconsequences "Addictive"redirectshere.Forotheruses,seeAddiction(disambiguation)andAddictive(disambiguation). NottobeconfusedwithPsychologicaldependence. ThisarticlemayrequirecleanuptomeetWikipedia'squalitystandards.Thespecificproblemis:Needexpansiononemptysections.Pleasehelpimprovethisarticleifyoucan.(July2022)(Learnhowandwhentoremovethistemplatemessage) MedicalconditionAddictionOthernamesSeveresubstanceusedisorder[1][2]BrainpositronemissiontomographyimagesthatcomparebrainmetabolisminahealthyindividualandanindividualwithacocaineaddictionSpecialtyPsychiatry,clinicalpsychology,toxicology,addictionmedicine Addictionanddependenceglossary[3][4][5][2] addiction–abiopsychosocialdisordercharacterizedbypersistentuseofdrugs(includingalcohol)despitesubstantialharmandadverseconsequences addictivedrug–psychoactivesubstancesthatwithrepeateduseareassociatedwithsignificantlyhigherratesofsubstanceusedisorders,dueinlargeparttothedrug'seffectonbrainrewardsystems dependence–anadaptivestateassociatedwithawithdrawalsyndromeuponcessationofrepeatedexposuretoastimulus(e.g.,drugintake) drugsensitizationorreversetolerance–theescalatingeffectofadrugresultingfromrepeatedadministrationatagivendose drugwithdrawal–symptomsthatoccuruponcessationofrepeateddruguse physicaldependence–dependencethatinvolvespersistentphysical–somaticwithdrawalsymptoms(e.g.,fatigueanddeliriumtremens) psychologicaldependence–dependencethatinvolvesemotional–motivationalwithdrawalsymptoms(e.g.,dysphoriaandanhedonia) reinforcingstimuli–stimulithatincreasetheprobabilityofrepeatingbehaviorspairedwiththem rewardingstimuli–stimulithatthebraininterpretsasintrinsicallypositiveanddesirableorassomethingtoapproach sensitization–anamplifiedresponsetoastimulusresultingfromrepeatedexposuretoit substanceusedisorder–aconditioninwhichtheuseofsubstancesleadstoclinicallyandfunctionallysignificantimpairmentordistress tolerance–thediminishingeffectofadrugresultingfromrepeatedadministrationatagivendose vte Addictionisaneuropsychologicaldisordercharacterizedbyapersistentandintenseurgetoengageincertainbehaviors,oftenusageofadrug,despitesubstantialharmandothernegativeconsequences.Repetitivedruguseoftenaltersbrainfunctioninwaysthatperpetuatecraving,andweakens(butdoesnotcompletelynegate)self-control.[6]Thisphenomenon–drugsreshapingbrainfunction–hasledtoanunderstandingofaddictionasabraindisorderwithacomplexvarietyofpsychosocialaswellasneurobiological(andthusinvoluntary)[a]factorsthatareimplicatedinaddiction'sdevelopment.[3][7][8]Classicsignsofaddictionincludecompulsiveengagementinrewardingstimuli,preoccupationwithsubstancesorbehavior,andcontinuedusedespitenegativeconsequences.Habitsandpatternsassociatedwithaddictionaretypicallycharacterizedbyimmediategratification(short-termreward),[9][10]coupledwithdelayeddeleteriouseffects(long-termcosts).[7][11] Examplesofdrugandbehavioraladdictionsincludealcoholism,marijuanaaddiction,amphetamineaddiction,cocaineaddiction,nicotineaddiction,opioidaddiction,videogameaddiction,gamblingaddiction,pornographyaddictionandsexualaddiction.TheonlybehavioraladdictionrecognizedbytheDSM-5andtheICD-10isgamblingaddiction.WiththeintroductionoftheICD-11gamingaddictionwasappended.[12]Theterm"addiction"isfrequentlymisusedwhenreferringtoothercompulsivebehaviorsordisorders,particularlydependence,innewsmedia.[13]Animportantdistinctionbetweendrugaddictionanddependenceisthatdrugdependenceisadisorderinwhichcessationofdruguseresultsinanunpleasantstateofwithdrawal,whichcanleadtofurtherdruguse.[14]Addictionisthecompulsiveuseofasubstanceorperformanceofabehaviorthatisindependentofwithdrawal.Addictioncanoccurintheabsenceofdependence,anddependencecanoccurintheabsenceofaddiction,althoughthetwooftenoccurtogether. Contents 1Behavioraladdiction 2Signsandsymptoms 3Causes 3.1Personalitytheories 3.2Neuropsychology 3.2.1Stimuluscontrolofbehavior 3.2.2Cognitivecontrolofbehavior 3.3Riskfactors 3.3.1Geneticfactors 3.3.2Environmentalfactors 3.3.2.1Age 3.3.2.2Comorbiddisorders 3.3.3Epigenetic 3.3.3.1Transgenerationalepigeneticinheritance 4Mechanisms 4.1Rewardsystem 4.1.1Mesocorticolimbicpathway 4.1.2Roleofdopamineandglutamate 4.2Rewardsensitization 4.3Neuroepigeneticmechanisms 5Diagnosis 5.1Classification 5.1.1DSM-5 5.1.2ICD-11 6Prevention 6.1Abuseliability 7Treatmentandmanagement 7.1Behavioraltherapy 7.2Medication 7.2.1Alcoholaddiction 7.2.2Behavioraladdictions 7.2.3Cannabinoidaddiction 7.2.4Nicotineaddiction 7.2.5Opioidaddiction 7.2.6Psychostimulantaddiction 7.2.7Research 8Epidemiology 8.1Asia 8.2Australia 8.3Europe 8.4UnitedStates 8.5SouthAmerica 9Historyandetymology 10Societyandculture 10.1Abiopsychosocial–spiritualunderstandingofaddiction 10.1.1TheCulturalModel 10.1.2TheSubculturalModel 10.1.3TheCriticalMedicalAnthropologyModel 10.2Thesuffixes"-holic"and"-holism" 11Seealso 12Endnotes 13Notes 14References 15Furtherreading 16Externallinks Behavioraladdiction[edit] Mainarticle:Behavioraladdiction Theterm"behavioraladdiction"referstoacompulsiontoengageinanaturalreward–whichisabehaviorthatisinherentlyrewarding(i.e.,desirableorappealing)–despiteadverseconsequences.[10][15][16]PreclinicalevidencehasdemonstratedthatmarkedincreasesintheexpressionofΔFosBthroughrepetitiveandexcessiveexposuretoanaturalrewardinducesthesamebehavioraleffectsandneuroplasticityasoccursinadrugaddiction.[15][17][18][19] ReviewsofbothclinicalresearchinhumansandpreclinicalstudiesinvolvingΔFosBhaveidentifiedcompulsivesexualactivity–specifically,anyformofsexualintercourse–asanaddiction(i.e.,sexualaddiction).[15][17]Moreover,rewardcross-sensitizationbetweenamphetamineandsexualactivity,meaningthatexposuretooneincreasesthedesireforboth,hasbeenshowntooccurpreclinicallyandclinicallyasadopaminedysregulationsyndrome;[15][17][18][19]ΔFosBexpressionisrequiredforthiscross-sensitizationeffect,whichintensifieswiththelevelofΔFosBexpression.[15][18][19] Reviewsofpreclinicalstudiesindicatethatlong-termfrequentandexcessiveconsumptionofhighfatorsugarfoodscanproduceanaddiction(foodaddiction).[15][16]Thiscanincludechocolate.Chocolates'sweetflavourandpharmacologicalingredientsisknowntocreateastrongcravingorfeel'addictive'bytheconsumer.[20]Apersonwhohasastronglikingforchocolatemayrefertothemselvesasachocoholic.ChocolateisnotyetformallyrecognisedbytheDSM-5asadiagnosableaddiction.[21] Gamblingprovidesanaturalrewardwhichisassociatedwithcompulsivebehaviorandforwhichclinicaldiagnosticmanuals,namelytheDSM-5,haveidentifieddiagnosticcriteriaforan"addiction".[15]Inorderforaperson'sgamblingbehaviortomeetcriteriaofanaddiction,itshowscertaincharacteristics,suchasmoodmodification,compulsivity,andwithdrawal.Thereisevidencefromfunctionalneuroimagingthatgamblingactivatestherewardsystemandthemesolimbicpathwayinparticular.[15][22]Similarly,shoppingandplayingvideogamesareassociatedwithcompulsivebehaviorsinhumansandhavealsobeenshowntoactivatethemesolimbicpathwayandotherpartsoftherewardsystem.[15]Baseduponthisevidence,gamblingaddiction,videogameaddiction,andshoppingaddictionareclassifiedaccordingly.[15][22] Signsandsymptoms[edit] Thissectionneedsexpansion.Youcanhelpbyaddingtoit.(July2022) Causes[edit] Personalitytheories[edit] Mainarticle:Personalitytheoriesofaddiction Personalitytheoriesofaddictionarepsychologicalmodelsthatassociatepersonalitytraitsormodesofthinking(i.e.,affectivestates)withanindividual'sproclivityfordevelopinganaddiction.Dataanalysisdemonstratesthatthereisasignificantdifferenceinthepsychologicalprofilesofdrugusersandnon-usersandthepsychologicalpredispositiontousingdifferentdrugsmaybedifferent.[23]Modelsofaddictionriskthathavebeenproposedinpsychologyliteratureincludeanaffectdysregulationmodelofpositiveandnegativepsychologicalaffects,thereinforcementsensitivitytheorymodelofimpulsivenessandbehavioralinhibition,andanimpulsivitymodelofrewardsensitizationandimpulsiveness.[24][25][26][27][28] Neuropsychology[edit] Cognitivecontrolandstimuluscontrol,whichisassociatedwithoperantandclassicalconditioning,representoppositeprocesses(i.e.,internalvsexternalorenvironmental,respectively)thatcompeteoverthecontrolofanindividual'selicitedbehaviors.[29]Cognitivecontrol,andparticularlyinhibitorycontroloverbehavior,isimpairedinbothaddictionandattentiondeficithyperactivitydisorder.[30][31]Stimulus-drivenbehavioralresponses(i.e.,stimuluscontrol)thatareassociatedwithaparticularrewardingstimulustendtodominateone'sbehaviorinanaddiction.[31] Stimuluscontrolofbehavior[edit] Seealso:Stimuluscontrol Cognitivecontrolofbehavior[edit] Seealso:Cognitivecontrol Riskfactors[edit] Furtherinformation:Addictionvulnerability Thereareanumberofgeneticandenvironmentalriskfactorsfordevelopinganaddiction,thatvaryacrossthepopulation.[3][32]Geneticandenvironmentalriskfactorseachaccountforroughlyhalfofanindividual'sriskfordevelopinganaddiction;[3]thecontributionfromepigeneticriskfactorstothetotalriskisunknown.[32]Eveninindividualswitharelativelylowgeneticrisk,exposuretosufficientlyhighdosesofanaddictivedrugforalongperiodoftime(e.g.,weeks–months)canresultinanaddiction.[3]Adversechildhoodeventsareassociatedwithnegativehealthoutcomes,suchassubstanceusedisorder.Studiesshowthatchildhoodabuseorexposuretoviolentcrimewaspositivelyrelatedtodevelopingamoodoranxietydisorder,aswellasasubstancedependencerisk.[33] Geneticfactors[edit] Seealso:Alcoholism§ Geneticvariation Geneticfactors,alongwithenvironmental(e.g.,psychosocial)factors,havebeenestablishedassignificantcontributorstoaddictionvulnerability.[3][32]Studiesdoneon350hospitalizeddrug-dependentpatientsshowedthatoverhalfmetthecriteriaforalcoholabuse,witharoleoffamilialfactorsbeingprevalent.[34]Epidemiologicalstudiesestimatethatgeneticfactorsaccountfor40–60%oftheriskfactorsforalcoholism.[35]Similarratesofheritabilityforothertypesofdrugaddictionhavebeenindicatedbyotherstudies,specificallyingenesthatencodetheAlpha5NicotinicAcetylcholineReceptor.[36]Knestlerhypothesizedin1964thatageneorgroupofgenesmightcontributetopredispositiontoaddictioninseveralways.Forexample,alteredlevelsofanormalproteinduetoenvironmentalfactorsmaychangethestructureorfunctioningofspecificbrainneuronsduringdevelopment.Thesealteredbrainneuronscouldaffectthesusceptibilityofanindividualtoaninitialdruguseexperience.Insupportofthishypothesis,animalstudieshaveshownthatenvironmentalfactorssuchasstresscanaffectananimal'sgeneticexpression.[36] Inhumans,twinstudiesintoaddictionhaveprovidedsomeofthehighest-qualityevidenceofthislink,withresultsfindingthatifonetwinisaffectedbyaddiction,theothertwinislikelytobeaswell,andoftentothesamesubstance.[37]Furtherevidenceofageneticcomponentisresearchfindingsfromfamilystudieswhichsuggestthatifonefamilymemberhasahistoryofaddiction,thechancesofarelativeorclosefamilydevelopingthosesamehabitsaremuchhigherthanonewhohasnotbeenintroducedtoaddictionatayoungage.[38] However,thedataimplicatingspecificgenesinthedevelopmentofdrugaddictionismixedformostgenes.Manyaddictionstudiesthataimtoidentifyspecificgenesfocusoncommonvariantswithanallelefrequencyofgreaterthan5%inthegeneralpopulation;however,whenassociatedwithdisease,theseonlyconferasmallamountofadditionalriskwithanoddsratioof1.1–1.3percent;thishasledtothedevelopmenttherarevarianthypothesis,whichstatesthatgeneswithlowfrequenciesinthepopulation(<1%)confermuchgreateradditionalriskinthedevelopmentofthedisease.[39] Genome-wideassociationstudies(GWAS)areusedtoexaminegeneticassociationswithdependence,addiction,anddruguse;however,thesestudiesrarelyidentifygenesfromproteinspreviouslydescribedviaanimalknockoutmodelsandcandidategeneanalysis.Instead,largepercentagesofgenesinvolvedinprocessessuchascelladhesionarecommonlyidentified.Theimportanteffectsofendophenotypesaretypicallynotcapableofbeingcapturedbythesemethods.GenesidentifiedinGWASfordrugaddictionmaybeinvolvedeitherinadjustingbrainbehaviorpriortodrugexperiences,subsequenttothem,orboth.[40] Environmentalfactors[edit] Environmentalriskfactorsforaddictionaretheexperiencesofanindividualduringtheirlifetimethatinteractwiththeindividual'sgeneticcompositiontoincreaseordecreasehisorhervulnerabilitytoaddiction.[3]Forexample,afterthenationwideoutbreakofCOVID-19,morepeoplequit(vs.started)smoking;andsmokers,onaverage,reducedthequantityofcigarettestheyconsumed.[41]Moregenerally,anumberofdifferentenvironmentalfactorshavebeenimplicatedasriskfactorsforaddiction,includingvariouspsychosocialstressors.TheNationalInstituteonDrugAbuse(NIDA)citeslackofparentalsupervision,theprevalenceofpeersubstanceuse,drugavailability,andpovertyasriskfactorsforsubstanceuseamongchildrenandadolescents.[42]Thebraindiseasemodelofaddictionpositsthatanindividual'sexposuretoanaddictivedrugisthemostsignificantenvironmentalriskfactorforaddiction.[43]However,manyresearchers,includingneuroscientists,indicatethatthebraindiseasemodelpresentsamisleading,incomplete,andpotentiallydetrimentalexplanationofaddiction.[44] Adversechildhoodexperiences(ACEs)arevariousformsofmaltreatmentandhouseholddysfunctionexperiencedinchildhood.TheAdverseChildhoodExperiencesStudybytheCentersforDiseaseControlandPreventionhasshownastrongdose–responserelationshipbetweenACEsandnumeroushealth,social,andbehavioralproblemsthroughoutaperson'slifespan,includingsubstanceusedisorder.[45]Children'sneurologicaldevelopmentcanbepermanentlydisruptedwhentheyarechronicallyexposedtostressfuleventssuchasphysical,emotional,orsexualabuse,physicaloremotionalneglect,witnessingviolenceinthehousehold,oraparentbeingincarceratedorhavingamentalillness.Asaresult,thechild'scognitivefunctioningorabilitytocopewithnegativeordisruptiveemotionsmaybeimpaired.Overtime,thechildmayadoptsubstanceuseasacopingmechanism,particularlyduringadolescence.[45]Astudyof900courtcasesinvolvingchildrenwhoexperiencedabusefoundthatavastamountofthemwentontohavesomeformofaddictionintheiradolescenceoradultlife.[46]Thispathwaytowardsaddictionthatisopenedthroughstressfulexperiencesduringchildhoodcanbeavoidedbyachangeinenvironmentalfactorsthroughoutanindividual'slifeandopportunitiesofprofessionalhelp.[46]Ifonehasfriendsorpeerswhoengageindrugusefavorably,thechancesofthemdevelopinganaddictionincreases.Familyconflictandhomemanagementisalsoacauseforonetobecomeengagedinalcoholorotherdruguse.[47] Age[edit] Adolescencerepresentsaperiodofuniquevulnerabilityfordevelopinganaddiction.[48]Inadolescence,theincentive-rewardssystemsinthebrainmaturewellbeforethecognitivecontrolcenter.Thisconsequentiallygrantstheincentive-rewardssystemsadisproportionateamountofpowerinthebehavioraldecision-makingprocess.Therefore,adolescentsareincreasinglylikelytoactontheirimpulsesandengageinrisky,potentiallyaddictingbehaviorbeforeconsideringtheconsequences.[49]Notonlyareadolescentsmorelikelytoinitiateandmaintaindruguse,butonceaddictedtheyaremoreresistanttotreatmentandmoreliabletorelapse.[50][51] Mostindividualsareexposedtoanduseaddictivedrugsforthefirsttimeduringtheirteenageyears.[52]IntheUnitedStates,therewerejustover2.8 millionnewusersofillicitdrugsin2013(~7,800newusersperday);[52]amongthem,54.1%wereunder18 yearsofage.[52]In2011,therewereapproximately20.6 millionpeopleintheUnitedStatesovertheageof12withanaddiction.[53]Over90%ofthosewithanaddictionbegandrinking,smokingorusingillicitdrugsbeforetheageof18.[53] Comorbiddisorders[edit] Individualswithcomorbid(i.e.,co-occurring)mentalhealthdisorderssuchasdepression,anxiety,attention-deficit/hyperactivitydisorder(ADHD)orpost-traumaticstressdisorderaremorelikelytodevelopsubstanceusedisorders.[54][55][56]TheNIDAcitesearlyaggressivebehaviorasariskfactorforsubstanceuse.[42]AstudybytheNationalBureauofEconomicResearchfoundthatthereisa"definiteconnectionbetweenmentalillnessandtheuseofaddictivesubstances"andamajorityofmentalhealthpatientsparticipateintheuseofthesesubstances:38%alcohol,44%cocaine,and40%cigarettes.[57] Epigenetic[edit] Transgenerationalepigeneticinheritance[edit] Seealso:Transgenerationalepigeneticinheritance Epigeneticgenesandtheirproducts(e.g.,proteins)arethekeycomponentsthroughwhichenvironmentalinfluencescanaffectthegenesofanindividual;[32]theyalsoserveasthemechanismresponsiblefortransgenerationalepigeneticinheritance,aphenomenoninwhichenvironmentalinfluencesonthegenesofaparentcanaffecttheassociatedtraitsandbehavioralphenotypesoftheiroffspring(e.g.,behavioralresponsestoenvironmentalstimuli).[32]Inaddiction,epigeneticmechanismsplayacentralroleinthepathophysiologyofthedisease;[3]ithasbeennotedthatsomeofthealterationstotheepigenomewhicharisethroughchronicexposuretoaddictivestimuliduringanaddictioncanbetransmittedacrossgenerations,inturnaffectingthebehaviorofone'schildren(e.g.,thechild'sbehavioralresponsestoaddictivedrugsandnaturalrewards).[32][58] ThegeneralclassesofepigeneticalterationsthathavebeenimplicatedintransgenerationalepigeneticinheritanceincludeDNAmethylation,histonemodifications,anddownregulationorupregulationofmicroRNAs.[32]Withrespecttoaddiction,moreresearchisneededtodeterminethespecificheritableepigeneticalterationsthatarisefromvariousformsofaddictioninhumansandthecorrespondingbehavioralphenotypesfromtheseepigeneticalterationsthatoccurinhumanoffspring.[32][58]Baseduponpreclinicalevidencefromanimalresearch,certainaddiction-inducedepigeneticalterationsinratscanbetransmittedfromparenttooffspringandproducebehavioralphenotypesthatdecreasetheoffspring'sriskofdevelopinganaddiction.[note1][32]Moregenerally,theheritablebehavioralphenotypesthatarederivedfromaddiction-inducedepigeneticalterationsandtransmittedfromparenttooffspringmayservetoeitherincreaseordecreasetheoffspring'sriskofdevelopinganaddiction.[32][58] Mechanisms[edit] Addictionisadisorderofthebrain'srewardsystemdevelopingthroughtranscriptionalandepigeneticmechanismsasaresultofchronicallyhighlevelsofexposuretoanaddictivestimulus(e.g.,eatingfood,theuseofcocaine,engagementinsexualactivity,participationinhigh-thrillculturalactivitiessuchasgambling,etc.)overextendedtime.[3][59][15]DeltaFosB(ΔFosB),agenetranscriptionfactor,isacriticalcomponentandcommonfactorinthedevelopmentofvirtuallyallformsofbehavioralanddrugaddictions.[59][15][60][16]TwodecadesofresearchintoΔFosB'sroleinaddictionhavedemonstratedthataddictionarises,andtheassociatedcompulsivebehaviorintensifiesorattenuates,alongwiththeoverexpressionofΔFosBintheD1-typemediumspinyneuronsofthenucleusaccumbens.[3][59][15][60]DuetothecausalrelationshipbetweenΔFosBexpressionandaddictions,itisusedpreclinicallyasanaddictionbiomarker.[3][59][60]ΔFosBexpressionintheseneuronsdirectlyandpositivelyregulatesdrugself-administrationandrewardsensitizationthroughpositivereinforcement,whiledecreasingsensitivitytoaversion.[note2][3][59] Transcriptionfactorglossary geneexpression–theprocessbywhichinformationfromageneisusedinthesynthesisofafunctionalgeneproductsuchasaprotein transcription–theprocessofmakingmessengerRNA(mRNA)fromaDNAtemplatebyRNApolymerase transcriptionfactor–aproteinthatbindstoDNAandregulatesgeneexpressionbypromotingorsuppressingtranscription transcriptionalregulation–controllingtherateofgenetranscriptionforexamplebyhelpingorhinderingRNApolymerasebindingtoDNA upregulation,activation,orpromotion–increasetherateofgenetranscription downregulation,repression,orsuppression–decreasetherateofgenetranscription coactivator–aprotein(orasmallmolecule)thatworkswithtranscriptionfactorstoincreasetherateofgenetranscription corepressor–aprotein(orasmallmolecule)thatworkswithtranscriptionfactorstodecreasetherateofgenetranscription responseelement–aspecificsequenceofDNAthatatranscriptionfactorbindsto vte Signalingcascadeinthenucleusaccumbensthatresultsinpsychostimulantaddictionvte Note:coloredtextcontainsarticlelinks. Nuclearpore Nuclearmembrane Plasmamembrane Cav1.2 NMDAR AMPAR DRD1 DRD5 DRD2 DRD3 DRD4 Gs Gi/o AC cAMP cAMP PKA CaM CaMKII DARPP-32 PP1 PP2B CREB ΔFosB JunD c-Fos SIRT1 HDAC1 [Colorlegend1] Thisdiagramdepictsthesignalingeventsinthebrain'srewardcenterthatareinducedbychronichigh-doseexposuretopsychostimulantsthatincreasetheconcentrationofsynapticdopamine,likeamphetamine,methamphetamine,andphenethylamine.Followingpresynapticdopamineandglutamateco-releasebysuchpsychostimulants,[61][62]postsynapticreceptorsfortheseneurotransmitterstriggerinternalsignalingeventsthroughacAMP-dependentpathwayandacalcium-dependentpathwaythatultimatelyresultinincreasedCREBphosphorylation.[61][63][64]PhosphorylatedCREBincreaseslevelsofΔFosB,whichinturnrepressesthec-Fosgenewiththehelpofcorepressors;[61][65][66]c-FosrepressionactsasamolecularswitchthatenablestheaccumulationofΔFosBintheneuron.[67]Ahighlystable(phosphorylated)formofΔFosB,onethatpersistsinneuronsfor1–2 months,slowlyaccumulatesfollowingrepeatedhigh-doseexposuretostimulantsthroughthisprocess.[65][66]ΔFosBfunctionsas"oneofthemastercontrolproteins"thatproducesaddiction-relatedstructuralchangesinthebrain,anduponsufficientaccumulation,withthehelpofitsdownstreamtargets(e.g.,nuclearfactorkappaB),itinducesanaddictivestate.[65][66] Chronicaddictivedrugusecausesalterationsingeneexpressioninthemesocorticolimbicprojection.[16][68][69]ThemostimportanttranscriptionfactorsthatproducethesealterationsareΔFosB,cAMPresponseelementbindingprotein(CREB),andnuclearfactorkappaB(NF-κB).[16]ΔFosBisthemostsignificantbiomolecularmechanisminaddictionbecausetheoverexpressionofΔFosBintheD1-typemediumspinyneuronsinthenucleusaccumbensisnecessaryandsufficientformanyoftheneuraladaptationsandbehavioraleffects(e.g.,expression-dependentincreasesindrugself-administrationandrewardsensitization)seenindrugaddiction.[16]ΔFosBexpressioninnucleusaccumbensD1-typemediumspinyneuronsdirectlyandpositivelyregulatesdrugself-administrationandrewardsensitizationthroughpositivereinforcementwhiledecreasingsensitivitytoaversion.[note2][3][59]ΔFosBhasbeenimplicatedinmediatingaddictionstomanydifferentdrugsanddrugclasses,includingalcohol,amphetamineandothersubstitutedamphetamines,cannabinoids,cocaine,methylphenidate,nicotine,opiates,phenylcyclidine,andpropofol,amongothers.[59][16][68][70][71]ΔJunD,atranscriptionfactor,andG9a,ahistonemethyltransferase,bothopposethefunctionofΔFosBandinhibitincreasesinitsexpression.[3][16][72]IncreasesinnucleusaccumbensΔJunDexpression(viaviralvector-mediatedgenetransfer)orG9aexpression(viapharmacologicalmeans)reduces,orwithalargeincreasecanevenblock,manyoftheneuralandbehavioralalterationsthatresultfromchronichigh-doseuseofaddictivedrugs(i.e.,thealterationsmediatedbyΔFosB).[60][16] ΔFosBalsoplaysanimportantroleinregulatingbehavioralresponsestonaturalrewards,suchaspalatablefood,sex,andexercise.[16][73]Naturalrewards,likedrugsofabuse,inducegeneexpressionofΔFosBinthenucleusaccumbens,andchronicacquisitionoftheserewardscanresultinasimilarpathologicaladdictivestatethroughΔFosBoverexpression.[15][16][73]Consequently,ΔFosBisthekeytranscriptionfactorinvolvedinaddictionstonaturalrewards(i.e.,behavioraladdictions)aswell;[16][15][73]inparticular,ΔFosBinthenucleusaccumbensiscriticalforthereinforcingeffectsofsexualreward.[73]Researchontheinteractionbetweennaturalanddrugrewardssuggeststhatdopaminergicpsychostimulants(e.g.,amphetamine)andsexualbehavioractonsimilarbiomolecularmechanismstoinduceΔFosBinthenucleusaccumbensandpossessbidirectionalcross-sensitizationeffectsthataremediatedthroughΔFosB.[15][18][19]Thisphenomenonisnotablesince,inhumans,adopaminedysregulationsyndrome,characterizedbydrug-inducedcompulsiveengagementinnaturalrewards(specifically,sexualactivity,shopping,andgambling),hasalsobeenobservedinsomeindividualstakingdopaminergicmedications.[15] ΔFosBinhibitors(drugsortreatmentsthatopposeitsaction)maybeaneffectivetreatmentforaddictionandaddictivedisorders.[74] Thereleaseofdopamineinthenucleusaccumbensplaysaroleinthereinforcingqualitiesofmanyformsofstimuli,includingnaturallyreinforcingstimulilikepalatablefoodandsex.[75][76]Altereddopamineneurotransmissionisfrequentlyobservedfollowingthedevelopmentofanaddictivestate.[15]Inhumansandlabanimalsthathavedevelopedanaddiction,alterationsindopamineoropioidneurotransmissioninthenucleusaccumbensandotherpartsofthestriatumareevident.[15]Studieshavefoundthatuseofcertaindrugs(e.g.,cocaine)affectcholinergicneuronsthatinnervatetherewardsystem,inturnaffectingdopaminesignalinginthisregion.[77] Rewardsystem[edit] Mainarticle:Rewardsystem Mesocorticolimbicpathway[edit] ΔFosBaccumulationfromexcessivedruguse Top:thisdepictstheinitialeffectsofhighdoseexposuretoanaddictivedrugongeneexpressioninthenucleusaccumbensforvariousFosfamilyproteins(i.e.,c-Fos,FosB,ΔFosB,Fra1,andFra2).Bottom:thisillustratestheprogressiveincreaseinΔFosBexpressioninthenucleusaccumbensfollowingrepeatedtwicedailydrugbinges,wherethesephosphorylated(35–37 kilodalton)ΔFosBisoformspersistintheD1-typemediumspinyneuronsofthenucleusaccumbensforupto2 months.[66][78] Understandingthepathwaysinwhichdrugsactandhowdrugscanalterthosepathwaysiskeywhenexaminingthebiologicalbasisofdrugaddiction.Therewardpathway,knownasthemesolimbicpathway,oritsextension,themesocorticolimbicpathway,ischaracterizedbytheinteractionofseveralareasofthebrain. Theprojectionsfromtheventraltegmentalarea(VTA)areanetworkofdopaminergicneuronswithco-localizedpostsynapticglutamatereceptors(AMPARandNMDAR).Thesecellsrespondwhenstimuliindicativeofarewardarepresent.TheVTAsupportslearningandsensitizationdevelopmentandreleasesDAintotheforebrain.[79]TheseneuronsalsoprojectandreleaseDAintothenucleusaccumbens,[80]throughthemesolimbicpathway.Virtuallyalldrugscausingdrugaddictionincreasethedopaminereleaseinthemesolimbicpathway,[81]inadditiontotheirspecificeffects. Thenucleusaccumbens(NAcc)isoneoutputoftheVTAprojections.ThenucleusaccumbensitselfconsistsmainlyofGABAergicmediumspinyneurons(MSNs).[82]TheNAccisassociatedwithacquiringandelicitingconditionedbehaviors,andisinvolvedintheincreasedsensitivitytodrugsasaddictionprogresses.[79]OverexpressionofΔFosBinthenucleusaccumbensisanecessarycommonfactorinessentiallyallknownformsofaddiction;[3]ΔFosBisastrongpositivemodulatorofpositivelyreinforcedbehaviors.[3] Theprefrontalcortex,includingtheanteriorcingulateandorbitofrontalcortices,[83]isanotherVTAoutputinthemesocorticolimbicpathway;itisimportantfortheintegrationofinformationwhichhelpsdeterminewhetherabehaviorwillbeelicited.[84]Itisalsocriticalforformingassociationsbetweentherewardingexperienceofdruguseandcuesintheenvironment.Importantly,thesecuesarestrongmediatorsofdrug-seekingbehaviorandcantriggerrelapseevenaftermonthsoryearsofabstinence.[85] Otherbrainstructuresthatareinvolvedinaddictioninclude: ThebasolateralamygdalaprojectsintotheNAccandisthoughttoalsobeimportantformotivation.[84] Thehippocampusisinvolvedindrugaddiction,becauseofitsroleinlearningandmemory.MuchofthisevidencestemsfrominvestigationsshowingthatmanipulatingcellsinthehippocampusaltersdopaminelevelsinNAccandfiringratesofVTAdopaminergiccells.[80] Roleofdopamineandglutamate[edit] Dopamineistheprimaryneurotransmitteroftherewardsysteminthebrain.Itplaysaroleinregulatingmovement,emotion,cognition,motivation,andfeelingsofpleasure.[86]Naturalrewards,likeeating,aswellasrecreationaldrugusecauseareleaseofdopamine,andareassociatedwiththereinforcingnatureofthesestimuli.[86][87]Nearlyalladdictivedrugs,directlyorindirectly,actuponthebrain'srewardsystembyheighteningdopaminergicactivity.[88] Excessiveintakeofmanytypesofaddictivedrugsresultsinrepeatedreleaseofhighamountsofdopamine,whichinturnaffectstherewardpathwaydirectlythroughheighteneddopaminereceptoractivation.Prolongedandabnormallyhighlevelsofdopamineinthesynapticcleftcaninducereceptordownregulationintheneuralpathway.Downregulationofmesolimbicdopaminereceptorscanresultinadecreaseinthesensitivitytonaturalreinforcers.[86] Drugseekingbehaviorisinducedbyglutamatergicprojectionsfromtheprefrontalcortextothenucleusaccumbens.ThisideaissupportedwithdatafromexperimentsshowingthatdrugseekingbehaviorcanbepreventedfollowingtheinhibitionofAMPAglutamatereceptorsandglutamatereleaseinthenucleusaccumbens.[83] Rewardsensitization[edit] NeuralandbehavioraleffectsofvalidatedΔFosBtranscriptionaltargetsinthestriatum[59][89] Targetgene Targetexpression Neuraleffects Behavioraleffects c-Fos ↓ MolecularswitchenablingthechronicinductionofΔFosB[note3] – dynorphin ↓[note4]  •Downregulationofκ-opioidfeedbackloop  •Increaseddrugreward NF-κB ↑  •ExpansionofNAccdendriticprocesses •NF-κBinflammatoryresponseintheNAcc •NF-κBinflammatoryresponseintheCP  •Increaseddrugreward •Increaseddrugreward •Locomotorsensitization GluR2 ↑  •Decreasedsensitivitytoglutamate  •Increaseddrugreward Cdk5 ↑  •GluR1synapticproteinphosphorylation •ExpansionofNAccdendriticprocesses Decreaseddrugreward(neteffect) Rewardsensitizationisaprocessthatcausesanincreaseintheamountofreward(specifically,incentivesalience[note5])thatisassignedbythebraintoarewardingstimulus(e.g.,adrug).Insimpleterms,whenrewardsensitizationtoaspecificstimulus(e.g.,adrug)occurs,anindividual's"wanting"ordesireforthestimulusitselfanditsassociatedcuesincreases.[91][90][92]Rewardsensitizationnormallyoccursfollowingchronicallyhighlevelsofexposuretothestimulus.ΔFosB(DeltaFosB)expressioninD1-typemediumspinyneuronsinthenucleusaccumbenshasbeenshowntodirectlyandpositivelyregulaterewardsensitizationinvolvingdrugsandnaturalrewards.[3][59][60] "Cue-inducedwanting"or"cue-triggeredwanting",aformofcravingthatoccursinaddiction,isresponsibleformostofthecompulsivebehaviorthatpeoplewithaddictionsexhibit.[90][92]Duringthedevelopmentofanaddiction,therepeatedassociationofotherwiseneutralandevennon-rewardingstimuliwithdrugconsumptiontriggersanassociativelearningprocessthatcausesthesepreviouslyneutralstimulitoactasconditionedpositivereinforcersofaddictivedruguse(i.e.,thesestimulistarttofunctionasdrugcues).[90][93][92]Asconditionedpositivereinforcersofdruguse,thesepreviouslyneutralstimuliareassignedincentivesalience(whichmanifestsasacraving) –sometimesatpathologicallyhighlevelsduetorewardsensitization –whichcantransfertotheprimaryreinforcer(e.g.,theuseofanaddictivedrug)withwhichitwasoriginallypaired.[90][93][92] Researchontheinteractionbetweennaturalanddrugrewardssuggeststhatdopaminergicpsychostimulants(e.g.,amphetamine)andsexualbehavioractonsimilarbiomolecularmechanismstoinduceΔFosBinthenucleusaccumbensandpossessabidirectionalrewardcross-sensitizationeffect[note6]thatismediatedthroughΔFosB.[15][18][19]IncontrasttoΔFosB'sreward-sensitizingeffect,CREBtranscriptionalactivitydecreasesuser'ssensitivitytotherewardingeffectsofthesubstance.CREBtranscriptioninthenucleusaccumbensisimplicatedinpsychologicaldependenceandsymptomsinvolvingalackofpleasureormotivationduringdrugwithdrawal.[3][78][89] Summaryofaddiction-relatedplasticity Formofneuroplasticityorbehavioralplasticity Typeofreinforcer Sources Opiates Psychostimulants Highfatorsugarfood Sexualintercourse Physicalexercise(aerobic) Environmentalenrichment ΔFosBexpressioninnucleusaccumbensD1-typeMSNs ↑ ↑ ↑ ↑ ↑ ↑ [15] Behavioralplasticity Escalationofintake Yes Yes Yes [15] Psychostimulantcross-sensitization Yes Notapplicable Yes Yes Attenuated Attenuated [15] Psychostimulantself-administration ↑ ↑ ↓ ↓ ↓ [15] Psychostimulantconditionedplacepreference ↑ ↑ ↓ ↑ ↓ ↑ [15] Reinstatementofdrug-seekingbehavior ↑ ↑ ↓ ↓ [15] Neurochemicalplasticity CREBphosphorylationinthenucleusaccumbens ↓ ↓ ↓ ↓ ↓ [15] Sensitizeddopamineresponseinthenucleusaccumbens No Yes No Yes [15] Alteredstriataldopaminesignaling ↓DRD2,↑DRD3 ↑DRD1,↓DRD2,↑DRD3 ↑DRD1,↓DRD2,↑DRD3 ↑DRD2 ↑DRD2 [15] Alteredstriatalopioidsignaling Nochangeor↑μ-opioidreceptors ↑μ-opioidreceptors↑κ-opioidreceptors ↑μ-opioidreceptors ↑μ-opioidreceptors Nochange Nochange [15] Changesinstriatalopioidpeptides ↑dynorphinNochange:enkephalin ↑dynorphin ↓enkephalin ↑dynorphin ↑dynorphin [15] Mesocorticolimbicsynapticplasticity Numberofdendritesinthenucleusaccumbens ↓ ↑ ↑ [15] Dendriticspinedensityinthenucleusaccumbens ↓ ↑ ↑ [15] Neuroepigeneticmechanisms[edit] Seealso:NeuroepigeneticsandChromatinremodeling Alteredepigeneticregulationofgeneexpressionwithinthebrain'srewardsystemplaysasignificantandcomplexroleinthedevelopmentofdrugaddiction.[72][94]Addictivedrugsareassociatedwiththreetypesofepigeneticmodificationswithinneurons.[72]Theseare(1)histonemodifications,(2)epigeneticmethylationofDNAatCpGsitesat(oradjacentto)particulargenes,and(3)epigeneticdownregulationorupregulationofmicroRNAswhichhaveparticulartargetgenes.[72][16][94]Asanexample,whilehundredsofgenesinthecellsofthenucleusaccumbens(NAc)exhibithistonemodificationsfollowingdrugexposure–particularly,alteredacetylationandmethylationstatesofhistoneresidues[94]–mostothergenesintheNAccellsdonotshowsuchchanges.[72] Diagnosis[edit] Furtherinformation:Substanceusedisorder§ Diagnosis,andProblemgambling§ Diagnosis Classification[edit] DSM-5[edit] The5theditionoftheDiagnosticandStatisticalManualofMentalDisorders(DSM-5)usestheterm"substanceusedisorder"torefertoaspectrumofdruguse-relateddisorders.TheDSM-5eliminatestheterms"abuse"and"dependence"fromdiagnosticcategories,insteadusingthespecifiersofmild,moderateandseveretoindicatetheextentofdisordereduse.Thesespecifiersaredeterminedbythenumberofdiagnosticcriteriapresentinagivencase.IntheDSM-5,thetermdrugaddictionissynonymouswithseveresubstanceusedisorder.[1][2] TheDSM-5introducedanewdiagnosticcategoryforbehavioraladdictions;however,problemgamblingistheonlyconditionincludedinthatcategoryinthe5thedition.[13]Internetgamingdisorderislistedasa"conditionrequiringfurtherstudy"intheDSM-5.[95] Pasteditionshaveusedphysicaldependenceandtheassociatedwithdrawalsyndrometoidentifyanaddictivestate.Physicaldependenceoccurswhenthebodyhasadjustedbyincorporatingthesubstanceintoits"normal"functioning–i.e.,attainshomeostasis–andthereforephysicalwithdrawalsymptomsoccuruponcessationofuse.[96]Toleranceistheprocessbywhichthebodycontinuallyadaptstothesubstanceandrequiresincreasinglylargeramountstoachievetheoriginaleffects.Withdrawalreferstophysicalandpsychologicalsymptomsexperiencedwhenreducingordiscontinuingasubstancethatthebodyhasbecomedependenton.Symptomsofwithdrawalgenerallyincludebutarenotlimitedtobodyaches,anxiety,irritability,intensecravingsforthesubstance,nausea,hallucinations,headaches,coldsweats,tremors,andseizures. MedicalresearcherswhoactivelystudyaddictionhavecriticizedtheDSMclassificationofaddictionforbeingflawedandinvolvingarbitrarydiagnosticcriteria.[14] ICD-11[edit] TheeleventhrevisionoftheInternationalClassificationofDiseases,commonlyreferredtoasICD-11,conceptualizesdiagnosissomewhatdifferently.ICD-11firstdistinguishesbetweenproblemswithpsychoactivesubstanceuse("Disordersduetosubstanceuse")andbehavioraladdictions("Disordersduetoaddictivebehaviours").[97]Withregardtopsychoactivesubstances,ICD-11explainsthattheincludedsubstancesinitiallyproduce"pleasantorappealingpsychoactiveeffectsthatarerewardingandreinforcingwithrepeateduse,[but]withcontinueduse,manyoftheincludedsubstanceshavethecapacitytoproducedependence.Theyalsohavethepotentialtocausenumerousformsofharm,bothtomentalandphysicalhealth."[98]InsteadoftheDSM-5approachofonediagnosis("SubstanceUseDisorder")coveringalltypesofproblematicsubstanceuse,ICD-11offersthreediagnosticpossibilities:1)EpisodeofHarmfulPsychoactiveSubstanceUse,2)HarmfulPatternofPsychoactiveSubstanceUse,and3)SubstanceDependence.[98] Prevention[edit] Abuseliability[edit] Abuseliability,whichisalsoknownasaddictionliability,isthetendencytousedrugsinanon-medicalsituation.Thisistypicallyforeuphoria,moodchanging,orsedation.[99]Abuseliabilityisusedwhenthepersonusingthedrugswantssomethingthattheyotherwisecannotobtain.Theonlywaytoobtainthisisthroughtheuseofdrugs.Whenlookingatabuseliabilitythereareanumberofdeterminingfactorsinwhetherthedrugisabused.Thesefactorsare:thechemicalmakeupofthedrug,theeffectsonthebrain,andtheage,vulnerability,andthehealth(mentalandphysical)ofthepopulationbeingstudied.[99]Thereareafewdrugswithaspecificchemicalmakeupthatleadstoahighabuseliability.Theseare:cocaine,heroin,inhalants,marijuana,MDMA(ecstasy),methamphetamine,PCP,syntheticcannabinoids,syntheticcathinones(bathsalts),nicotine(e.g.tobacco),andalcohol.[100] Treatmentandmanagement[edit] Seealso:Addictionrecoverygroups,Cognitivebehavioraltherapy,andDrugrehabilitation Accordingtoareview,"inordertobeeffective,allpharmacologicalorbiologicallybasedtreatmentsforaddictionneedtobeintegratedintootherestablishedformsofaddictionrehabilitation,suchascognitivebehavioraltherapy,individualandgrouppsychotherapy,behaviormodificationstrategies,twelve-stepprograms,andresidentialtreatmentfacilities."[101] Abiosocialapproachtothetreatmentofaddictionbringstotheforethesocialdeterminantsofillnessandwellbeingandconsidersthedynamicandreciprocalrelationshipsthatexistfor,andinfluence,theindividual'sexperience.[102] TheworkofA.V.Schlosser(2018)aimstopronouncetheindividuallivedexperiencesofwomenreceivingmedication-assistedtreatment(e.g.,methadone,naltrexone,burprenorphine)inalong-termrehabilitationsetting,throughatwentymonthlongethnographicfieldworkinvestigation.Thisperson-centredresearchshowshowtheexperiencesofthesewomen"emergefromstablesystemsofinequalitybasedinintersectionalgender,race,andclassmarginalizationentangledwithprocessesofintra-action."[103] Viewingaddictiontreatmentthroughthislensalsohighlightstheimportanceofframingclients'ownbodiesas"socialflesh."AsSchlosser(2018)pointsout,"clientbodies"aswellasthe"embodiedexperiencesofselfandsocialbelongingemergeinandthroughthestructures,temporalities,andexpectationsofthetreatmentcentre."[103] Furtherchallengesandembodiedtensionshavethepotentialtoariseasaresultofthedynamicsinherentinthepatient-providerrelationship,inadditiontotheexperienceofbeing"alienatedfromtheirownbodies,psychesandsociality'swhensedatedonmedicationsintreatment."[103] Biotechnologiescurrentlymakeupalargeportionofthefuturetreatmentsforaddiction.Tonameafew,deep-brainstimulation,agonist/antagonistimplantsandhaptenconjugatevaccines.Vaccinationsagainstaddictionspecificallyoverlapswiththebeliefthatmemoryplaysalargeroleinthedamagingeffectsofaddictionandrelapses.Haptenconjugatevaccinesaredesignedtoblockopioidreceptorsinonearea,whileallowingotherreceptorstobehavenormally.Essentially,onceahighcannolongerbeachievedinrelationtoatraumaticevent,therelationofdrugstoatraumaticmemorycanbedisconnectedandtherapycanthenplayaroleintreatment.[104] Behavioraltherapy[edit] Ameta-analyticreviewontheefficacyofvariousbehavioraltherapiesfortreatingdrugandbehavioraladdictionsfoundthatcognitivebehavioraltherapy(e.g.,relapsepreventionandcontingencymanagement),motivationalinterviewing,andacommunityreinforcementapproachwereeffectiveinterventionswithmoderateeffectsizes.[105] Clinicalandpreclinicalevidenceindicatethatconsistentaerobicexercise,especiallyenduranceexercise(e.g.,marathonrunning),actuallypreventsthedevelopmentofcertaindrugaddictionsandisaneffectiveadjuncttreatmentfordrugaddiction,andforpsychostimulantaddictioninparticular.[15][106][107][108][109]Consistentaerobicexercisemagnitude-dependently(i.e.,bydurationandintensity)reducesdrugaddictionrisk,whichappearstooccurthroughthereversalofdruginducedaddiction-relatedneuroplasticity.[15][107]OnereviewnotedthatexercisemaypreventthedevelopmentofdrugaddictionbyalteringΔFosBorc-Fosimmunoreactivityinthestriatumorotherpartsoftherewardsystem.[109]Aerobicexercisedecreasesdrugself-administration,reducesthelikelihoodofrelapse,andinducesoppositeeffectsonstriataldopaminereceptorD2(DRD2)signaling(increasedDRD2density)tothoseinducedbyaddictionstoseveraldrugclasses(decreasedDRD2density).[15][107]Consequently,consistentaerobicexercisemayleadtobettertreatmentoutcomeswhenusedasanadjuncttreatmentfordrugaddiction.[15][107][108] Medication[edit] Alcoholaddiction[edit] Furtherinformation:Alcoholism Alcohol,likeopioids,caninduceaseverestateofphysicaldependenceandproducewithdrawalsymptomssuchasdeliriumtremens.Becauseofthis,treatmentforalcoholaddictionusuallyinvolvesacombinedapproachdealingwithdependenceandaddictionsimultaneously.Benzodiazepineshavethelargestandthebestevidencebaseinthetreatmentofalcoholwithdrawalandareconsideredthegoldstandardofalcoholdetoxification.[110] Pharmacologicaltreatmentsforalcoholaddictionincludedrugslikenaltrexone(opioidantagonist),disulfiram,acamprosate,andtopiramate.[111][112]Ratherthansubstitutingforalcohol,thesedrugsareintendedtoaffectthedesiretodrink,eitherbydirectlyreducingcravingsaswithacamprosateandtopiramate,orbyproducingunpleasanteffectswhenalcoholisconsumed,aswithdisulfiram.Thesedrugscanbeeffectiveiftreatmentismaintained,butcompliancecanbeanissueasalcoholicpatientsoftenforgettotaketheirmedication,ordiscontinueusebecauseofexcessivesideeffects.[113][114]AccordingtoaCochraneCollaborationreview,theopioidantagonistnaltrexonehasbeenshowntobeaneffectivetreatmentforalcoholism,withtheeffectslastingthreetotwelvemonthsaftertheendoftreatment.[115] Behavioraladdictions[edit] ThissectionistranscludedfromBehavioraladdiction.(edit|history) Behavioraladdictionisatreatablecondition.Treatmentoptionsincludepsychotherapyandpsychopharmacotherapy(i.e.,medications)oracombinationofboth.Cognitivebehavioraltherapy(CBT)isthemostcommonformofpsychotherapyusedintreatingbehavioraladdictions;itfocusesonidentifyingpatternsthattriggercompulsivebehaviorandmakinglifestylechangestopromotehealthierbehaviors.Becausecognitivebehavioraltherapyisconsideredashorttermtherapy,thenumberofsessionsfortreatmentnormallyrangesfromfivetotwenty.Duringthesession,therapistswillleadpatientsthroughthetopicsofidentifyingtheissue,becomingawareofone'sthoughtssurroundingtheissue,identifyinganynegativeorfalsethinking,andreshapingsaidnegativeandfalsethinking.WhileCBTdoesnotcurebehavioraladdiction,itdoeshelpwithcopingwiththeconditioninahealthyway.Currently,therearenomedicationsapprovedfortreatmentofbehavioraladdictionsingeneral,butsomemedicationsusedfortreatmentofdrugaddictionmayalsobebeneficialwithspecificbehavioraladdictions.[22]Anyunrelatedpsychiatricdisordersshouldbekeptundercontrol,anddifferentiatedfromthecontributingfactorsthatcausetheaddiction. Cannabinoidaddiction[edit] A2013reviewoncannabinoidaddictionnotedthatthedevelopmentofCB1receptoragoniststhathavereducedinteractionwithβ-arrestin2signallingmightbetherapeuticallyuseful.[116]Asof2019[update],therehasbeensomeevidenceofeffectivepharmacologicalinterventionsforcannabinoidaddiction,however,nonehavebeenapprovedyet.[117] Nicotineaddiction[edit] Furtherinformation:Smokingcessation Anotherareainwhichdrugtreatmenthasbeenwidelyusedisinthetreatmentofnicotineaddiction,whichusuallyinvolvestheuseofnicotinereplacementtherapy,nicotinicreceptorantagonists,ornicotinicreceptorpartialagonists.[118][119]Examplesofdrugsthatactonnicotinicreceptorsandhavebeenusedfortreatingnicotineaddictionincludeantagonistslikebupropionandthepartialagonistvarenicline.[118][119]A2019reviewlookingatthepartialagonistcytisine,namesitaneffective,andaffordablecessationtreatmentforsmokers.[120]Whenaccesstovareniclineandnicotinereplacementtherapyislimited(duetoavailabilityorcost),cytisineisconsideredthefirstlineoftreatmentforsmokingcessation.[120] Opioidaddiction[edit] Furtherinformation:Opioidusedisorder Opioidscausephysicaldependence,andtreatmenttypicallyaddressesbothdependenceandaddiction. Physicaldependenceistreatedusingreplacementdrugssuchassuboxoneorsubutex(bothcontainingtheactiveingredientsbuprenorphine)andmethadone.[121][122]Althoughthesedrugsperpetuatephysicaldependence,thegoalofopiatemaintenanceistoprovideameasureofcontroloverbothpainandcravings.Useofreplacementdrugsincreasestheaddictedindividual'sabilitytofunctionnormallyandeliminatesthenegativeconsequencesofobtainingcontrolledsubstancesillicitly.Onceaprescribeddosageisstabilized,treatmententersmaintenanceortaperingphases.IntheUnitedStates,opiatereplacementtherapyistightlyregulatedinmethadoneclinicsandundertheDATA2000legislation.Insomecountries,otheropioidderivativessuchasdihydrocodeine,[123]dihydroetorphine[124]andevenheroin[125][126]areusedassubstitutedrugsforillegalstreetopiates,withdifferentprescriptionsbeinggivendependingontheneedsoftheindividualpatient.Baclofenhasledtosuccessfulreductionsofcravingsforstimulants,alcohol,andopioids,andalsoalleviatesalcoholwithdrawalsyndrome.Manypatientshavestatedthey"becameindifferenttoalcohol"or"indifferenttococaine"overnightafterstartingbaclofentherapy.[127]Somestudiesshowtheinterconnectionbetweenopioiddrugdetoxificationandoverdosemortality.[128] Psychostimulantaddiction[edit] AsofMay2014[update],thereisnoeffectivepharmacotherapyforanyformofpsychostimulantaddiction.[101][129][130][131]Reviewsfrom2015,2016,and2018indicatedthatTAAR1-selectiveagonistshavesignificanttherapeuticpotentialasatreatmentforpsychostimulantaddictions;[132][133][134]however,asof2018[update],theonlycompoundswhichareknowntofunctionasTAAR1-selectiveagonistsareexperimentaldrugs.[132][133][134] Research[edit] Researchindicatesthatvaccineswhichutilizeanti-drugmonoclonalantibodiescanmitigatedrug-inducedpositivereinforcementbypreventingthedrugfrommovingacrosstheblood–brainbarrier;[135]however,currentvaccine-basedtherapiesareonlyeffectiveinarelativelysmallsubsetofindividuals.[135][136]AsofNovember2015[update],vaccine-basedtherapiesarebeingtestedinhumanclinicaltrialsasatreatmentforaddictionandpreventivemeasureagainstdrugoverdosesinvolvingnicotine,cocaine,andmethamphetamine.[135] Thenewstudyshows,thatthevaccinemayalsosavelivesduringadrugoverdose.Inthisinstance,theideaisthatthebodywillrespondtothevaccinebyquicklyproducingantibodiestopreventtheopioidsfromaccessingthebrain.[137] SinceaddictioninvolvesabnormalitiesinglutamateandGABAergicneurotransmission,[138][139]receptorsassociatedwiththeseneurotransmitters(e.g.,AMPAreceptors,NMDAreceptors,andGABABreceptors)arepotentialtherapeutictargetsforaddictions.[138][139][140][141]N-acetylcysteine,whichaffectsmetabotropicglutamatereceptorsandNMDAreceptors,hasshownsomebenefitinpreclinicalandclinicalstudiesinvolvingaddictionstococaine,heroin,andcannabinoids.[138]Itmayalsobeusefulasanadjuncttherapyforaddictionstoamphetamine-typestimulants,butmoreclinicalresearchisrequired.[138] Currentmedicalreviewsofresearchinvolvinglabanimalshaveidentifiedadrugclass–classIhistonedeacetylaseinhibitors[note7]–thatindirectlyinhibitsthefunctionandfurtherincreasesintheexpressionofaccumbalΔFosBbyinducingG9aexpressioninthenucleusaccumbensafterprolongeduse.[60][72][142][94]ThesereviewsandsubsequentpreliminaryevidencewhichusedoraladministrationorintraperitonealadministrationofthesodiumsaltofbutyricacidorotherclassIHDACinhibitorsforanextendedperiodindicatethatthesedrugshaveefficacyinreducingaddictivebehaviorinlabanimals[note8]thathavedevelopedaddictionstoethanol,psychostimulants(i.e.,amphetamineandcocaine),nicotine,andopiates;[72][94][143][144]however,fewclinicaltrialsinvolvinghumanswithaddictionsandanyHDACclassIinhibitorshavebeenconductedtotestfortreatmentefficacyinhumansoridentifyanoptimaldosingregimen.[note9] Genetherapyforaddictionisanactiveareaofresearch.OnelineofgenetherapyresearchinvolvestheuseofviralvectorstoincreasetheexpressionofdopamineD2receptorproteinsinthebrain.[146][147][148][149][150] Epidemiology[edit] Duetoculturalvariations,theproportionofindividualswhodevelopadrugorbehavioraladdictionwithinaspecifiedtimeperiod(i.e.,theprevalence)variesovertime,bycountry,andacrossnationalpopulationdemographics(e.g.,byagegroup,socioeconomicstatus,etc.).[32] Asia[edit] Theprevalenceofalcoholdependenceisnotashighasisseeninotherregions.InAsia,notonlysocioeconomicfactorsbutalsobiologicalfactorsinfluencedrinkingbehavior.[151] Theoverallprevalenceofsmartphoneownershipis62%,rangingfrom41%inChinato84%inSouthKorea.Moreover,participationinonlinegamingrangesfrom11%inChinato39%inJapan.HongKonghasthehighestnumberofadolescentsreportingdailyoraboveInternetuse(68%).InternetaddictiondisorderishighestinthePhilippines,accordingtoboththeIAT(InternetAddictionTest)–5%andtheCIAS-R(RevisedChenInternetAddictionScale)–21%.[152] Australia[edit] TheprevalenceofsubstanceusedisorderamongAustralianswasreportedat5.1%in2009.[153] Europe[edit] In2015,theestimatedprevalenceamongtheadultpopulationwas18.4%forheavyepisodicalcoholuse(inthepast30days);15.2%fordailytobaccosmoking;and3.8,0.77,0.37and0.35%in2017cannabis,amphetamine,opioidandcocaineuse.ThemortalityratesforalcoholandillicitdrugswerehighestinEasternEurope.[154] UnitedStates[edit] BaseduponrepresentativesamplesoftheUSyouthpopulationin2011,thelifetimeprevalence[note10]ofaddictionstoalcoholandillicitdrugshasbeenestimatedtobeapproximately8%and2–3%respectively.[155]BaseduponrepresentativesamplesoftheUSadultpopulationin2011,the12monthprevalenceofalcoholandillicitdrugaddictionswereestimatedat12%and2–3%respectively.[155]Thelifetimeprevalenceofprescriptiondrugaddictionsiscurrentlyaround4.7%.[156] Asof2016,[update]about22 millionpeopleintheUnitedStatesneedtreatmentforanaddictiontoalcohol,nicotine,orotherdrugs.[157][158]Onlyabout10%,oralittleover2 million,receiveanyformoftreatments,andthosethatdogenerallydonotreceiveevidence-basedcare.[157][158]One-thirdofinpatienthospitalcostsand20%ofalldeathsintheUSeveryyeararetheresultofuntreatedaddictionsandriskysubstanceuse.[157][158]Inspiteofthemassiveoveralleconomiccosttosociety,whichisgreaterthanthecostofdiabetesandallformsofcancercombined,mostdoctorsintheUSlackthetrainingtoeffectivelyaddressadrugaddiction.[157][158] AnotherreviewlistedestimatesoflifetimeprevalenceratesforseveralbehavioraladdictionsintheUnitedStates,including1–2%forcompulsivegambling,5%forsexualaddiction,2.8%forfoodaddiction,and5–6%forcompulsiveshopping.[15]Asystematicreviewindicatedthatthetime-invariantprevalencerateforsexualaddictionandrelatedcompulsivesexualbehavior(e.g.,compulsivemasturbationwithorwithoutpornography,compulsivecybersex,etc.)withintheUnitedStatesrangesfrom3–6%ofthepopulation.[17] Accordingtoa2017pollconductedbythePewResearchCenter,almosthalfofUSadultsknowafamilymemberorclosefriendwhohasstruggledwithadrugaddictionatsomepointintheirlife.[159] In2019,opioidaddictionwasacknowledgedasanationalcrisisintheUnitedStates.[160]AnarticleinTheWashingtonPoststatedthat"America'slargestdrugcompaniesfloodedthecountrywithpainpillsfrom2006through2012,evenwhenitbecameapparentthattheywerefuelingaddictionandoverdoses." TheNationalEpidemiologicSurveyonAlcoholandRelatedConditionsfoundthatfrom2012-2013theprevalenceofCannabisusedisorderinU.S.adultswas2.9%.[161] SouthAmerica[edit] TherealitiesofopioiduseandopioidusedisorderinLatinAmericamaybedeceptiveifobservationsarelimitedtoepidemiologicalfindings.IntheUnitedNationsOfficeonDrugsandCrimereport,[162]althoughSouthAmericaproduced3%oftheworld'smorphineandheroinand0.01%ofitsopium,prevalenceofuseisuneven.AccordingtotheInter-AmericanCommissiononDrugAbuseControl,consumptionofheroinislowinmostLatinAmericancountries,althoughColombiaisthearea'slargestopiumproducer.Mexico,becauseofitsborderwiththeUnitedStates,hasthehighestincidenceofuse.[163] Historyandetymology[edit] Mainarticle:Recreationaldruguse Furtherinformation:Evolutionarymodelsofhumandruguse,Historyofdrinking,Historyofsmoking,andSubstanceabuseinAncientRome Theetymologyofthetermaddictionthroughouthistoryhasbeenoftenmisunderstoodandhastakenonvariousmeaningsassociatedwiththeword.[164]AnexampleistheusageofthewordinthereligiouslandscapeofearlymodernEurope.[165]"Addiction"atthetimemeant"toattach"tosomething,givingitbothpositiveandnegativeconnotations.Theobjectofthisattachmentcouldbecharacterisedas"goodorbad".[166]However,themeaningofaddictionduringtheearlymodernperiodwasmostlyassociatedwithpositivityandgoodness;[165]duringthisearlymodernandhighlyreligiouseraofChristianrevivalismandPietistictendencies,[165]itwasseenasawayof"devotingoneselftoanother".[166] Modernresearchonaddictionhasledtoabetterunderstandingofthediseasewithresearchstudiesonthetopicdatingbackto1875,specificallyonmorphineaddiction.[167]Thisfurtheredtheunderstandingofaddictionbeingamedicalcondition.Itwasn'tuntilthe19thcenturythataddictionwasseenandacknowledgedintheWesternworldasadisease,beingbothaphysicalconditionandmentalillness.[168]Today,addictionisunderstoodbothasabiopsychosocialandneurologicaldisorderthatnegativelyimpactsthosewhoareaffectedbyit,mostcommonlyassociatedwiththeuseofdrugsandexcessiveuseofalcohol.[7]Theunderstandingofaddictionhaschangedthroughouthistory,whichhasimpactedandcontinuestoimpactthewaysitismedicallytreatedanddiagnosed. Societyandculture[edit] Acuteconfusionalstatecausedbyalcoholwithdrawal,alsoknownasdeliriumtremens Abiopsychosocial–spiritualunderstandingofaddiction[edit] Whileregardedbiomedicallyasaneuropsychologicaldisorder,addictionismulti-layered,withbiological,psychological,social,culturalandspiritual(biopsychosocial–spiritual)elements.[169][170]Abiopsychosocial–spiritualapproachfostersthecrossingofdisciplinaryboundaries,andpromotesholisticconsiderationsofaddiction.[171][172][173]Abiopsychosocial–spiritualapproachconsiders,forexample,howphysicalenvironmentsinfluenceexperiences,habits,andpatternsofaddiction. Ethnographicengagementsanddevelopmentsinfieldsofknowledgehavecontributedtobiopsychosocial–spiritualunderstandingsofaddiction,includingtheworkofPhilippeBourgois,whosefieldworkwithstreet-leveldrugdealersinEastHarlemhighlightscorrelationsbetweendruguseandstructuraloppressionintheUnitedStates.[174][3]Priormodelsthathaveinformedtheprevailingbiopsychosocial–spiritualconsiderationofaddictioninclude: TheCulturalModel[edit] Theculturalmodel,ananthropologicalunderstandingoftheemergenceofdruguseandabuse,wasdevelopedbyDwightHeath.[175]HeathundertookethnographicresearchandfieldworkwiththeCambapeopleofBoliviafromJune1956toAugust1957.[176]Heathobservedthatadultmembersofsocietydrank‘largequantitiesofrumandbecameintoxicatedforseveralcontiguousdaysatleasttwiceamonth’.[175]Thisfrequent,heavydrinkingfromwhichintoxicationfollowedwastypicallyundertakensocially,duringfestivals.[176]Havingreturnedin1989,Heathobservedthatwhilstmuchhadchanged,‘drinkingparties’remained,asperhisinitialobservations,and‘thereappeartobenoharmfulconsequencestoanyone’.[177]Heath’sobservationsandinteractionsreflectedthatthisformofsocialbehaviour,thehabitualheavyconsumptionofalcohol,wasencouragedandvalued,enforcingsocialbondsintheCambacommunity.[176]Despitefrequentintoxication,“eventothepointofunconsciousness”,theCambaheldnoconceptofalcoholism(aformofaddiction),andnovisiblesocialproblemsassociatedwithdrunkenness,oraddiction,wereapparent.[175] AsnotedbyMerrillSinger,Heath’sfindings,whenconsideredalongsidesubsequentcross-culturalexperiences,challengedtheperceptionthatintoxicationissocially‘inherentlydisruptive’.[175]Followingthisfieldwork,Heathproposedthe‘culturalmodel’,suggestingthat‘problems’associatedwithheavydrinking,suchasalcoholism–arecognisedformaddiction–werecultural:thatis,thatalcoholismisdeterminedbyculturalbeliefs,andthereforevariesamongcultures.Heath’sfindingschallengedthenotionthat‘continueduse[ofalcohol]isinexorablyaddictiveanddamagingtotheconsumer’shealth’.[176][175] TheculturalmodeldidfacecriticismbySociologistRobinRoomandothers,whofeltanthropologistscould“downgradetheseverityoftheproblem”.[175]MerrillSingerfounditnotablethattheethnographersworkingwithintheprominenceoftheculturalmodelwerepartofthe‘wetgeneration’:whilenotblindtothe‘disruptive,dysfunctionalanddebilitatingeffectsofalcoholconsumption’,theywereproducts‘socializedtoviewalcoholconsumptionasnormal’.[175] TheSubculturalModel[edit] Historically,addictionhasbeenviewedfromtheeticperspective,definingusersthroughthepathologyoftheircondition.[178]Asreportsofdruguserapidlyincreased,theculturalmodelfoundapplicationinanthropologicalresearchexploringwesterndrugsubculturepractices.[175] Theapproachevolvedfromtheethnographicexplorationintothelivedexperiencesandsubjectivitiesof1960sand1970sdrugsubcultures.[175]Theseminalpublication“Takingcareofbusiness”,byEdwardPrebleandJohnJ.Casey,documentedthedailylivesofNewYorkstreet-basedintravenousheroinusersinrichdetail,providinguniqueinsightintothedynamicsocialworldsandactivitiesthatsurroundedtheirdruguse.[179] Thesefindingschallengepopularnarrativesofimmoralityanddeviance,conceptualisingsubstanceabuseasasocialphenomenon.Furthermore,itsuggeststhattheprevailingculturecanhaveagreaterinfluenceondrugtakingbehavioursthanthephysicalandpsychologicaleffectsofthedrugitself.[180]Tomarginalisedindividuals,drugsubculturescanprovidesocialconnection,symbolicmeaning,andsociallyconstructedpurposethattheymayfeelisunattainablethroughconventionalmeans.[180]Thesubculturalmodeldemonstratesthecomplexitiesofaddiction,highlightingtheneedforanintegratedapproach.Itcontendsthatabiosocialapproachisrequiredtoachieveaholisticunderstandingofaddiction.[175] TheCriticalMedicalAnthropologyModel[edit] Emergingintheearly1980s,thecriticalmedicalanthropologymodelwasintroduced,andasMerrillSingeroffers‘wasappliedquicklytotheanalysisofdruguse’.[175]Wheretheculturalmodelofthe1950slookedatthesocialbody,thecriticalmedicalanthropologymodelrevealedthebodypolitic,consideringdruguseandaddictionwithinthecontextofmacrolevelstructuresincludinglargerpoliticalsystems,economicinequalities,andtheinstitutionalpowerheldoversocialprocesses.[175] Highlyrelevanttoaddiction,thethreeissuesemphasizedinthemodelare: Thesocialproductionofsuffering Self-medication Thepoliticaleconomy(licitandillicitdrugs)[175] Thesethreekeypointshighlighthowdrugsmaycometobeusedtoself-medicatethepsychologicaltraumaofsocio-politicaldisparityandinjustice,intertwiningwithlicitandillicitdrugmarketpolitics.[175]Socialsuffering,“themiseryamongthoseontheweakerendofpowerrelationsintermsofphysicalhealth,mentalhealthandlivedexperience”,isusedbyanthropologiststoanalysehowindividualsmayhavepersonalproblemscausedbypoliticalandeconomicpower.[175]Fromtheperspectiveofcriticalmedicalanthropologyheavydruguseandaddictionisaconsequenceofsuchlargerscaleunequaldistributionsofpower.[175] Thethreemodelsdevelopedhere–theculturalmodel,thesubculturalmodel,andtheCriticalMedicalAnthropologyModel–displayhowaddictionisnotanexperiencetobeconsideredonlybiomedically.Throughconsiderationofaddictionalongsidethebiological,psychological,social,culturalandspiritual(biopsychosocial–spiritual)elementswhichinfluenceitsexperience,aholisticandcomprehensiveunderstandingcanbebuilt. Addictioncausesan"astoundinglyhighfinancialandhumantoll"onindividualsandsocietyasawhole.[181][155][157]IntheUnitedStates,thetotaleconomiccosttosocietyisgreaterthanthatofalltypesofdiabetesandallcancerscombined.[157]Thesecostsarisefromthedirectadverseeffectsofdrugsandassociatedhealthcarecosts(e.g.,emergencymedicalservicesandoutpatientandinpatientcare),long-termcomplications(e.g.,lungcancerfromsmokingtobaccoproducts,livercirrhosisanddementiafromchronicalcoholconsumption,andmethmouthfrommethamphetamineuse),thelossofproductivityandassociatedwelfarecosts,fatalandnon-fatalaccidents(e.g.,trafficcollisions),suicides,homicides,andincarceration,amongothers.[181][155][157][182]IntheUnitedStates,astudyconductedbytheNationalInstituteonDrugAbusehasfoundthatoverdosedeathsintheUnitedStateshavealmosttripledamongstmaleandfemalesfrom2002to2017,with72,306overdosedeathsreportedin2017intheU.S.[183]2020markedtheyearwithhighestnumberofoverdosedeathsovera12-monthperiod,with81,000overdosedeaths,exceedingtherecordssetin2017.[184] Thesuffixes"-holic"and"-holism"[edit] IncontemporarymodernEnglish"-holic"isasuffixthatcanbeaddedtoasubjecttodenoteanaddictiontoit.Itwasextractedfromthewordalcoholism(oneofthefirstaddictionstobewidelyidentifiedbothmedicallyandsocially)(correctlytheroot"wikt:alcohol"plusthesuffix"-ism")bymisdividingorrebracketingitinto"alco"and"-holism".(Anothersuchmisdivisionisinterpreting"helicopter"as"heli-copter"ratherthantheetymologicallycorrect"helico-pter",givingrisetosuchderivedwordsas"heliport"and"jetcopter".[185])Therearecorrectmedico-legaltermsforsuchaddictions:dipsomaniaisthemedico-legaltermforalcoholism;[186]otherexamplesareinthistable: Colloquialterm Addictionto Medico-legalterm danceaholic dance choreomania workaholic work ergomania sexaholic sex erotomania,satyromania,nymphomania sugarholic sugar saccharomania chocoholic chocolate rageaholic rage/anger Seealso[edit] Autonomicnervoussystem Bingedrinking Bingeeatingdisorder Discriminationagainstdrugaddicts Dopaminergicpathways Pavlovian-instrumentaltransfer Philosophyofmedicine Substancedependence Endnotes[edit] ^Inotherwords,apersoncannotcontroltheneurobiologicalprocessesthatoccurinthebodyinresponsetousinganaddictivedrug.Apersoncanmakeavoluntarychoiceto,forexample,startusingadrugortoseekhelpafterbecomingaddicted,althoughresistingtheurgetousebecomesincreasinglydifficultasaddictionworsens.See[6]fordetaileddiscussion. Notes[edit] ^Accordingtoareviewofexperimentalanimalmodelsthatexaminedthetransgenerationalepigeneticinheritanceofepigeneticmarksthatoccurinaddiction,alterationsinhistoneacetylation–specifically,di-acetylationoflysineresidues9and14onhistone3(i.e.,H3K9ac2andH3K14ac2)inassociationwithBDNFgenepromoters–havebeenshowntooccurwithinthemedialprefrontalcortex(mPFC),testes,andspermofcocaine-addictedmalerats.[32]TheseepigeneticalterationsintheratmPFCresultinincreasedBDNFgeneexpressionwithinthemPFC,whichinturnbluntstherewardingpropertiesofcocaineandreducescocaineself-administration.[32]Themalebutnotfemaleoffspringofthesecocaine-exposedratsinheritedbothepigeneticmarks(i.e.,di-acetylationoflysineresidues9and14onhistone3)withinmPFCneurons,thecorrespondingincreaseinBDNFexpressionwithinmPFCneurons,andthebehavioralphenotypeassociatedwiththeseeffects(i.e.,areductionincocainereward,resultinginreducedcocaine-seekingbythesemaleoffspring).[32]Consequently,thetransmissionofthesetwococaine-inducedepigeneticalterations(i.e.,H3K9ac2andH3K14ac2)inratsfrommalefatherstomaleoffspringservedtoreducetheoffspring'sriskofdevelopinganaddictiontococaine.[32]Asof2018,[update]neithertheheritabilityoftheseepigeneticmarksinhumansnorthebehavioraleffectsofthemarkswithinhumanmPFCneuronshasbeenestablished.[32] ^abAdecreaseinaversionsensitivity,insimplerterms,meansthatanindividual'sbehaviorislesslikelytobeinfluencedbyundesirableoutcomes. ^Inotherwords,c-FosrepressionallowsΔFosBtomorerapidlyaccumulatewithintheD1-typemediumspinyneuronsofthenucleusaccumbensbecauseitisselectivelyinducedinthisstate.[3]Priortoc-Fosrepression,allFosfamilyproteins(e.g.,c-Fos,Fra1,Fra2,FosB,andΔFosB)areinducedtogether,withΔFosBexpressionincreasingtoalesserextent.[3] ^Accordingtotwomedicalreviews,ΔFosBhasbeenimplicatedincausingbothincreasesanddecreasesindynorphinexpressionindifferentstudies;[59][89]thistableentryreflectsonlyadecrease. ^Incentivesalience,the"motivationalsalience"forareward,isa"desire"or"want"attribute,whichincludesamotivationalcomponent,thatthebrainassignstoarewardingstimulus.[90][91]Asaconsequence,incentivesalienceactsasamotivational"magnet"forarewardingstimulusthatcommandsattention,inducesapproach,andcausestherewardingstimulustobesoughtout.[90] ^Insimplestterms,thismeansthatwheneitheramphetamineorsexisperceivedasmorealluringordesirablethroughrewardsensitization,thiseffectoccurswiththeotheraswell. ^InhibitorsofclassIhistonedeacetylase(HDAC)enzymesaredrugsthatinhibitfourspecifichistone-modifyingenzymes:HDAC1,HDAC2,HDAC3,andHDAC8.MostoftheanimalresearchwithHDACinhibitorshasbeenconductedwithfourdrugs:butyratesalts(mainlysodiumbutyrate),trichostatinA,valproicacid,andSAHA;[142][94]butyricacidisanaturallyoccurringshort-chainfattyacidinhumans,whilethelattertwocompoundsareFDA-approveddrugswithmedicalindicationsunrelatedtoaddiction. ^Specifically,prolongedadministrationofaclassIHDACinhibitorappearstoreduceananimal'smotivationtoacquireanduseanaddictivedrugwithoutaffectingananimalsmotivationtoattainotherrewards(i.e.,itdoesnotappeartocausemotivationalanhedonia)andreducetheamountofthedrugthatisself-administeredwhenitisreadilyavailable.[72][94][143] ^AmongthefewclinicaltrialsthatemployedaclassIHDACinhibitor,oneutilizedvalproateformethamphetamineaddiction.[145] ^Thelifetimeprevalenceofanaddictionisthepercentageofindividualsinapopulationthatdevelopedanaddictionatsomepointintheirlife. Imagelegend ^  Ionchannel  Gproteins&linkedreceptors  (Textcolor)Transcriptionfactors References[edit] ^ab"FacingAddictioninAmerica:TheSurgeonGeneral'sReportonAlcohol,Drugs,andHealth"(PDF).OfficeoftheSurgeonGeneral.USDepartmentofHealthandHumanServices.November2016.pp. 35–37,45,63,155,317,338.Retrieved28January2017. ^abcVolkowND,KoobGF,McLellanAT(January2016)."NeurobiologicAdvancesfromtheBrainDiseaseModelofAddiction".NewEnglandJournalofMedicine.374(4):363–371.doi:10.1056/NEJMra1511480.PMC 6135257.PMID 26816013.Substance-usedisorder:AdiagnosticterminthefiftheditionoftheDiagnosticandStatisticalManualofMentalDisorders(DSM-5)referringtorecurrentuseofalcoholorotherdrugsthatcausesclinicallyandfunctionallysignificantimpairment,suchashealthproblems,disability,andfailuretomeetmajorresponsibilitiesatwork,school,orhome.Dependingonthelevelofseverity,thisdisorderisclassifiedasmild,moderate,orsevere.Addiction:Atermusedtoindicatethemostsevere,chronicstageofsubstance-usedisorder,inwhichthereisasubstantiallossofself-control,asindicatedbycompulsivedrugtakingdespitethedesiretostoptakingthedrug.IntheDSM-5,thetermaddictionissynonymouswiththeclassificationofseveresubstance-usedisorder. ^abcdefghijklmnopqrstNestlerEJ(December2013)."Cellularbasisofmemoryforaddiction".DialoguesinClinicalNeuroscience.15(4):431–443.PMC 3898681.PMID 24459410.Despitetheimportanceofnumerouspsychosocialfactors,atitscore,drugaddictioninvolvesabiologicalprocess:theabilityofrepeatedexposuretoadrugofabusetoinducechangesinavulnerablebrainthatdrivethecompulsiveseekingandtakingofdrugs,andlossofcontroloverdruguse,thatdefineastateofaddiction. ...AlargebodyofliteraturehasdemonstratedthatsuchΔFosBinductioninD1-type[nucleusaccumbens]neuronsincreasesananimal'ssensitivitytodrugaswellasnaturalrewardsandpromotesdrugself-administration,presumablythroughaprocessofpositivereinforcement ...AnotherΔFosBtargetiscFos:asΔFosBaccumulateswithrepeateddrugexposureitrepressesc-FosandcontributestothemolecularswitchwherebyΔFosBisselectivelyinducedinthechronicdrug-treatedstate.41 ...Moreover,thereisincreasingevidencethat,despitearangeofgeneticrisksforaddictionacrossthepopulation,exposuretosufficientlyhighdosesofadrugforlongperiodsoftimecantransformsomeonewhohasrelativelylowergeneticloadingintoanaddict. ^MalenkaRC,NestlerEJ,HymanSE(2009)."Chapter15:ReinforcementandAddictiveDisorders".InSydorA,BrownRY(eds.).MolecularNeuropharmacology:AFoundationforClinicalNeuroscience(2nd ed.).NewYork:McGraw-HillMedical.pp. 364–375.ISBN 9780071481274. ^"GlossaryofTerms".MountSinaiSchoolofMedicine.DepartmentofNeuroscience.Retrieved9February2015. ^abHeiligM,MacKillopJ,MartinezD,RehmJ,LeggioL,VanderschurenLJ(September2021)."Addictionasabraindiseaserevised:whyitstillmatters,andtheneedforconsilience".Neuropsychopharmacology.46(10):1715–1723.doi:10.1038/s41386-020-00950-y.PMC 8357831.PMID 33619327.pre-existingvulnerabilitiesandpersistentdruguseleadtoaviciouscircleofsubstantivedisruptionsinthebrainthatimpairandunderminechoicecapacitiesforadaptivebehavior,butdonotannihilatethem. ^abc"Drugs,Brains,andBehavior:TheScienceofAddiction–DrugMisuseandAddiction".www.drugabuse.gov.NorthBethesda,Maryland:NationalInstituteonDrugAbuse.13July2020.Retrieved23December2021. ^HendenE(2017)."Addiction,Compulsion,andWeaknessoftheWill:ADual-ProcessPerspective.".InHeatherN,GabrielS(eds.).AddictionandChoice:RethinkingtheRelationship.Oxford,UK:OxfordUniversityPress.pp. 116–132. ^AngresDH,Bettinardi-AngresK(October2008)."Thediseaseofaddiction:origins,treatment,andrecovery".Disease-a-Month.54(10):696–721.doi:10.1016/j.disamonth.2008.07.002.PMID 18790142. ^abMalenkaRC,NestlerEJ,HymanSE(2009)."Chapter15:ReinforcementandAddictiveDisorders".InSydorA,BrownRY(eds.).MolecularNeuropharmacology:AFoundationforClinicalNeuroscience(2nd ed.).NewYork:McGraw-HillMedical.pp. 364–65,375.ISBN 978-0-07-148127-4.Thedefiningfeatureofaddictioniscompulsive,out-of-controldruguse,despitenegativeconsequences. ...compulsiveeating,shopping,gambling,andsex –so-called"naturaladdictions" –Indeed,addictiontobothdrugsandbehavioralrewardsmayarisefromsimilardysregulationofthemesolimbicdopaminesystem. ^MarlattGA,BaerJS,DonovanDM,KivlahanDR(1988)."Addictivebehaviors:etiologyandtreatment".AnnuRevPsychol.39:223–52.doi:10.1146/annurev.ps.39.020188.001255.PMID 3278676. ^ME(12September2019)."GamingAddictioninICD-11:IssuesandImplications".PsychiatricTimes.PsychiatricTimesVol36,Issue9.36(9).Retrieved3March2020. ^abAmericanPsychiatricAssociation(2013)."Substance-RelatedandAddictiveDisorders"(PDF).AmericanPsychiatricPublishing.pp. 1–2.Archivedfromtheoriginal(PDF)on15August2015.Retrieved10July2015.Additionally,thediagnosisofdependencecausedmuchconfusion.Mostpeoplelinkdependencewith"addiction"wheninfactdependencecanbeanormalbodyresponsetoasubstance. ^abMalenkaRC,NestlerEJ,HymanSE,HoltzmanDM(2015)."Chapter16:ReinforcementandAddictiveDisorders".MolecularNeuropharmacology:AFoundationforClinicalNeuroscience(3rd ed.).NewYork:McGraw-HillMedical.ISBN 978-0-07-182770-6.TheofficialdiagnosisofdrugaddictionbytheDiagnosticandStatisticManualofMentalDisorders(2013),whichusesthetermsubstanceusedisorder,isflawed.Criteriausedtomakethediagnosisofsubstanceusedisordersincludetoleranceandsomaticdependence/withdrawal,eventhoughtheseprocessesarenotintegraltoaddictionasnoted.Itisironicandunfortunatethatthemanualstillavoidsuseofthetermaddictionasanofficialdiagnosis,eventhoughaddictionprovidesthebestdescriptionoftheclinicalsyndrome. ^abcdefghijklmnopqrstuvwxyzaaabacadaeafagahaiajakalOlsenCM(December2011)."Naturalrewards,neuroplasticity,andnon-drugaddictions".Neuropharmacology.61(7):1109–22.doi:10.1016/j.neuropharm.2011.03.010.PMC 3139704.PMID 21459101.Functionalneuroimagingstudiesinhumanshaveshownthatgambling(Breiteretal,2001),shopping(Knutsonetal,2007),orgasm(Komisaruketal,2004),playingvideogames(Koeppetal,1998;Hoeftetal,2008)andthesightofappetizingfood(Wangetal,2004a)activatemanyofthesamebrainregions(i.e.,themesocorticolimbicsystemandextendedamygdala)asdrugsofabuse(Volkowetal,2004). ...Cross-sensitizationisalsobidirectional,asahistoryofamphetamineadministrationfacilitatessexualbehaviorandenhancestheassociatedincreaseinNAcDA ...Asdescribedforfoodreward,sexualexperiencecanalsoleadtoactivationofplasticity-relatedsignalingcascades.ThetranscriptionfactordeltaFosBisincreasedintheNAc,PFC,dorsalstriatum,andVTAfollowingrepeatedsexualbehavior(Wallaceetal.,2008;Pitchersetal.,2010b).ThisnaturalincreaseindeltaFosBorviraloverexpressionofdeltaFosBwithintheNAcmodulatessexualperformance,andNAcblockadeofdeltaFosBattenuatesthisbehavior(Hedgesetal,2009;Pitchersetal.,2010b).Further,viraloverexpressionofdeltaFosBenhancestheconditionedplacepreferenceforanenvironmentpairedwithsexualexperience(Hedgesetal.,2009). ...Insomepeople,thereisatransitionfrom"normal"tocompulsiveengagementinnaturalrewards(suchasfoodorsex),aconditionthatsomehavetermedbehavioralornon-drugaddictions(Holden,2001;Grantetal.,2006a). ...Inhumans,theroleofdopaminesignalinginincentive-sensitizationprocesseshasrecentlybeenhighlightedbytheobservationofadopaminedysregulationsyndromeinsomepatientstakingdopaminergicdrugs.Thissyndromeischaracterizedbyamedication-inducedincreasein(orcompulsive)engagementinnon-drugrewardssuchasgambling,shopping,orsex(Evansetal,2006;Aiken,2007;Lader,2008)."Table1:Summaryofplasticityobservedfollowingexposuretodrugornaturalreinforcers" ^abcdefghijklmRobisonAJ,NestlerEJ(November2011)."Transcriptionalandepigeneticmechanismsofaddiction".Nat.Rev.Neurosci.12(11):623–37.doi:10.1038/nrn3111.PMC 3272277.PMID 21989194.ΔFosBhasbeenlinkeddirectlytoseveraladdiction-relatedbehaviors ...Importantly,geneticorviraloverexpressionofΔJunD,adominantnegativemutantofJunDwhichantagonizesΔFosB-andotherAP-1-mediatedtranscriptionalactivity,intheNAcorOFCblocksthesekeyeffectsofdrugexposure14,22–24.ThisindicatesthatΔFosBisbothnecessaryandsufficientformanyofthechangeswroughtinthebrainbychronicdrugexposure.ΔFosBisalsoinducedinD1-typeNAcMSNsbychronicconsumptionofseveralnaturalrewards,includingsucrose,highfatfood,sex,wheelrunning,whereitpromotesthatconsumption14,26–30.ThisimplicatesΔFosBintheregulationofnaturalrewardsundernormalconditionsandperhapsduringpathologicaladdictive-likestates. ^abcdKarilaL,WéryA,WeinsteinA,CottencinO,PetitA,ReynaudM,BillieuxJ(2014)."Sexualaddictionorhypersexualdisorder:differenttermsforthesameproblem?Areviewoftheliterature".Curr.Pharm.Des.20(25):4012–20.doi:10.2174/13816128113199990619.PMID 24001295.Sexualaddiction,whichisalsoknownashypersexualdisorder,haslargelybeenignoredbypsychiatrists,eventhoughtheconditioncausesseriouspsychosocialproblemsformanypeople.Alackofempiricalevidenceonsexualaddictionistheresultofthedisease'scompleteabsencefromversionsoftheDiagnosticandStatisticalManualofMentalDisorders. ...Existingprevalenceratesofsexualaddiction-relateddisordersrangefrom3%to6%.Sexualaddiction/hypersexualdisorderisusedasanumbrellaconstructtoencompassvarioustypesofproblematicbehaviors,includingexcessivemasturbation,cybersex,pornographyuse,sexualbehaviorwithconsentingadults,telephonesex,stripclubvisitation,andotherbehaviors.Theadverseconsequencesofsexualaddictionaresimilartotheconsequencesofotheraddictivedisorders.Addictive,somaticandpsychiatricdisorderscoexistwithsexualaddiction.Inrecentyears,researchonsexualaddictionhasproliferated,andscreeninginstrumentshaveincreasinglybeendevelopedtodiagnoseorquantifysexualaddictiondisorders.Inoursystematicreviewoftheexistingmeasures,22questionnaireswereidentified.Aswithotherbehavioraladdictions,theappropriatetreatmentofsexualaddictionshouldcombinepharmacologicalandpsychologicalapproaches. ^abcdePitchersKK,VialouV,NestlerEJ,LavioletteSR,LehmanMN,CoolenLM(February2013)."NaturalanddrugrewardsactoncommonneuralplasticitymechanismswithΔFosBasakeymediator".TheJournalofNeuroscience.33(8):3434–42.doi:10.1523/JNEUROSCI.4881-12.2013.PMC 3865508.PMID 23426671.Drugsofabuseinduceneuroplasticityinthenaturalrewardpathway,specificallythenucleusaccumbens(NAc),therebycausingdevelopmentandexpressionofaddictivebehavior. ...Together,thesefindingsdemonstratethatdrugsofabuseandnaturalrewardbehaviorsactoncommonmolecularandcellularmechanismsofplasticitythatcontrolvulnerabilitytodrugaddiction,andthatthisincreasedvulnerabilityismediatedbyΔFosBanditsdownstreamtranscriptionaltargets. ...Sexualbehaviorishighlyrewarding(Tenketal.,2009),andsexualexperiencecausessensitizeddrug-relatedbehaviors,includingcross-sensitizationtoamphetamine(Amph)-inducedlocomotoractivity(BradleyandMeisel,2001;Pitchersetal.,2010a)andenhancedAmphreward(Pitchersetal.,2010a).Moreover,sexualexperienceinducesneuralplasticityintheNAcsimilartothatinducedbypsychostimulantexposure,includingincreaseddendriticspinedensity(MeiselandMullins,2006;Pitchersetal.,2010a),alteredglutamatereceptortrafficking,anddecreasedsynapticstrengthinprefrontalcortex-respondingNAcshellneurons(Pitchersetal.,2012).Finally,periodsofabstinencefromsexualexperiencewerefoundtobecriticalforenhancedAmphreward,NAcspinogenesis(Pitchersetal.,2010a),andglutamatereceptortrafficking(Pitchersetal.,2012).Thesefindingssuggestthatnaturalanddrugrewardexperiencessharecommonmechanismsofneuralplasticity ^abcdeBeloateLN,WeemsPW,CaseyGR,WebbIC,CoolenLM(February2016)."NucleusaccumbensNMDAreceptoractivationregulatesamphetaminecross-sensitizationanddeltaFosBexpressionfollowingsexualexperienceinmalerats".Neuropharmacology.101:154–64.doi:10.1016/j.neuropharm.2015.09.023.PMID 26391065.S2CID 25317397. ^NehligA(2004).Coffee,tea,chocolate,andthebrain.BocaRaton:CRCPress.pp. 203–218.ISBN 9780429211928. ^MeuleA,GearhardtAN(September2014)."FoodaddictioninthelightofDSM-5".Nutrients.6(9):3653–71.doi:10.3390/nu6093653.PMC 4179181.PMID 25230209. ^abcGrantJE,PotenzaMN,WeinsteinA,GorelickDA(September2010)."Introductiontobehavioraladdictions".Am.J.DrugAlcoholAbuse.36(5):233–241.doi:10.3109/00952990.2010.491884.PMC 3164585.PMID 20560821.Naltrexone,amu-opioidreceptorantagonistapprovedbytheUSFoodandDrugAdministrationforthetreatmentofalcoholismandopioiddependence,hasshownefficacyincontrolledclinicaltrialsforthetreatmentofpathologicalgamblingandkleptomania(76–79),andpromiseinuncontrolledstudiesofcompulsivebuying(80),compulsivesexualbehavior(81),internetaddiction(82),andpathologicskinpicking(83). ...Topiramate,ananti-convulsantwhichblockstheAMPAsubtypeofglutamatereceptor(amongotheractions),hasshownpromiseinopen-labelstudiesofpathologicalgambling,compulsivebuying,andcompulsiveskinpicking(85),aswellasefficacyinreducingalcohol(86),cigarette(87),andcocaine(88)use.N-acetylcysteine,anaminoacidthatrestoresextracellularglutamateconcentrationinthenucleusaccumbens,reducedgamblingurgesandbehaviorinonestudyofpathologicalgamblers(89),andreducescocainecraving(90)andcocaineuse(91)incocaineaddicts.Thesestudiessuggestthatglutamatergicmodulationofdopaminergictoneinthenucleusaccumbensmaybeamechanismcommontobehavioraladdictionandsubstanceusedisorders(92). ^FehrmanE,EganV,GorbanAN,LevesleyJ,MirkesEM,MuhammadAK(2019).PersonalityTraitsandDrugConsumption.AStoryToldbyData.Springer,Cham.arXiv:2001.06520.doi:10.1007/978-3-030-10442-9.ISBN 978-3-030-10441-2.S2CID 151160405. ^CheethamA,AllenNB,YücelM,LubmanDI(August2010)."Theroleofaffectivedysregulationindrugaddiction".ClinPsycholRev.30(6):621–34.doi:10.1016/j.cpr.2010.04.005.PMID 20546986. ^FrankenIH,MurisP(2006)."BIS/BASpersonalitycharacteristicsandcollegestudents'substanceuse".PersonalityandIndividualDifferences.40(7):1497–503.doi:10.1016/j.paid.2005.12.005. ^GenoveseJE,WallaceD(December2007)."Rewardsensitivityandsubstanceabuseinmiddleschoolandhighschoolstudents".JGenetPsychol.168(4):465–69.doi:10.3200/GNTP.168.4.465-469.PMID 18232522.S2CID 207640075. ^KimbrelNA,Nelson-GrayRO,MitchellJT(April2007)."Reinforcementsensitivityandmaternalstyleaspredictorsofpsychopathology".PersonalityandIndividualDifferences.42(6):1139–49.doi:10.1016/j.paid.2006.06.028. ^DaweS,LoxtonNJ(May2004)."Theroleofimpulsivityinthedevelopmentofsubstanceuseandeatingdisorders".NeurosciBiobehavRev.28(3):343–51.doi:10.1016/j.neubiorev.2004.03.007.PMID 15225976.S2CID 24435589. ^WashburnDA(2016)."TheStroopeffectat80:Thecompetitionbetweenstimuluscontrolandcognitivecontrol".JExpAnalBehav.105(1):3–13.doi:10.1002/jeab.194.PMID 26781048.Today,arguablymorethanatanytimeinhistory,theconstructsofattention,executivefunctioning,andcognitivecontrolseemtobepervasiveandpreeminentinresearchandtheory.Evenwithinthecognitiveframework,however,therehaslongbeenanunderstandingthatbehaviorismultiplydetermined,andthatmanyresponsesarerelativelyautomatic,unattended,contention-scheduled,andhabitual.Indeed,thecognitiveflexibility,responseinhibition,andself-regulationthatappeartobehallmarksofcognitivecontrolarenoteworthyonlyincontrasttoresponsesthatarerelativelyrigid,associative,andinvoluntary. ^DiamondA(2013)."Executivefunctions".AnnuRevPsychol.64:135–68.doi:10.1146/annurev-psych-113011-143750.PMC 4084861.PMID 23020641.CoreEFsareinhibition[responseinhibition(self-control –resistingtemptationsandresistingactingimpulsively)andinterferencecontrol(selectiveattentionandcognitiveinhibition)],workingmemory,andcognitiveflexibility(includingcreativelythinking"outsidethebox,"seeinganythingfromdifferentperspectives,andquicklyandflexiblyadaptingtochangedcircumstances). ...EFsandprefrontalcortexarethefirsttosuffer,andsufferdisproportionately,ifsomethingisnotrightinyourlife.Theysufferfirst,andmost,ifyouarestressed(Arnsten1998,Listonetal.2009,Oaten&Cheng2005),sad(Hirtetal.2008,vonHecker&Meiser2005),lonely(Baumeisteretal.2002,Cacioppo&Patrick2008,Campbelletal.2006,Tunetal.2012),sleepdeprived(Barnesetal.2012,Huangetal.2007),ornotphysicallyfit(Best2010,Chaddocketal.2011,Hillmanetal.2008).AnyofthesecancauseyoutoappeartohaveadisorderofEFs,suchasADHD,whenyoudonot.Youcanseethedeleteriouseffectsofstress,sadness,loneliness,andlackofphysicalhealthorfitnessatthephysiologicalandneuroanatomicallevelinprefrontalcortexandatthebehaviorallevelinworseEFs(poorerreasoningandproblemsolving,forgettingthings,andimpairedabilitytoexercisedisciplineandself-control). ...EFscanbeimproved(Diamond&Lee2011,Klingberg2010). ...AtanyageacrossthelifecycleEFscanbeimproved,includingintheelderlyandininfants.TherehasbeenmuchworkwithexcellentresultsonimprovingEFsintheelderlybyimprovingphysicalfitness(Erickson&Kramer2009,Vossetal.2011) ...Inhibitorycontrol(oneofthecoreEFs)involvesbeingabletocontrolone'sattention,behavior,thoughts,and/oremotionstooverrideastronginternalpredispositionorexternallure,andinsteaddowhat'smoreappropriateorneeded.Withoutinhibitorycontrolwewouldbeatthemercyofimpulses,oldhabitsofthoughtoraction(conditionedresponses),and/orstimuliintheenvironmentthatpullusthiswayorthat.Thus,inhibitorycontrolmakesitpossibleforustochangeandforustochoosehowwereactandhowwebehaveratherthanbeingunthinkingcreaturesofhabit.Itdoesn'tmakeiteasy.Indeed,weusuallyarecreaturesofhabitandourbehaviorisunderthecontrolofenvironmentalstimulifarmorethanweusuallyrealize,buthavingtheabilitytoexerciseinhibitorycontrolcreatesthepossibilityofchangeandchoice. ...Thesubthalamicnucleusappearstoplayacriticalroleinpreventingsuchimpulsiveorprematureresponding(Frank2006). ^abMalenkaRC,NestlerEJ,HymanSE(2009)."Chapter13:HigherCognitiveFunctionandBehavioralControl".InSydorA,BrownRY(eds.).MolecularNeuropharmacology:AFoundationforClinicalNeuroscience(2nd ed.).NewYork:McGraw-HillMedical.pp. 313–21.ISBN 978-0-07-148127-4. •Executivefunction,thecognitivecontrolofbehavior,dependsontheprefrontalcortex,whichishighlydevelopedinhigherprimatesandespeciallyhumans. •Workingmemoryisashort-term,capacity-limitedcognitivebufferthatstoresinformationandpermitsitsmanipulationtoguidedecision-makingandbehavior. ...Thesediverseinputsandbackprojectionstobothcorticalandsubcorticalstructuresputtheprefrontalcortexinapositiontoexertwhatisoftencalled"top-down"controlorcognitivecontrolofbehavior. ...Theprefrontalcortexreceivesinputsnotonlyfromothercorticalregions,includingassociationcortex,butalso,viathethalamus,inputsfromsubcorticalstructuressubservingemotionandmotivation,suchastheamygdala(Chapter14)andventralstriatum(ornucleusaccumbens;Chapter15). ...Inconditionsinwhichprepotentresponsestendtodominatebehavior,suchasindrugaddiction,wheredrugcuescanelicitdrugseeking(Chapter15),orinattentiondeficithyperactivitydisorder(ADHD;describedbelow),significantnegativeconsequencescanresult. ...ADHDcanbeconceptualizedasadisorderofexecutivefunction;specifically,ADHDischaracterizedbyreducedabilitytoexertandmaintaincognitivecontrolofbehavior.Comparedwithhealthyindividuals,thosewithADHDhavediminishedabilitytosuppressinappropriateprepotentresponsestostimuli(impairedresponseinhibition)anddiminishedabilitytoinhibitresponsestoirrelevantstimuli(impairedinterferencesuppression). ...Functionalneuroimaginginhumansdemonstratesactivationoftheprefrontalcortexandcaudatenucleus(partofthestriatum)intasksthatdemandinhibitorycontrolofbehavior.SubjectswithADHDexhibitlessactivationofthemedialprefrontalcortexthanhealthycontrolsevenwhentheysucceedinsuchtasksandutilizedifferentcircuits. ...EarlyresultswithstructuralMRIshowthinningofthecerebralcortexinADHDsubjectscomparedwithage-matchedcontrolsinprefrontalcortexandposteriorparietalcortex,areasinvolvedinworkingmemoryandattention. ^abcdefghijklmnopVassolerFM,Sadri-VakiliG(2014)."Mechanismsoftransgenerationalinheritanceofaddictive-likebehaviors".Neuroscience.264:198–206.doi:10.1016/j.neuroscience.2013.07.064.PMC 3872494.PMID 23920159.However,thecomponentsthatareresponsiblefortheheritabilityofcharacteristicsthatmakeanindividualmoresusceptibletodrugaddictioninhumansremainlargelyunknowngiventhatpatternsofinheritancecannotbeexplainedbysimplegeneticmechanisms(Cloningeretal.,1981;Schuckitetal.,1972).Theenvironmentalsoplaysalargeroleinthedevelopmentofaddictionasevidencedbygreatsocietalvariabilityindrugusepatternsbetweencountriesandacrosstime(UNODC,2012).Therefore,bothgeneticsandtheenvironmentcontributetoanindividual'svulnerabilitytobecomeaddictedfollowinganinitialexposuretodrugsofabuse. ...Theevidencepresentedheredemonstratesthatrapidenvironmentaladaptationoccursfollowingexposuretoanumberofstimuli.Epigeneticmechanismsrepresentthekeycomponentsbywhichtheenvironmentcaninfluencegenetics,andtheyprovidethemissinglinkbetweengeneticheritabilityandenvironmentalinfluencesonthebehavioralandphysiologicalphenotypesoftheoffspring. ^DouglasKR,ChanG,GelernterJ,AriasAJ,AntonRF,WeissRD,et al.(January2010)."Adversechildhoodeventsasriskfactorsforsubstancedependence:partialmediationbymoodandanxietydisorders".AddictiveBehaviors.35(1):7–13.doi:10.1016/j.addbeh.2009.07.004.PMC 2763992.PMID 19720467. ^MirinSM,WeissRD,GriffinML,MichaelJL(1January1991)."Psychopathologyindrugabusersandtheirfamilies".ComprehensivePsychiatry.32(1):36–51.doi:10.1016/0010-440X(91)90068-N.PMID 2001619. ^MayfieldRD,HarrisRA,SchuckitMA(May2008)."Geneticfactorsinfluencingalcoholdependence".BritishJournalofPharmacology.154(2):275–287.doi:10.1038/bjp.2008.88.PMC 2442454.PMID 18362899. ^abKendlerKS,NealeMC,HeathAC,KesslerRC,EavesLJ(May1994)."Atwin-familystudyofalcoholisminwomen".TheAmericanJournalofPsychiatry.151(5):707–715.doi:10.1176/ajp.151.5.707.PMID 8166312. ^CroweJR."Geneticsofalcoholism".AlcoholHealthandResearchWorld:1–11.Retrieved13December2017. 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^SpearLP(June2000)."Theadolescentbrainandage-relatedbehavioralmanifestations".NeuroscienceandBiobehavioralReviews.24(4):417–63.CiteSeerX 10.1.1.461.3295.doi:10.1016/s0149-7634(00)00014-2.PMID 10817843.S2CID 14686245. ^HammondCJ,MayesLC,PotenzaMN(April2014)."Neurobiologyofadolescentsubstanceuseandaddictivebehaviors:treatmentimplications".AdolescentMedicine.25(1):15–32.PMC 4446977.PMID 25022184. ^CatalanoRF,HawkinsJD,WellsEA,MillerJ,BrewerD(1990)."Evaluationoftheeffectivenessofadolescentdrugabusetreatment,assessmentofrisksforrelapse,andpromisingapproachesforrelapseprevention".TheInternationalJournaloftheAddictions.25(9A–10A):1085–140.doi:10.3109/10826089109081039.PMID 2131328. ^PerepletchikovaF,KrystalJH,KaufmanJ(November2008)."Practitionerreview:adolescentalcoholusedisorders:assessmentandtreatmentissues".JournalofChildPsychologyandPsychiatry,andAlliedDisciplines.49(11):1131–54.doi:10.1111/j.1469-7610.2008.01934.x.PMC 4113213.PMID 19017028. ^abc"NationwideTrends".NationalInstituteonDrugAbuse.June2015.Retrieved15December2017. ^ab"AddictionStatistics–FactsonDrugandAlcoholAddiction".AddictionCenter.Retrieved17September2018. ^SAMHSA."RiskandProtectiveFactors".SubstanceAbuseandMentalHealthAdministration.Archivedfromtheoriginalon8December2016.Retrieved19December2016. ^"Infographic–RiskFactorsofAddiction|RecoveryResearchInstitute".www.recoveryanswers.org.Archivedfromtheoriginalon17December2016.Retrieved19December2016. ^"DrugaddictionRiskfactors–MayoClinic".www.mayoclinic.org.Retrieved19December2016. ^"TheConnectionBetweenMentalIllnessandSubstanceAbuse|DualDiagnosis".DualDiagnosis.Retrieved17September2018. ^abcYuanTF,LiA,SunX,OuyangH,CamposC,RochaNB,Arias-CarriónO,MachadoS,HouG,SoKF(2015)."TransgenerationalInheritanceofPaternalNeurobehavioralPhenotypes:Stress,Addiction,AgeingandMetabolism".Mol.Neurobiol.53(9):6367–76.doi:10.1007/s12035-015-9526-2.hdl:10400.22/7331.PMID 26572641.S2CID 25694221. ^abcdefghijRuffleJK(November2014)."Molecularneurobiologyofaddiction:what'sallthe(Δ)FosBabout?".Am.J.DrugAlcoholAbuse.40(6):428–37.doi:10.3109/00952990.2014.933840.PMID 25083822.S2CID 19157711.ΔFosBisanessentialtranscriptionfactorimplicatedinthemolecularandbehavioralpathwaysofaddictionfollowingrepeateddrugexposure.TheformationofΔFosBinmultiplebrainregions,andthemolecularpathwayleadingtotheformationofAP-1complexesiswellunderstood.TheestablishmentofafunctionalpurposeforΔFosBhasallowedfurtherdeterminationastosomeofthekeyaspectsofitsmolecularcascades[…]AsaconsequenceofourimprovedunderstandingofΔFosBinaddiction,itispossibletoevaluatetheaddictivepotentialofcurrentmedications(119),aswellasuseitasabiomarkerforassessingtheefficacyoftherapeuticinterventions(121,122,124).Someoftheseproposedinterventionshavelimitations(125)orareintheirinfancy(75).However,itishopedthatsomeofthesepreliminaryfindingsmayleadtoinnovativetreatments,whicharemuchneededinaddiction. ^abcdefBilińskiP,WojtyłaA,Kapka-SkrzypczakL,ChwedorowiczR,CyrankaM,StudzińskiT(2012)."Epigeneticregulationindrugaddiction".Ann.Agric.Environ.Med.19(3):491–96.PMID 23020045.[…]ΔFosBisconsideredaprimaryandcausativetranscriptionfactorincreatingnewneuralconnectionsintherewardcentre,prefrontalcortex,andotherregionsofthelimbicsystem.Thisisreflectedintheincreased,stableandlong-lastinglevelofsensitivitytococaineandotherdrugs,andtendencytorelapseevenafterlongperiodsofabstinence. ^abcRenthalW,NestlerEJ(September2009)."Chromatinregulationindrugaddictionanddepression".DialoguesinClinicalNeuroscience.11(3):257–268.PMC 2834246.PMID 19877494.[Psychostimulants]increasecAMPlevelsinstriatum,whichactivatesproteinkinaseA(PKA)andleadstophosphorylationofitstargets.ThisincludesthecAMPresponseelementbindingprotein(CREB),thephosphorylationofwhichinducesitsassociationwiththehistoneacetyltransferase,CREBbindingprotein(CBP)toacetylatehistonesandfacilitategeneactivation.ThisisknowntooccuronmanygenesincludingfosBandc-fosinresponsetopsychostimulantexposure.ΔFosBisalsoupregulatedbychronicpsychostimulanttreatments,andisknowntoactivatecertaingenes(eg,cdk5)andrepressothers(eg,c-fos)whereitrecruitsHDAC1asacorepressor. ...Chronicexposuretopsychostimulantsincreasesglutamatergic[signaling]fromtheprefrontalcortextotheNAc.GlutamatergicsignalingelevatesCa2+levelsinNAcpostsynapticelementswhereitactivatesCaMK(calcium/calmodulinproteinkinases)signaling,which,inadditiontophosphorylatingCREB,alsophosphorylatesHDAC5.Figure2:Psychostimulant-inducedsignalingevents ^BroussardJI(January2012)."Co-transmissionofdopamineandglutamate".TheJournalofGeneralPhysiology.139(1):93–96.doi:10.1085/jgp.201110659.PMC 3250102.PMID 22200950.Coincidentandconvergentinputofteninducesplasticityonapostsynapticneuron.TheNAcintegratesprocessedinformationabouttheenvironmentfrombasolateralamygdala,hippocampus,andprefrontalcortex(PFC),aswellasprojectionsfrommidbraindopamineneurons.Previousstudieshavedemonstratedhowdopaminemodulatesthisintegrativeprocess.Forexample,highfrequencystimulationpotentiateshippocampalinputstotheNAcwhilesimultaneouslydepressingPFCsynapses(GotoandGrace,2005).Theconversewasalsoshowntobetrue;stimulationatPFCpotentiatesPFC–NAcsynapsesbutdepresseshippocampal–NAcsynapses.Inlightofthenewfunctionalevidenceofmidbraindopamine/glutamateco-transmission(referencesabove),newexperimentsofNAcfunctionwillhavetotestwhethermidbrainglutamatergicinputsbiasorfiltereitherlimbicorcorticalinputstoguidegoal-directedbehavior. ^KanehisaLaboratories(10October2014)."Amphetamine–Homosapiens(human)".KEGGPathway.Retrieved31October2014.Mostaddictivedrugsincreaseextracellularconcentrationsofdopamine(DA)innucleusaccumbens(NAc)andmedialprefrontalcortex(mPFC),projectionareasofmesocorticolimbicDAneuronsandkeycomponentsofthe"brainrewardcircuit".AmphetamineachievesthiselevationinextracellularlevelsofDAbypromotingeffluxfromsynapticterminals. ...ChronicexposuretoamphetamineinducesauniquetranscriptionfactordeltaFosB,whichplaysanessentialroleinlong-termadaptivechangesinthebrain. ^CadetJL,BrannockC,JayanthiS,KrasnovaIN(2015)."Transcriptionalandepigeneticsubstratesofmethamphetamineaddictionandwithdrawal:evidencefromalong-accessself-administrationmodelintherat".MolecularNeurobiology.51(2):696–717(Figure1).doi:10.1007/s12035-014-8776-8.PMC 4359351.PMID 24939695. ^abcRobisonAJ,NestlerEJ(November2011)."Transcriptionalandepigeneticmechanismsofaddiction".NatureReviewsNeuroscience.12(11):623–637.doi:10.1038/nrn3111.PMC 3272277.PMID 21989194.ΔFosBservesasoneofthemastercontrolproteinsgoverningthisstructuralplasticity. ...ΔFosBalsorepressesG9aexpression,leadingtoreducedrepressivehistonemethylationatthecdk5gene.ThenetresultisgeneactivationandincreasedCDK5expression. ...Incontrast,ΔFosBbindstothec-fosgeneandrecruitsseveralco-repressors,includingHDAC1(histonedeacetylase1)andSIRT1(sirtuin1). ...Thenetresultisc-fosgenerepression.Figure4:Epigeneticbasisofdrugregulationofgeneexpression ^abcdNestlerEJ(December2012)."Transcriptionalmechanismsofdrugaddiction".ClinicalPsychopharmacologyandNeuroscience.10(3):136–143.doi:10.9758/cpn.2012.10.3.136.PMC 3569166.PMID 23430970.The35-37kDΔFosBisoformsaccumulatewithchronicdrugexposureduetotheirextraordinarilylonghalf-lives. ...Asaresultofitsstability,theΔFosBproteinpersistsinneuronsforatleastseveralweeksaftercessationofdrugexposure. ...ΔFosBoverexpressioninnucleusaccumbensinducesNFκB ...Incontrast,theabilityofΔFosBtorepressthec-Fosgeneoccursinconcertwiththerecruitmentofahistonedeacetylaseandpresumablyseveralotherrepressiveproteinssuchasarepressivehistonemethyltransferase ^NestlerEJ(October2008)."Transcriptionalmechanismsofaddiction:RoleofΔFosB".PhilosophicalTransactionsoftheRoyalSocietyB:BiologicalSciences.363(1507):3245–3255.doi:10.1098/rstb.2008.0067.PMC 2607320.PMID 18640924.RecentevidencehasshownthatΔFosBalsorepressesthec-fosgenethathelpscreatethemolecularswitch—fromtheinductionofseveralshort-livedFosfamilyproteinsafteracutedrugexposuretothepredominantaccumulationofΔFosBafterchronicdrugexposure ^abHymanSE,MalenkaRC,NestlerEJ(2006)."Neuralmechanismsofaddiction:theroleofreward-relatedlearningandmemory".Annu.Rev.Neurosci.29:565–98.doi:10.1146/annurev.neuro.29.051605.113009.PMID 16776597. ^SteinerH,VanWaesV(January2013)."Addiction-relatedgeneregulation:risksofexposuretocognitiveenhancersvs.otherpsychostimulants".Prog.Neurobiol.100:60–80.doi:10.1016/j.pneurobio.2012.10.001.PMC 3525776.PMID 23085425. ^KanehisaLaboratories(2August2013)."Alcoholism–Homosapiens(human)".KEGGPathway.Retrieved10April2014. ^KimY,TeylanMA,BaronM,SandsA,NairnAC,GreengardP(February2009)."Methylphenidate-induceddendriticspineformationandDeltaFosBexpressioninnucleusaccumbens".Proc.Natl.Acad.Sci.USA.106(8):2915–20.Bibcode:2009PNAS..106.2915K.doi:10.1073/pnas.0813179106.PMC 2650365.PMID 19202072. ^abcdefghNestlerEJ(January2014)."Epigeneticmechanismsofdrugaddiction".Neuropharmacology.76(PtB):259–68.doi:10.1016/j.neuropharm.2013.04.004.PMC 3766384.PMID 23643695.Short-termincreasesinhistoneacetylationgenerallypromotebehavioralresponsestothedrugs,whilesustainedincreasesopposecocaine'seffects,basedontheactionsofsystemicorintra-NAcadministrationofHDACinhibitors. ...GeneticorpharmacologicalblockadeofG9aintheNAcpotentiatesbehavioralresponsestococaineandopiates,whereasincreasingG9afunctionexertstheoppositeeffect(Mazeetal.,2010;Sunetal.,2012a).Suchdrug-induceddownregulationofG9aandH3K9me2alsosensitizesanimalstothedeleteriouseffectsofsubsequentchronicstress(Covingtonetal.,2011).DownregulationofG9aincreasesthedendriticarborizationofNAcneurons,andisassociatedwithincreasedexpressionofnumerousproteinsimplicatedinsynapticfunction,whichdirectlyconnectsalteredG9a/H3K9me2inthesynapticplasticityassociatedwithaddiction(Mazeetal.,2010).G9aappearstobeacriticalcontrolpointforepigeneticregulationinNAc,asweknowitfunctionsintwonegativefeedbackloops.ItopposestheinductionofΔFosB,along-lastingtranscriptionfactorimportantfordrugaddiction(RobisonandNestler,2011),whileΔFosBinturnsuppressesG9aexpression(Mazeetal.,2010;Sunetal.,2012a). ...Also,G9aisinducedinNAcuponprolongedHDACinhibition,whichexplainstheparadoxicalattenuationofcocaine'sbehavioraleffectsseenundertheseconditions,asnotedabove(Kennedyetal.,2013).GABAAreceptorsubunitgenesareamongthosethatarecontrolledbythisfeedbackloop.Thus,chroniccocaine,orprolongedHDACinhibition,inducesseveralGABAAreceptorsubunitsinNAc,whichisassociatedwithincreasedfrequencyofinhibitorypostsynapticcurrents(IPSCs).Instrikingcontrast,combinedexposuretococaineandHDACinhibition,whichtriggerstheinductionofG9aandincreasedgloballevelsofH3K9me2,leadstoblockadeofGABAAreceptorandIPSCregulation. ^abcdBlumK,WernerT,CarnesS,CarnesP,BowirratA,GiordanoJ,Oscar-BermanM,GoldM(2012)."Sex,drugs,androck'n'roll:hypothesizingcommonmesolimbicactivationasafunctionofrewardgenepolymorphisms".JournalofPsychoactiveDrugs.44(1):38–55.doi:10.1080/02791072.2012.662112.PMC 4040958.PMID 22641964.IthasbeenfoundthatdeltaFosBgeneintheNAciscriticalforreinforcingeffectsofsexualreward.Pitchersandcolleagues(2010)reportedthatsexualexperiencewasshowntocauseDeltaFosBaccumulationinseverallimbicbrainregionsincludingtheNAc,medialpre-frontalcortex,VTA,caudate,andputamen,butnotthemedialpreopticnucleus.Next,theinductionofc-Fos,adownstream(repressed)targetofDeltaFosB,wasmeasuredinsexuallyexperiencedandnaiveanimals.Thenumberofmating-inducedc-Fos-IRcellswassignificantlydecreasedinsexuallyexperiencedanimalscomparedtosexuallynaivecontrols.Finally,DeltaFosBlevelsanditsactivityintheNAcweremanipulatedusingviral-mediatedgenetransfertostudyitspotentialroleinmediatingsexualexperienceandexperience-inducedfacilitationofsexualperformance.AnimalswithDeltaFosBoverexpressiondisplayedenhancedfacilitationofsexualperformancewithsexualexperiencerelativetocontrols.Incontrast,theexpressionofDeltaJunD,adominant-negativebindingpartnerofDeltaFosB,attenuatedsexualexperience-inducedfacilitationofsexualperformance,andstuntedlong-termmaintenanceoffacilitationcomparedtoDeltaFosBoverexpressinggroup.Together,thesefindingssupportacriticalroleforDeltaFosBexpressionintheNAcinthereinforcingeffectsofsexualbehaviorandsexualexperience-inducedfacilitationofsexualperformance. ...bothdrugaddictionandsexualaddictionrepresentpathologicalformsofneuroplasticityalongwiththeemergenceofaberrantbehaviorsinvolvingacascadeofneurochemicalchangesmainlyinthebrain'srewardingcircuitry. ^MalenkaRC,NestlerEJ,HymanSE(2009)."Chapter15:Reinforcementandaddictivedisorders".InSydorA,BrownRY(eds.).MolecularNeuropharmacology:AFoundationforClinicalNeuroscience(2nd ed.).NewYork:McGraw-HillMedical.pp. 384–85.ISBN 978-0-07-148127-4. ^SalamoneJD(1992)."Complexmotorandsensorimotorfunctionsofstriatalandaccumbensdopamine:involvementininstrumentalbehaviorprocesses".Psychopharmacology.107(2–3):160–74.doi:10.1007/bf02245133.PMID 1615120.S2CID 30545845. ^KauerJA,MalenkaRC(November2007)."Synapticplasticityandaddiction".NatureReviews.Neuroscience.8(11):844–58.doi:10.1038/nrn2234.PMID 17948030.S2CID 38811195. ^WittenIB,LinSC,BrodskyM,PrakashR,DiesterI,AnikeevaP,et al.(December2010)."Cholinergicinterneuronscontrollocalcircuitactivityandcocaineconditioning".Science.330(6011):1677–81.Bibcode:2010Sci...330.1677W.doi:10.1126/science.1193771.PMC 3142356.PMID 21164015. ^abNestlerEJ,BarrotM,SelfDW(September2001)."DeltaFosB:asustainedmolecularswitchforaddiction".Proc.Natl.Acad.Sci.U.S.A.98(20):11042–46.Bibcode:2001PNAS...9811042N.doi:10.1073/pnas.191352698.PMC 58680.PMID 11572966.AlthoughtheΔFosBsignalisrelativelylong-lived,itisnotpermanent.ΔFosBdegradesgraduallyandcannolongerbedetectedin[the]brainafter1–2monthsofdrugwithdrawal ...Indeed,ΔFosBisthelongest-livedadaptationknowntooccurin[the]adultbrain,notonlyinresponsetodrugsofabuse,buttoanyotherperturbation(thatdoesn'tinvolvelesions)aswell. ^abJonesS,BonciA(2005)."Synapticplasticityanddrugaddiction".CurrentOpinioninPharmacology.5(1):20–25.doi:10.1016/j.coph.2004.08.011.PMID 15661621. ^abEischAJ,HarburgGC(2006)."Opiates,psychostimulants,andadulthippocampalneurogenesis:Insightsforaddictionandstemcellbiology".Hippocampus.16(3):271–86.doi:10.1002/hipo.20161.PMID 16411230.S2CID 23667629. ^RangHP(2003).Pharmacology.Edinburgh:ChurchillLivingstone.p. 596.ISBN 978-0-443-07145-4. ^KourrichS,RothwellPE,KlugJR,ThomasMJ(2007)."Cocaineexperiencecontrolsbidirectionalsynapticplasticityinthenucleusaccumbens".J.Neurosci.27(30):7921–28.doi:10.1523/JNEUROSCI.1859-07.2007.PMC 6672735.PMID 17652583. ^abKalivasPW,VolkowND(August2005)."Theneuralbasisofaddiction:apathologyofmotivationandchoice".TheAmericanJournalofPsychiatry.162(8):1403–13.doi:10.1176/appi.ajp.162.8.1403.PMID 16055761. ^abFlorescoSB,Ghods-SharifiS(February2007)."Amygdala-prefrontalcorticalcircuitryregulateseffort-baseddecisionmaking".CerebralCortex.17(2):251–60.CiteSeerX 10.1.1.335.4681.doi:10.1093/cercor/bhj143.PMID 16495432. ^PerryCJ,ZbukvicI,KimJH,LawrenceAJ(October2014)."Roleofcuesandcontextsondrug-seekingbehaviour".BritishJournalofPharmacology.171(20):4636–72.doi:10.1111/bph.12735.PMC 4209936.PMID 24749941. ^abcVolkowND,FowlerJS,WangGJ,SwansonJM,TelangF(2007)."Dopamineindrugabuseandaddiction:resultsofimagingstudiesandtreatmentimplications".Arch.Neurol.64(11):1575–79.doi:10.1001/archneur.64.11.1575.PMID 17998440. ^"Drugs,Brains,andBehavior:TheScienceofAddiction".NationalInstituteonDrugAbuse. ^"UnderstandingDrugAbuseandAddiction".NationalInstituteonDrugAbuse.November2012.Archivedfromtheoriginalon16August2011.Retrieved12February2015. ^abcNestlerEJ(October2008)."Review.Transcriptionalmechanismsofaddiction:roleofDeltaFosB".PhilosophicalTransactionsoftheRoyalSocietyofLondon.SeriesB,BiologicalSciences.363(1507):3245–55.doi:10.1098/rstb.2008.0067.PMC 2607320.PMID 18640924.RecentevidencehasshownthatΔFosBalsorepressesthec-fosgenethathelpscreatethemolecularswitch–fromtheinductionofseveralshort-livedFosfamilyproteinsafteracutedrugexposuretothepredominantaccumulationofΔFosBafterchronicdrugexposure –citedearlier(Renthaletal.inpress).ThemechanismresponsibleforΔFosBrepressionofc-fosexpressioniscomplexandiscoveredbelow. ...ExamplesofvalidatedtargetsforΔFosBinnucleusaccumbens ...GluR2 ...dynorphin ...Cdk5 ...NFκB ...c-FosTable3 ^abcdefBerridgeKC(April2012)."Frompredictionerrortoincentivesalience:mesolimbiccomputationofrewardmotivation".Eur.J.Neurosci.35(7):1124–43.doi:10.1111/j.1460-9568.2012.07990.x.PMC 3325516.PMID 22487042.HereIdiscusshowmesocorticolimbicmechanismsgeneratethemotivationcomponentofincentivesalience.IncentivesaliencetakesPavlovianlearningandmemoryasoneinputandasanequallyimportantinputtakesneurobiologicalstatefactors(e.g.drugstates,appetitestates,satietystates)thatcanvaryindependentlyoflearning.Neurobiologicalstatechangescanproduceunlearnedfluctuationsorevenreversalsintheabilityofapreviouslylearnedrewardcuetotriggermotivation.Suchfluctuationsincue-triggeredmotivationcandramaticallydepartfromallpreviouslylearnedvaluesabouttheassociatedrewardoutcome. ...Associativelearningandpredictionareimportantcontributorstomotivationforrewards.LearninggivesincentivevaluetoarbitrarycuessuchasaPavlovianconditionedstimulus(CS)thatisassociatedwithareward(unconditionedstimulusorUCS).Learnedcuesforrewardareoftenpotenttriggersofdesires.Forexample,learnedcuescantriggernormalappetitesineveryone,andcansometimestriggercompulsiveurgesandrelapseinindividualswithaddictions.Cue-triggered'wanting'fortheUCSAbriefCSencounter(orbriefUCSencounter)oftenprimesapulseofelevatedmotivationtoobtainandconsumemorerewardUCS.Thisisasignaturefeatureofincentivesalience.CueasattractivemotivationalmagnetsWhenaPavlovianCS+isattributedwithincentivesalienceitnotonlytriggers'wanting'foritsUCS,butoftenthecueitselfbecomeshighlyattractive–eventoanirrationaldegree.Thiscueattractionisanothersignaturefeatureofincentivesalience ...Tworecognizablefeaturesofincentivesalienceareoftenvisiblethatcanbeusedinneuroscienceexperiments:(i)UCS-directed'wanting'–CS-triggeredpulsesofintensified'wanting'fortheUCSreward;and(ii)CS-directed'wanting'–motivatedattractiontothePavloviancue,whichmakesthearbitraryCSstimulusintoamotivationalmagnet. ^abMalenkaRC,NestlerEJ,HymanSE(2009).SydorA,BrownRY(eds.).MolecularNeuropharmacology:AFoundationforClinicalNeuroscience(2nd ed.).NewYork:McGraw-HillMedical.pp. 147–48,366–67,375–76.ISBN 978-0-07-148127-4.VTADAneuronsplayacriticalroleinmotivation,reward-relatedbehavior(Chapter15),attention,andmultipleformsofmemory.ThisorganizationoftheDAsystem,wideprojectionfromalimitednumberofcellbodies,permitscoordinatedresponsestopotentnewrewards.Thus,actingindiverseterminalfields,dopamineconfersmotivationalsalience("wanting")ontherewarditselforassociatedcues(nucleusaccumbensshellregion),updatesthevalueplacedondifferentgoalsinlightofthisnewexperience(orbitalprefrontalcortex),helpsconsolidatemultipleformsofmemory(amygdalaandhippocampus),andencodesnewmotorprogramsthatwillfacilitateobtainingthisrewardinthefuture(nucleusaccumbenscoreregionanddorsalstriatum).Inthisexample,dopaminemodulatestheprocessingofsensorimotorinformationindiverseneuralcircuitstomaximizetheabilityoftheorganismtoobtainfuturerewards. ...Thebrainrewardcircuitrythatistargetedbyaddictivedrugsnormallymediatesthepleasureandstrengtheningofbehaviorsassociatedwithnaturalreinforcers,suchasfood,water,andsexualcontact.DopamineneuronsintheVTAareactivatedbyfoodandwater,anddopaminereleaseintheNAcisstimulatedbythepresenceofnaturalreinforcers,suchasfood,water,orasexualpartner. ...TheNAcandVTAarecentralcomponentsofthecircuitryunderlyingrewardandmemoryofreward.Aspreviouslymentioned,theactivityofdopaminergicneuronsintheVTAappearstobelinkedtorewardprediction.TheNAcisinvolvedinlearningassociatedwithreinforcementandthemodulationofmotoricresponsestostimulithatsatisfyinternalhomeostaticneeds.TheshelloftheNAcappearstobeparticularlyimportanttoinitialdrugactionswithinrewardcircuitry;addictivedrugsappeartohaveagreatereffectondopaminereleaseintheshellthaninthecoreoftheNAc. ...Ifmotivationaldriveisdescribedintermsofwanting,andhedonicevaluationintermsofliking,itappearsthatwantingcanbedissociatedfromlikingandthatdopaminemayinfluencethesephenomenadifferently.Differencesbetweenwantingandlikingareconfirmedinreportsbyhumanswithaddictions,whostatethattheirdesirefordrugs(wanting)increaseswithcontinueduseevenwhenpleasure(liking)decreasesbecauseoftolerance. ^abcdEdwardsS(2016)."Reinforcementprinciplesforaddictionmedicine;fromrecreationaldrugusetopsychiatricdisorder".NeuroscienceforAddictionMedicine:FromPreventiontoRehabilitation-ConstructsandDrugs.ProgressinBrainResearch.Vol. 223.pp. 63–76.doi:10.1016/bs.pbr.2015.07.005.ISBN 978-0-444-63545-7.PMID 26806771.Animportantdimensionofreinforcementhighlyrelevanttotheaddictionprocess(andparticularlyrelapse)issecondaryreinforcement(Stewart,1992).Secondaryreinforcers(inmanycasesalsoconsideredconditionedreinforcers)likelydrivethemajorityofreinforcementprocessesinhumans.Inthespecificcaseofdrugaddiction,cuesandcontextsthatareintimatelyandrepeatedlyassociatedwithdrugusewilloftenthemselvesbecomereinforcing ...AfundamentalpieceofRobinsonandBerridge'sincentive-sensitizationtheoryofaddictionpositsthattheincentivevalueorattractivenatureofsuchsecondaryreinforcementprocesses,inadditiontotheprimaryreinforcersthemselves,maypersistandevenbecomesensitizedovertimeinleaguewiththedevelopmentofdrugaddiction(RobinsonandBerridge,1993). ^abBerridgeKC,KringelbachML(May2015)."Pleasuresystemsinthebrain".Neuron.86(3):646–664.doi:10.1016/j.neuron.2015.02.018.PMC 4425246.PMID 25950633. ^abcdefgWalkerDM,CatesHM,HellerEA,NestlerEJ(February2015)."Regulationofchromatinstatesbydrugsofabuse".Curr.Opin.Neurobiol.30:112–21.doi:10.1016/j.conb.2014.11.002.PMC 4293340.PMID 25486626.StudiesinvestigatinggeneralHDACinhibitiononbehavioraloutcomeshaveproducedvaryingresultsbutitseemsthattheeffectsarespecifictothetimingofexposure(eitherbefore,duringorafterexposuretodrugsofabuse)aswellasthelengthofexposure ^PetryNM,RehbeinF,GentileDA,LemmensJS,RumpfHJ,MößleT,BischofG,TaoR,FungDS,BorgesG,AuriacombeM,GonzálezIbáñezA,TamP,O'BrienCP(September2014)."AninternationalconsensusforassessinginternetgamingdisorderusingthenewDSM-5approach".Addiction.109(9):1399–406.doi:10.1111/add.12457.PMID 24456155. ^TorresG,HorowitzJM(1999)."Drugsofabuseandbraingeneexpression".PsychosomMed.61(5):630–50.CiteSeerX 10.1.1.326.4903.doi:10.1097/00006842-199909000-00007.PMID 10511013. ^"ICD-11forMortalityandMorbidityStatistics-Disordersduetosubstanceuseoraddictivebehaviours".icd.who.int.Retrieved10April2022. ^ab"ICD-11forMortalityandMorbidityStatistics-Disordersduetosubstanceuse".icd.who.int.Retrieved10April2022. ^ab"Drugabuseliability".www.cambridgecognition.com.Retrieved9March2021. ^NationalInstituteonDrugAbuse(20August2020)."CommonlyUsedDrugsCharts".NationalInstituteonDrugAbuse.Retrieved9March2021. ^abTaylorSB,LewisCR,OliveMF(February2013)."Theneurocircuitryofillicitpsychostimulantaddiction:acuteandchroniceffectsinhumans".Subst.AbuseRehabil.4:29–43.doi:10.2147/SAR.S39684.PMC 3931688.PMID 24648786.Initialdrugusecanbeattributedtotheabilityofthedrugtoactasareward(ie,apleasurableemotionalstateorpositivereinforcer),whichcanleadtorepeateddruguseanddependence.8,9Agreatdealofresearchhasfocusedonthemolecularandneuroanatomicalmechanismsoftheinitialrewardingorreinforcingeffectofdrugsofabuse. ...Atpresent,nopharmacologicaltherapyhasbeenapprovedbytheFDAtotreatpsychostimulantaddiction.Manydrugshavebeentested,butnonehaveshownconclusiveefficacywithtolerablesideeffectsinhumans.172 ...Anewemphasisonlarger-scalebiomarker,genetic,andepigeneticresearchfocusedonthemoleculartargetsofmentaldisordershasbeenrecentlyadvocated.212Inaddition,theintegrationofcognitiveandbehavioralmodificationofcircuit-wideneuroplasticity(ie,computer-basedtrainingtoenhanceexecutivefunction)mayprovetobeaneffectiveadjunct-treatmentapproachforaddiction,particularlywhencombinedwithcognitiveenhancers.198,213–216Furthermore,inordertobeeffective,allpharmacologicalorbiologicallybasedtreatmentsforaddictionneedtobeintegratedintootherestablishedformsofaddictionrehabilitation,suchascognitivebehavioraltherapy,individualandgrouppsychotherapy,behavior-modificationstrategies,twelve-stepprograms,andresidentialtreatmentfacilities. ^MagnussonD(1998).TheoreticalModelsofHumandevelopment.NewYork:JohnWiley&sons.pp. 685–759. ^abcSchlosserAV(September2018)."'TheyMedicatedMeOut':SocialFleshandEmbodiedCitizenshipinAddictionTreatment".ContemporaryDrugProblems.45(3):188–207.doi:10.1177/0091450918781590.S2CID 149842084. ^WolfeD,SaucierR(February2021)."Biotechnologiesandthefutureofopioidaddictiontreatments".TheInternationalJournalonDrugPolicy.88:103041.doi:10.1016/j.drugpo.2020.103041.PMID 33246267.S2CID 227191111. ^WalterM,DürstelerKM,PetitjeanSA,WiesbeckGA,EulerS,SollbergerD,et al.(April2015)."[PsychosocialTreatmentofAddictiveDisorders--AnOverviewofPsychotherapeuticOptionsandtheirEfficacy]"[PsychosocialTreatmentofAddictiveDisorders–AnOverviewofPsychotherapeuticOptionsandtheirEfficacy].FortschrittederNeurologie-Psychiatrie(inGerman).83(4):201–210.doi:10.1055/s-0034-1399338.PMID 25893493. ^CarrollME,SmethellsJR(February2016)."SexDifferencesinBehavioralDyscontrol:RoleinDrugAddictionandNovelTreatments".Front.Psychiatry.6:175.doi:10.3389/fpsyt.2015.00175.PMC 4745113.PMID 26903885.EnvironmentalEnrichment ...Inhumans,non-drugrewardsdeliveredinacontingencymanagement(CM)formatsuccessfullyreduceddrugdependence ...Ingeneral,CMprogramspromotedrugabstinencethroughacombinationofpositivereinforcementfordrug-freeurinesamples.Forinstance,voucher-basedreinforcementtherapyinwhichmedicationcompliance,therapysessionattendance,andnegativedrugscreeningsreinforcedwithvoucherstolocalbusiness(e.g.,movietheater,restaurants,etc.)directlyreinforcesdrugabstinence,providescompetingreinforcers,enrichestheenvironment,anditisarobusttreatmentacrossabroadrangeofabuseddrugs(189). ...PhysicalExerciseThereisacceleratingevidencethatphysicalexerciseisausefultreatmentforpreventingandreducingdrugaddiction ...Insomeindividuals,exercisehasitsownrewardingeffects,andabehavioraleconomicinteractionmayoccur,suchthatphysicalandsocialrewardsofexercisecansubstitutefortherewardingeffectsofdrugabuse. ...Thevalueofthisformoftreatmentfordrugaddictioninlaboratoryanimalsandhumansisthatexercise,ifitcansubstitutefortherewardingeffectsofdrugs,couldbeself-maintainedoveranextendedperiodoftime.Worktodatein[laboratoryanimalsandhumans]regardingexerciseasatreatmentfordrugaddictionsupportsthishypothesis. ...However,aRTCstudywasrecentlyreportedbyRawsonetal.(226),wherebytheyused8weeksofexerciseasapost-residentialtreatmentforMETHaddiction,showedasignificantreductioninuse(confirmedbyurinescreens)inparticipantswhohadbeenusingmeth18daysorlessamonth. ...Animalandhumanresearchonphysicalexerciseasatreatmentforstimulantaddictionindicatesthatthisisoneofthemostpromisingtreatmentsonthehorizon.[(emphasisadded)] ^abcdLynchWJ,PetersonAB,SanchezV,AbelJ,SmithMA(September2013)."Exerciseasanoveltreatmentfordrugaddiction:aneurobiologicalandstage-dependenthypothesis".NeurosciBiobehavRev.37(8):1622–44.doi:10.1016/j.neubiorev.2013.06.011.PMC 3788047.PMID 23806439.[exercise]efficacymayberelatedtoitsabilitytonormalizeglutamatergicanddopaminergicsignalingandreversedrug-inducedchangesinchromatinviaepigeneticinteractionswithbrain-derivedneurotrophicfactor(BDNF)intherewardpathway. ...thesedatashowthatexercisecanaffectdopaminergicsignalingatmanydifferentlevels,whichmayunderlieitsabilitytomodifyvulnerabilityduringdruguseinitiation.Exercisealsoproducesneuroadaptationsthatmayinfluenceanindividual'svulnerabilitytoinitiatedruguse.Consistentwiththisidea,chronicmoderatelevelsofforcedtreadmillrunningblocksnotonlysubsequentmethamphetamine-inducedconditionedplacepreference,butalsostimulant-inducedincreasesindopaminereleaseintheNAc(Chenetal.,2008)andstriatum(Marquesetal.,2008). ...[These]findingsindicatetheefficacyofexerciseatreducingdrugintakeindrug-dependentindividuals ...wheelrunning[reduces]methamphetamineself-administrationunderextendedaccessconditions(Engelmannetal.,2013) ...Thesefindingssuggestthatexercisemay"magnitude"-dependentlypreventthedevelopmentofanaddictedphenotypepossiblybyblocking/reversingbehavioralandneuro-adaptivechangesthatdevelopduringandfollowingextendedaccesstothedrug. ...Exercisehasbeenproposedasatreatmentfordrugaddictionthatmayreducedrugcravingandriskofrelapse.Althoughfewclinicalstudieshaveinvestigatedtheefficacyofexerciseforpreventingrelapse,thefewstudiesthathavebeenconductedgenerallyreportareductionindrugcravingandbettertreatmentoutcomes(seeTable4). ...Takentogether,thesedatasuggestthatthepotentialbenefitsofexerciseduringrelapse,particularlyforrelapsetopsychostimulants,maybemediatedviachromatinremodelingandpossiblyleadtogreatertreatmentoutcomes. ^abLinkeSE,UssherM(2015)."Exercise-basedtreatmentsforsubstanceusedisorders:evidence,theory,andpracticality".AmJDrugAlcoholAbuse.41(1):7–15.doi:10.3109/00952990.2014.976708.PMC 4831948.PMID 25397661.ThelimitedresearchconductedsuggeststhatexercisemaybeaneffectiveadjunctivetreatmentforSUDs.Incontrasttothescarceinterventiontrialstodate,arelativeabundanceofliteratureonthetheoreticalandpracticalreasonssupportingtheinvestigationofthistopichasbeenpublished. ...numeroustheoreticalandpracticalreasonssupportexercise-basedtreatmentsforSUDs,includingpsychological,behavioral,neurobiological,nearlyuniversalsafetyprofile,andoverallpositivehealtheffects. ^abZhouY,ZhaoM,ZhouC,LiR(July2015)."Sexdifferencesindrugaddictionandresponsetoexerciseintervention:Fromhumantoanimalstudies".Front.Neuroendocrinol.40:24–41.doi:10.1016/j.yfrne.2015.07.001.PMC 4712120.PMID 26182835.Collectively,thesefindingsdemonstratethatexercisemayserveasasubstituteorcompetitionfordrugabusebychangingΔFosBorcFosimmunoreactivityintherewardsystemtoprotectagainstlaterorpreviousdruguse. ...Asbrieflyreviewedabove,alargenumberofhumanandrodentstudiesclearlyshowthattherearesexdifferencesindrugaddictionandexercise.Thesexdifferencesarealsofoundintheeffectivenessofexerciseondrugaddictionpreventionandtreatment,aswellasunderlyingneurobiologicalmechanisms.Thepostulatethatexerciseservesasanidealinterventionfordrugaddictionhasbeenwidelyrecognizedandusedinhumanandanimalrehabilitation. ...Inparticular,morestudiesontheneurobiologicalmechanismofexerciseanditsrolesinpreventingandtreatingdrugaddictionareneeded. ^SachdevaA,ChoudharyM,ChandraM(September2015)."AlcoholWithdrawalSyndrome:BenzodiazepinesandBeyond".JournalofClinicalandDiagnosticResearch.9(9):VE01–VE07.doi:10.7860/JCDR/2015/13407.6538.PMC 4606320.PMID 26500991. ^SoykaM,RoesnerS(December2006)."Newpharmacologicalapproachesforthetreatmentofalcoholism".ExpertOpiniononPharmacotherapy.7(17):2341–53.doi:10.1517/14656566.7.17.2341.PMID 17109610.S2CID 2587029. ^PettinatiHM,RabinowitzAR(October2006)."Choosingtherightmedicationforthetreatmentofalcoholism".CurrentPsychiatryReports.8(5):383–88.doi:10.1007/s11920-006-0040-0.PMID 16968619.S2CID 39826013. ^BouzaC,AngelesM,MagroA,MuñozA,AmateJM(July2004)."Efficacyandsafetyofnaltrexoneandacamprosateinthetreatmentofalcoholdependence:asystematicreview".Addiction.99(7):811–28.doi:10.1111/j.1360-0443.2004.00763.x.PMID 15200577. ^WilliamsSH(November2005)."Medicationsfortreatingalcoholdependence".AmericanFamilyPhysician.72(9):1775–80.PMID 16300039. 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^MetrebianN,ShanahanW,WellsB,StimsonGV(June1998)."Feasibilityofprescribinginjectableheroinandmethadonetoopiate-dependentdrugusers:associatedhealthgainsandharmreductions".TheMedicalJournalofAustralia.168(12):596–600.doi:10.5694/j.1326-5377.1998.tb141444.x.PMID 9673620.S2CID 43302721. ^MetrebianN,MottJ,CarnwathZ,CarnwathT,StimsonGV,SellL(2007)."Pathwaysintoreceivingaprescriptionfordiamorphine(heroin)forthetreatmentofopiatedependenceintheUnitedkingdom".EuropeanAddictionResearch.13(3):144–7.doi:10.1159/000101550.PMID 17570910.S2CID 7397513. ^KennaGA,NielsenDM,MelloP,SchieslA,SwiftRM(2007)."Pharmacotherapyofdualsubstanceabuseanddependence".CNSDrugs.21(3):213–37.doi:10.2165/00023210-200721030-00003.PMID 17338593.S2CID 25979050. ^StrangJ,McCambridgeJ,BestD,BeswickT,BearnJ,ReesS,GossopM(May2003)."Lossoftoleranceandoverdosemortalityafterinpatientopiatedetoxification:followupstudy".BMJ(ClinicalResearchEd.).326(7396):959–60.doi:10.1136/bmj.326.7396.959.PMC 153851.PMID 12727768. ^StoopsWW,RushCR(May2014)."Combinationpharmacotherapiesforstimulantusedisorder:areviewofclinicalfindingsandrecommendationsforfutureresearch".ExpertRevClinPharmacol.7(3):363–74.doi:10.1586/17512433.2014.909283.PMC 4017926.PMID 24716825.Despiteconcertedeffortstoidentifyapharmacotherapyformanagingstimulantusedisorders,nowidelyeffectivemedicationshavebeenapproved. ^Perez-ManaC,CastellsX,TorrensM,CapellaD,FarreM(September2013)."Efficacyofpsychostimulantdrugsforamphetamineabuseordependence".CochraneDatabaseSyst.Rev.9(9):CD009695.doi:10.1002/14651858.CD009695.pub2.PMID 23996457.Todate,nopharmacologicaltreatmenthasbeenapprovedfor[addiction],andpsychotherapyremainsthemainstayoftreatment. ...Resultsofthisreviewdonotsupporttheuseofpsychostimulantmedicationsatthetesteddosesasareplacementtherapy ^ForrayA,SofuogluM(February2014)."Futurepharmacologicaltreatmentsforsubstanceusedisorders".Br.J.Clin.Pharmacol.77(2):382–400.doi:10.1111/j.1365-2125.2012.04474.x.PMC 4014020.PMID 23039267. ^abGrandyDK,MillerGM,LiJX(February2016).""TAARgetingAddiction"–TheAlamoBearsWitnesstoAnotherRevolution:AnOverviewofthePlenarySymposiumofthe2015Behavior,BiologyandChemistryConference".DrugAlcoholDepend.159:9–16.doi:10.1016/j.drugalcdep.2015.11.014.PMC 4724540.PMID 26644139.WhenconsideredtogetherwiththerapidlygrowingliteratureinthefieldacompellingcaseemergesinsupportofdevelopingTAAR1-selectiveagonistsasmedicationsforpreventingrelapsetopsychostimulantabuse. ^abJingL,LiJX(August2015)."Traceamine-associatedreceptor1:Apromisingtargetforthetreatmentofpsychostimulantaddiction".Eur.J.Pharmacol.761:345–52.doi:10.1016/j.ejphar.2015.06.019.PMC 4532615.PMID 26092759.Takentogether,thedatareviewedherestronglysupportthatTAAR1isimplicatedinthefunctionalregulationofmonoaminergicsystems,especiallydopaminergicsystem,andthatTAAR1servesasahomeostatic"brake"systemthatisinvolvedinthemodulationofdopaminergicactivity.ExistingdataprovidedrobustpreclinicalevidencesupportingthedevelopmentofTAAR1agonistsaspotentialtreatmentforpsychostimulantabuseandaddiction. ...GiventhatTAAR1isprimarilylocatedintheintracellularcompartmentsandexistingTAAR1agonistsareproposedtogetaccesstothereceptorsbytranslocationtothecellinterior(Miller,2011),futuredrugdesignanddevelopmenteffortsmayneedtotakestrategiesofdrugdeliveryintoconsideration(Rajendranetal.,2010). ^abLiuJF,LiJX(December2018)."Drugaddiction:acurablementaldisorder?".ActaPharmacologicaSinica.39(12):1823–1829.doi:10.1038/s41401-018-0180-x.PMC 6289334.PMID 30382181. ^abcZalewska-KaszubskaJ(November2015)."Isimmunotherapyanopportunityforeffectivetreatmentofdrugaddiction?".Vaccine.33(48):6545–51.doi:10.1016/j.vaccine.2015.09.079.PMID 26432911. ^LaudenbachM,BaruffaldiF,VervackeJS,DistefanoMD,TitcombePJ,MuellerDL,TuboNJ,GriffithTS,PravetoniM(June2015)."Thefrequencyofnaiveandearly-activatedhapten-specificBcellsubsetsdictatestheefficacyofatherapeuticvaccineagainstprescriptionopioidabuse".J.Immunol.194(12):5926–36.doi:10.4049/jimmunol.1500385.PMC 4458396.PMID 25972483.Translationoftherapeuticvaccinesforaddiction,cancer,orotherchronicnoncommunicablediseaseshasbeenslowbecauseonlyasmallsubsetofimmunizedsubjectsachievedeffectiveAblevels. ^PainterA.(2019)"Researchersworkingtodevelopvaccinestofightopioidaddiction"Vtnews.vt.edu ^abcdCaoDN,ShiJJ,HaoW,WuN,LiJ(March2016)."Advancesandchallengesinpharmacotherapeuticsforamphetamine-typestimulantsaddiction".Eur.J.Pharmacol.780:129–35.doi:10.1016/j.ejphar.2016.03.040.PMID 27018393. ^abMoellerSJ,LondonED,NorthoffG(February2016)."NeuroimagingmarkersofglutamatergicandGABAergicsystemsindrugaddiction:Relationshipstoresting-statefunctionalconnectivity".NeurosciBiobehavRev.61:35–52.doi:10.1016/j.neubiorev.2015.11.010.PMC 4731270.PMID 26657968. ^AgabioR,ColomboG(April2015)."[GABABreceptorastherapeutictargetfordrugaddiction:frombaclofentopositiveallostericmodulators]".Psychiatr.Pol.(inPolish).49(2):215–23.doi:10.12740/PP/33911.PMID 26093587. ^FilipM,FrankowskaM,Sadakierska-ChudyA,SuderA,SzumiecL,MierzejewskiP,BienkowskiP,PrzegalińskiE,CryanJF(January2015)."GABABreceptorsasatherapeuticstrategyinsubstanceusedisorders:focusonpositiveallostericmodulators".Neuropharmacology.88:36–47.doi:10.1016/j.neuropharm.2014.06.016.PMID 24971600.S2CID 207229988. ^abMcCowanTJ,DhasarathyA,CarvelliL(February2015)."TheEpigeneticMechanismsofAmphetamine".J.Addict.Prev.2015(Suppl1).PMC 4955852.PMID 27453897.Epigeneticmodificationscausedbyaddictivedrugsplayanimportantroleinneuronalplasticityandindrug-inducedbehavioralresponses.AlthoughfewstudieshaveinvestigatedtheeffectsofAMPHongeneregulation(Table1),currentdatasuggestthatAMPHactsatmultiplelevelstoalterhistone/DNAinteractionandtorecruittranscriptionfactorswhichultimatelycauserepressionofsomegenesandactivationofothergenes.Importantly,somestudieshavealsocorrelatedtheepigeneticregulationinducedbyAMPHwiththebehavioraloutcomescausedbythisdrug,suggestingthereforethatepigeneticsremodelingunderliesthebehavioralchangesinducedbyAMPH.Ifthisprovestobetrue,theuseofspecificdrugsthatinhibithistoneacetylation,methylationorDNAmethylationmightbeanimportanttherapeuticalternativetopreventand/orreverseAMPHaddictionandmitigatethesideeffectsgeneratebyAMPHwhenusedtotreatADHD. ^abPrimaryreferencesinvolvingsodiumbutyrate: •KennedyPJ,FengJ,RobisonAJ,MazeI,BadimonA,MouzonE,ChaudhuryD,Damez-WernoDM,HaggartySJ,HanMH,Bassel-DubyR,OlsonEN,NestlerEJ(April2013)."ClassIHDACinhibitionblockscocaine-inducedplasticitybytargetedchangesinhistonemethylation".Nat.Neurosci.16(4):434–40.doi:10.1038/nn.3354.PMC 3609040.PMID 23475113.WhileacuteHDACinhibitionenhancesthebehavioraleffectsofcocaineoramphetamine1,3,4,13,14,studiessuggestthatmorechronicregimensblockpsychostimulant-inducedplasticity3,5,11,12. ...TheeffectsofpharmacologicalinhibitionofHDACsonpsychostimulant-inducedplasticityappeartodependonthetimecourseofHDACinhibition.Studiesemployingco-administrationproceduresinwhichinhibitorsaregivenacutely,justpriortopsychostimulantadministration,reportheightenedbehavioralresponsestothedrug1,3,4,13,14.Incontrast,experimentalparadigmsliketheoneemployedhere,inwhichHDACinhibitorsareadministeredmorechronically,forseveraldayspriortopsychostimulantexposure,showinhibitedexpression3ordecreasedacquisitionofbehavioraladaptationstodrug5,11,12.Theclusteringofseeminglydiscrepantresultsbasedonexperimentalmethodologiesisinterestinginlightofourpresentfindings.BothHDACinhibitorsandpsychostimulantsincreasegloballevelsofhistoneacetylationinNAc.Thus,whenco-administeredacutely,thesedrugsmayhavesynergisticeffects,leadingtoheightenedtranscriptionalactivationofpsychostimulant-regulatedtargetgenes.Incontrast,whenapsychostimulantisgiveninthecontextofprolonged,HDACinhibitor-inducedhyperacetylation,homeostaticprocessesmaydirectAcH3bindingtothepromotersofgenes(e.g.,G9a)responsibleforinducingchromatincondensationandgenerepression(e.g.,viaH3K9me2)inordertodampenalreadyheightenedtranscriptionalactivation.OurpresentfindingsthusdemonstrateclearcrosstalkamonghistonePTMsandsuggestthatdecreasedbehavioralsensitivitytopsychostimulantsfollowingprolongedHDACinhibitionmightbemediatedthroughdecreasedactivityofHDAC1atH3K9KMTpromotersandsubsequentincreasesinH3K9me2andgenerepression. •Simon-O'BrienE,Alaux-CantinS,WarnaultV,ButtoloR,NaassilaM,VilpouxC(July2015)."Thehistonedeacetylaseinhibitorsodiumbutyratedecreasesexcessiveethanolintakeindependentanimals".AddictBiol.20(4):676–89.doi:10.1111/adb.12161.PMID 25041570.S2CID 28667144.Altogether,ourresultsclearlydemonstratedtheefficacyofNaBinpreventingexcessiveethanolintakeandrelapseandsupportthehypothesisthatHDACimayhaveapotentialuseinalcoholaddictiontreatment. •CastinoMR,CornishJL,ClemensKJ(April2015)."Inhibitionofhistonedeacetylasesfacilitatesextinctionandattenuatesreinstatementofnicotineself-administrationinrats".PLOSONE.10(4):e0124796.Bibcode:2015PLoSO..1024796C.doi:10.1371/journal.pone.0124796.PMC 4399837.PMID 25880762.treatmentwithNaBsignificantlyattenuatednicotineandnicotine+cuereinstatementwhenadministeredimmediately ...TheseresultsprovidethefirstdemonstrationthatHDACinhibitionfacilitatestheextinctionofrespondingforanintravenouslyself-administereddrugofabuseandfurtherhighlightthepotentialofHDACinhibitorsinthetreatmentofdrugaddiction. ^KyzarEJ,PandeySC(August2015)."Molecularmechanismsofsynapticremodelinginalcoholism".Neurosci.Lett.601:11–19.doi:10.1016/j.neulet.2015.01.051.PMC 4506731.PMID 25623036.IncreasedHDAC2expressiondecreasestheexpressionofgenesimportantforthemaintenanceofdendriticspinedensitysuchasBDNF,Arc,andNPY,leadingtoincreasedanxietyandalcohol-seekingbehavior.DecreasingHDAC2reversesboththemolecularandbehavioralconsequencesofalcoholaddiction,thusimplicatingthisenzymeasapotentialtreatmenttarget(Fig.3).HDAC2isalsocrucialfortheinductionandmaintenanceofstructuralsynapticplasticityinotherneurologicaldomainssuchasmemoryformation[115].Takentogether,thesefindingsunderscorethepotentialusefulnessofHDACinhibitionintreatingalcoholusedisorders ...GiventheabilityofHDACinhibitorstopotentlymodulatethesynapticplasticityoflearningandmemory[118],thesedrugsholdpotentialastreatmentforsubstanceabuse-relateddisorders. ...OurlabandothershavepublishedextensivelyontheabilityofHDACinhibitorstoreversethegeneexpressiondeficitscausedbymultiplemodelsofalcoholismandalcoholabuse,theresultsofwhichwerediscussedabove[25,112,113].Thisdatasupportsfurtherexaminationofhistonemodifyingagentsaspotentialtherapeuticdrugsinthetreatmentofalcoholaddiction ...Futurestudiesshouldcontinuetoelucidatethespecificepigeneticmechanismsunderlyingcompulsivealcoholuseandalcoholism,asthisislikelytoprovidenewmoleculartargetsforclinicalintervention. 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^abcdefg"AmericanBoardofMedicalSpecialtiesrecognizesthenewsubspecialtyofaddictionmedicine"(PDF).AmericanBoardofAddictionMedicine.14March2016.Archivedfromtheoriginal(PDF)on21March2021.Retrieved3April2016.Sixteenpercentofthenon-institutionalizedU.S.populationage12andover–morethan40millionAmericans–meetsmedicalcriteriaforaddictioninvolvingnicotine,alcoholorotherdrugs.ThisismorethanthenumberofAmericanswithcancer,diabetesorheartconditions.In2014,22.5millionpeopleintheUnitedStatesneededtreatmentforaddictioninvolvingalcoholordrugsotherthannicotine,butonly11.6percentreceivedanyformofinpatient,residential,oroutpatienttreatment.Ofthosewhodoreceivetreatment,fewreceiveevidence-basedcare.(Thereisnoinformationavailableonhowmanyindividualsreceivetreatmentforaddictioninvolvingnicotine.)Riskysubstanceuseanduntreatedaddictionaccountforone-thirdofinpatienthospitalcostsand20percentofalldeathsintheUnitedStateseachyear,andcauseorcontributetomorethan100otherconditionsrequiringmedicalcare,aswellasvehicularcrashes,otherfatalandnon-fatalinjuries,overdosedeaths,suicides,homicides,domesticdiscord,thehighestincarcerationrateintheworldandmanyothercostlysocialconsequences.Theeconomiccosttosocietyisgreaterthanthecostofdiabetesandallcancerscombined.Despitethesestartlingstatisticsontheprevalenceandcostsofaddiction,fewphysicianshavebeentrainedtopreventortreatit. 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^HeathDB(January1995)."ChangesinDrinkingPatternsinBolivianCultures:ACautionaryTaleAboutHistoricalApproaches".AddictionResearch.2(3):307–318.doi:10.3109/16066359509005215.ISSN 1058-6989. ^BurrawayJ(October2020).SteinF,DiembergerH,StaschR,RobbinsJ,SanchezA,LazarS,CandeaM(eds.)."Addiction".CambridgeEncyclopediaofAnthropology.doi:10.29164/20addiction.S2CID 241689890. ^PrebleE,CaseyJJ(January1969)."TakingCareofBusiness—TheHeroinUser'sLifeontheStreet".InternationalJournaloftheAddictions.4(1):1–24.doi:10.3109/10826086909061998.ISSN 0020-773X. ^abGolubA,JohnsonBD,DunlapE(May2005)."Subculturalevolutionandillicitdruguse".AddictionResearch&Theory.13(3):217–229.doi:10.1080/16066350500053497.PMC 3690817.PMID 23805068. ^abMalenkaRC,NestlerEJ,HymanSE(2009)."Chapter1:BasicPrinciplesofNeuropharmacology".InSydorA,BrownRY(eds.).MolecularNeuropharmacology:AFoundationforClinicalNeuroscience(2nd ed.).NewYork:McGraw-HillMedical.p. 4.ISBN 978-0-07-148127-4.Drugabuseandaddictionexactanastoundinglyhighfinancialandhumantollonsocietythroughdirectadverseeffects,suchaslungcancerandhepaticcirrhosis,andindirectadverseeffects –forexample,accidentsandAIDS –onhealthandproductivity. ^"Economicconsequencesofdrugabuse"(PDF).InternationalNarcoticsControlBoardReport:2013(PDF).UnitedNations –InternationalNarcoticsControlBoard.2013.ISBN 978-92-1-148274-4.Retrieved28September2018. ^"OverdoseDeathRates".NationalInstituteonDrugAbuse.9August2018.Retrieved17September2018. ^"OverdoseDeathsAcceleratingDuringCovid-19".CentersForDiseaseControlPrevention.18December2020.Retrieved10February2021. ^jetcopter ^OnlineEtymologyDictionary :alcohol Furtherreading[edit] SzalavitzM(2016).UnbrokenBrain.St.Martin'sPress.ISBN 978-1-250-05582-8. Externallinks[edit] Lookup-isminWiktionary,thefreedictionary. Lookup-holicinWiktionary,thefreedictionary. ClassificationDICD-10:F10-F19subdivision.2 WikimediaCommonshasmediarelatedtoAddictions. "TheScienceofAddiction:GeneticsandtheBrain".learn.genetics.utah.edu.Learn.Genetics–UniversityofUtah. Whydoourbrainsgetaddicted? –aTEDMED2014talkbyNoraVolkow,thedirectoroftheNationalInstituteonDrugAbuseatNIH. GordonHW(April2016)."LateralityofBrainActivationforRiskFactorsofAddiction".CurrentDrugAbuseReviews.9(1):1–18.doi:10.2174/1874473709666151217121309.PMC 4811731.PMID 26674074. KyotoEncyclopediaofGenesandGenomes(KEGG)signaltransductionpathways: KEGG–humanalcoholaddiction KEGG–humanamphetamineaddiction KEGG–humancocaineaddiction –WhataredifferenttypesofDrugAddictionTreatmentPrograms vteReinforcementdisorders:AddictionandDependenceAddictionDrug Alcohol Amphetamine Cocaine Methamphetamine Methylphenidate Nicotine Opioid Behavioral Financial Gambling Shopping Palatablefood Sex-related Intercourse Pornography Internet-related Internetaddictiondisorder Internetsexaddiction Videogameaddiction Digitalmediaaddictions Cellularmechanisms Transcriptional ΔFosB c-Fos Cdk5 CREB GluR2 NF-κB Epigenetic G9a G9a-likeprotein HDAC1 HDAC2 HDAC3 HDAC4 HDAC5 HDAC9 HDAC10 SIRT1 SIRT2 ... DependenceConcepts Physicaldependence Psychologicaldependence Withdrawal Disorders Drugs Alcoholism Amphetamine Barbiturate Benzodiazepine Caffeine Cannabis Cocaine Nicotine Opioid Non-drugstimuli Tanningdependence TreatmentandmanagementDetoxification Alcoholdetoxification Drugdetoxification Behavioraltherapies Cognitivebehavioraltherapy Relapseprevention Contingencymanagement Communityreinforcementapproachandfamilytraining Motivationalenhancementtherapy Motivationalinterviewing Motivationaltherapy Physicalexercise Treatmentprograms Drugrehab Residentialtreatmentcenter Heroin-assistedtreatment Intensiveoutpatientprogram Methadonemaintenance Smokingcessation Nicotinereplacementtherapy TobaccocessationclinicsinIndia Twelve-stepprogram Supportgroups Addictionrecoverygroups Listoftwelve-stepgroups Harmreduction Category:Harmreduction Drugchecking Reagenttesting Low-thresholdtreatmentprograms Managedalcoholprogram ModerationManagement Needleexchangeprogram Responsibledruguse Stimulantmaintenance Supervisedinjectionsite Tobaccoharmreduction Seealso Addictionmedicine AllenCarr Category:Addiction Category:Vaccinesagainstdrugs Discriminationagainstdrugaddicts Dopaminedysregulationsyndrome Cognitivecontrol Inhibitorycontrol Motivationalsalience Incentivesalience Sobercompanion Category vteNeuroscience Outline History Basicscience Behavioralepigenetics Behavioralgenetics Brainmapping Brain-reading Cellularneuroscience Computationalneuroscience Connectomics Imaginggenetics Integrativeneuroscience Molecularneuroscience Neuraldecoding Neuralengineering Neuroanatomy Neurochemistry Neuroendocrinology Neurogenetics Neuroinformatics Neurometrics Neuromorphology Neurophysics Neurophysiology Systemsneuroscience Clinicalneuroscience Behavioralneurology Clinicalneurophysiology Neurocardiology Neuroepidemiology Neurogastroenterology Neuroimmunology Neurointensivecare Neurology Neurooncology Neuro-ophthalmology Neuropathology Neuropharmacology Neuroprosthetics 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