Reinforcement and Addiction 1 lecture slides PDF

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Reinforcement and Addiction 1 lecture slide 2021...

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Reinforcemen and Addiction Drugsaffectingthenervoussys PHRM30002Monday11th Oct DrRobynBrown [email protected] DepartmentofBiochemistryandPharmacology SchoolofBiomedicalSciences

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Reinforcement and addiction • Transmittersystemsinvolvedinrewardandaddiction • Mechanismofactionofdrugsofabuse • Mechanismofactionofpharmacotherapiesforsubstanceuse disorderandothertypesofaddiction

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What is addiction?

Amentaldisordercharacterisedbycompulsiveconsumptionorengagementwith rewardingstimuliwhichpersistsdespitenegativeconsequences

Drug and alcohol use in Australia •

Druguseisthesinglelargestcontributortodiseaseburdenaffecting Australians

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Alcoholuseandcigarettesmokingarethetwohighestcausesofpreventable deaths(approximately15,000peryear)

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38%ofAustralianshaveusedanillicitdrugduringtheirlifetime – 9%haveusedapsychostimulantinthepast12months

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Ofthoseregularlyusingadrug,10‐15%willdevelopaproblemwiththeir druguse

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Perceptions of addiction

“Moral Failure”

“Disease of the will”

Addictionisnowrecognizedasabraindisease

www.drugabuse.gov

The ‘brain disease model’ of addiction DrMarcLewisproposes: ‐addictionisnotabrain ‘disease’ ‐Addictionisanentrenched habitthataltersthebrainin thewaythatotherlearned habitsdo ‐Medicalisationisunhelpful andpotentiallyharmful

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Psychoactive drugs Substancesthataffectmentalprocesses e.g.perception,consciousness,mood,cognitionor emotions(“mind‐altering”). Theseeffectsareoftenrewarding Euphoria:anintensefeelingofwell‐being, excitement,pleasantnessorhappiness Canbeused: ‐medicinallye.g.anxiolytics ‐recreationallye.g.alcohol ‐toimproveperformancee.g.stimulants ‐forritualistic/shamanicpurposese.g.ayahuasca 0

Substance use disorder (SUD) TheDSM5recognizessubstance‐relateddisordersresultingfromtheuseof9 separateclassesofpsychoactive drugs: •

Alcohol

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Cannabis(activecomponent=tetrahydrocannabinol(THC))

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Hallucinogense.g.phencyclidine,ketamine,LSD,psilocybin

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Inhalantse.g.solventssuchasglue,paint(activecomponent=toluene)

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Opioidse.g.heroin,morphine,oxycodone,fentanyl,desomorphine (krokodil)

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Sedatives(decreaseactivity/arousal)/hypnotics(inducesleep)/anxiolytics (reduceanxiety)e.g.barbiturates,benzodiazepines,gammahydroxybutyrate

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Stimulant(cocaine/amphetaminesandamphetamine‐likesubstances)

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Tobacco(activeagent=nicotine;outofdatewithrespectto‘vaping’)

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ConditionsforfurtherstudyinDSM5:caffeineusedisorder, 11

Substance use disorder (SUD)

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2‐3symptoms=mild4‐5symptoms=moderate6+symptoms=severe

The mesocorticolimbic dopamine system

https://interstem.us/2021/04/23/dopamine‐the‐molecule‐that‐drives‐addiction

Drugs of abuse all interact with this system

cocaine

opiates

amphetamine alcohol

nicotine

caffeine

Drugs increase synaptic DA in different ways

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https://basicmedicalkey.com/drugs‐of‐abuse/

Route of administration important AbuseliabilityisgreaterthequickerthedrugcanreachtheCNStoincreaseDA Intravenous>smoking>transmucosal>ingestion

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Psychostimulants Thinkofas‘uppers’– increaseoverallactivationofCNS/activity/arousal Increaseactivityofcatecholamines– DA,NA,5HT(sympathomimetics) Cocaine(cocaleaf,cocainesalt,crackcocaine) Amphetaminesalsoinclude: ‐methamphetamine(“crystal”“ice) ‐MDMA ‐methylphenidate ‐dexamphetamine Cathinones: ‐khat(floweringplantnativetoAfrica) ‐methcathinone“meowmeow” 18

Psychostimulants: mechanisms Normally

Cocaineblocksneuronaluptake

DA

DA Cocaine

DA D1/D2

All cause increase inDAlevelsin synapticcleft(plusNAand5HT)

DA D1/D2

DA

Amphetamines DA D1/D2

Nicotine (tobacco) Alsoastimulant,activeingredientin tobaccoaswell asvaping products Actsonα4β2nAchR locatedpresynaptically and somatodendritically onDAneuronsto increaseDArelease

20 https://doi.org/10.3389/fpsyt.2013.00029

Opioids

opioids

Opioid:naturalorsynthetic drugwhichhasaffinityfor opioidreceptorse.g. oxycodone,fentanyl Opiate:naturalalkaloidproductofopium e.g.morphine,codeine,heroin(semi‐synthetic) µ‐OR (inhibitoryGPRC)isthereceptorresponsiblefortherewardingeffectsof opioiddrugs. Locatedpresynaptically oninhibitoryGABAneuronssynapsingontoVTADA neurons– activationbyopioidsindirectlycausesdisinhibitionofDAneurons. Tolerance/withdrawalduetoµ‐ORinternalization/downregulation

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https://doi.org/10.3390/ijms20174302

Cannabis TherewardingeffectsofcannabisisduetotheactivecomponentTHCwhichisanagonist of CB1 receptors CB1R:inhibitoryGPCRslocatedpre‐synaptically onGABAergicneuronssynapsingonto VTADAneurons SimilartoopioidsactivationofthesereceptorscausesdisinhibitionofDAneurons‐>high Cannabiscanalsobeaversive: 1)actionsatCB1 onglu neurons synapsingontoDAneurons 2)actionsatCB2 receptorsonDA neurons CBD≠THC Cannabiscanhavedifferent concentrationsofTHC/CBD

22 https://www.drugabuse.gov/news‐events/nida‐notes/2018/03/why‐marijuana‐displeases

Alcohol (ethanol) Solvent Actsonalmostallionchannels ConsideredaCNSdepressant Rewardingactionsthoughttobevia actionsatGABAAreceptorslocated presynaptically onGABAergic neuronsinVTA ActivationoftheseGABAneurons causesdisinhibitionofDAneurons ‐>increaseDA Barbituratesandbenzodiazapines alsodothis (3-

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Hallucinogens/psychedelics Thehallucinogenicactionsof ‘classical’hallucinogensaretypically viaagonismof5HT2A receptors e.g.LSD,DMT,psilocybin,mescaline Ketamine: NMDA antagonist Salvia:KappaORantagonist Manypeoplefindthesedrugs aversive– lowabusepotential (ratswon’tself‐administerthese drugs) Currentlybeingresearchedfortheir utilityintreatingdrugaddiction!

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What does DA signaling mean?

What does the DA signal mean? Abuseliabilityisrelatedtotheamountof DA that is released DAacts onD1andD2receptorsinnucleusaccumbens Initiallythoughttosignal“reward” Nowbelievedtosignal“salience”(importance)becauseDAalsosignalsaversion andisalsoreleasedinresponsetocuespairedwithrewards Can alsobealearningsignal Drugs of abuse interact with DA system more powerfully and potentlythan naturalrewards‐>thinkofaddictionasapathologicalformoflearning Positive reinforcement:engagingwithastimulusmeansthatyouaremorelikely toengagewiththatstimulusinthefuture Negative reinforcement:engagingwithastimulusmeansthatyouarelesslikely toengagewiththatstimulus in the future 26

Why Are Drugs Addictive?

Rewardandreinforcement≠addiction

What causes addiction?

Drug-induced plasticity Synaptic plasticity Repeated exposure todrugs

Changes inbrain activity

Gene expression

Receptor expression Spine density

Corticostriatal circuits in addiction

The brain during development

You are born with twice as many neurons than you will have when you turn 18 Neurons die at a rate of 200,000 per day Brain development continues into your 20’s The brain is particularly vulnerable during this period

Can the brain recover?

www.drugabuse.gov

www.drugabuse.gov

Summary Drugaddiction Acompulsivepatternofdrug‐seekinganddrug‐takingbehaviour thatpersistsdespiteadverseconsequences

Drugsofabuse Variedmechanismsofaction UltimatelyallresultinincreasedsynapticlevelsofDAinthenucleus accumbens DA signal=salience/learningsignal Reward≠addiction With repeated drug use drug‐inducedchangescanresultin addiction(10‐15%ofpopulation)...