Theories of Addiction.pdf

WEDNESDAY, OCTOBER 18, 2023 Theories of Addiction (1) Addiction: maladaptive behavioural pattern of drug use, characterized by overwhelming involvement with the use of drug (compulsivity), securing the supply, and high tendency to relapse after withdrawal, with disregard to negative consequence SU...

WEDNESDAY, OCTOBER 18, 2023 Theories of Addiction (1) Addiction: maladaptive behavioural pattern of drug use, characterized by overwhelming involvement with the use of drug (compulsivity), securing the supply, and high tendency to relapse after withdrawal, with disregard to negative consequence SUD IS A DISEASE - Until mid-19th century: was considered a sin/moral de ciency and should be treated by priests or the legal system, punished - Late 19th century: idea that addiction is actually a disease and addicts should be treated not punish - Jellinek: alcoholism can be de ned as changes in structure/function of the body, due to drinking, that cause disability or death (similar to any other disease) - Instead of being sinners/criminals, they are patients - Can remove the guilt associated with stigma (supposed) - if it is a disease, we should have a clear idea of the biological and physiological causes SUSCEPTIBILITY MODELS: FOCUS ON THE INDIVIDUALS VARIABILITY - Variation of susceptibility model, with predisposition: some people have a higher likelihood to use substances and to addiction - This would explain why some can use and not abuse drugs and why others are hooked at rst try (individual variability) - Large individual di erences in both development, susceptibility - Genetics: - Research is focused on genetics to identify risks for SUD (i.e. gene that synthesizes enzyme that metabolizes alcohol: if low, then more side e ects = lower risk because cannot reach the rewarding e ects; if high, then less side e ect = higher risk) - No addiction gene per se ENVIRONMENT - has a lot of input - Can change the whether exposure leads to SUD or not - Can increase the risk if predispositions are there EXPOSURE MODELS: DRUG CHANGES THE BRAIN / “COMBINATION” MODELS: SUSCEPTIBILITY + EXPOSURE - Wise: “exposure is most important thing” - When exposed to substances, the brain adapts to them - Doesn’t discredit the susceptibility model: both can occur, can be causal, can be downstream - You need the right exposure including exposure ADDICTION: A DISORDER OF CHOICE (HEYMAN) - although it can be disease, it is one that people choose to make ff ff fi fi ff ff fi PAGE 1 OF 16 WEDNESDAY, OCTOBER 18, 2023 - Peak of addiction in adolescence and clear drop in late 20s-early 30s as they start being family people - Thus people choose to continue the drug use - people in rehabs, most, actually stop drug use altogether during the program - treatment: replacement/contingency management - Highly successful - Starts with a clean drug test, then gets voucher to buy anything - Unsustainable: you cannot give people everything all the time - As soon as it is stopped, people relapse - being “sick” removes the responsibility Reinforcement models NEGATIVE REINFORCEMENT MODELS 1 PHYSICAL DEPENDENCE MODEL - addiction = physical dependence - If drug use is stopped/reduce = withdrawal - Probably arose because most drugs that were abused were alcohol and opiates which result in very severe withdrawal symptoms - To relieve withdrawal: take more drugs - user goes through cycle: - use > tolerance > take more > abuse > stop usage > withdrawal > take drug > relief - withdrawal symptoms: aversive - By taking the drug, it relieves withdrawal symptoms = negative reinforcer - Conditioned withdrawal might be triggered by the environment ad result in relapse in abstinent subject - cues can be associated with both the rewarding e ects - Contact with them can trigger negative a ect and physiological e ects - Robust even after years; can relapse Limitations: 1. does not address the reason for developing the drugs use leading to addiction 2. Addiction ca develop without withdrawal - Opiates can be rewarding independently from their withdrawal alleviating properties (Wise) - Morphine infused into VTA (but leaked to the PVG through di usion) - Low level of withdrawal - Compulsive self-administration - Morphine infused in VTA at 30 degrees (bypass the PVG) - Almost no withdrawal - Infusion into opiate R rich area (PVG), does not lead to self-administration - High level of withdrawal symptoms - No self-administration - Supports that withdrawal and self-administration are in 2 di erent systems ff ff ff ff ff PAGE 2 OF 16 WEDNESDAY, OCTOBER 18, 2023 3. Addicts often mention that its not withdrawal that drives their cravings and relapse - Craving: very intense need for a substance, it is not related to being sick/feeling withdrawal symptoms 4. Self-reported craving for cocaine is higher after taking the drug - Drug primes craving 2 SELF-MEDICATION HYPOTHESIS - drug is used to medicate an existing negative state (anxiety, stress, pain, etc.) - The substance abuse is derived from the psychiatric disorder - i.e. Valium is used to avoid anxiety; alcohol is used to avoid stress - support from the literature - When the results are from a controlled environment, it usually is hard to translate to the real world - tested by de Wit et al.: - Every day, subjects get a pill (blue or red), it changes every day, they don’t know what it’s in the pill - Participants scored higher on the anxiety scale - They are then o ered a choice between both pills - Blue was actually Valium - Expected that people would choose Valium - repeated with depressive participants and amphetamine - Results: 1. No preference for “blue pill”, even after screening for anxiety level 2. Same results with depression and amphetamine 3. Exception: preference develops for opiates if pain is expected - somewhat related to Reward De ciency Syndrome (Kenneth Blum - only group) - DA resistance (lower level of DA-R) - Higher level of enzymes that metabolize DA - Because they’re always below the normal level of DA, they consume substances to raise that level 3 THE OPPONENT PROCESS AND ALLOSTASIS MODEL - opponent process model of a ective equilibrium - Consuming drugs a ect the normal balance of our a ective state - Body needs an opposing re ex to bring that a ect back to the equilibrium range - This occurs during the rst few exposures - Once use is chronic, the B process will adapt - That range will move depending on how the body adapts to that consumption - i.e. taking amphetamine will increase the a ective state, the B process will work harder and longer to bring the a ect back to the original state - However it might not be brought back to baseline, just a little bit deviated but in the comfortable range ff ff ff fi ff fl ff fi ff ff PAGE 3 OF 16 WEDNESDAY, OCTOBER 18, 2023 - A process: kicks in as soon as drug is consumed, but leaves relatively quick - B process: is slower to begin, and is slower to end - Once A process leaves, there’s a crash because B process still occurring (regardless of drug dosage) - Once adapted, it will be faster/triggered by cues and stronger - Crash is more intense 4 THE ALLOSTATIC MODEL *** following the previous model *** - addiction is the results of decreased function of the reward system and recruitment of “antireward” systems - Similar to A & B processes - the reward system (A): mesolimbic DA, opiate R and peptides, GABA-R - The anti-reward system (B): process opposing the reward system - includes reduced DAd2R in the striatum of cocaine addicts (DA doesn’t have as many R to bind to as it used to have), increased ICSS (intracranial self-stimulation) threshold in rats after chronic use in the mFB - If self-stimulate in the mFB, animals will self-stimulate an electrical current until death with no motivation for anything else - Almost all drugs that we abuse (rewarding) would shift to the left (antagonist to the right) - When m50 is lower, that means you need less frequency for the same rewarding value - When m50 is higher, then you need more frequency - Long access to cocaine: m50 is shifting more and more to the right (less rewarding) their reward system is somehow de cient - Increase the amount of cocaine needed to feel the same - Short access: m50 is shifting more and more to the left (less rewarding) - Adapts and becomes more e cient with repeated use KOBB’S DARK SIDE OF ADDICTION - Anti-rewarding system that’s related to aversive responses in relation to stress - CRF: neuropeptide that activates HPA axis and releases cortisol and adrenaline - Not only a hormone, but a NT for stress responses - Stress response becomes sensitized - Amygdala: involved in emotional responses that has a lot of CRF - Every time you experience stress, it adapts and becomes more intense that stays for a long time - Related to relapse (stress = trigger) - Even after period of abstinence (even after long time) - Baseline has changed (lower) - System is able to anticipate: works before the A process so the e ects are reduced and it doesn’t have to work as hard to bring back to baseline - Repeated use because of the reward system being less e cient the anti-rewarding system becoming more e cient = allostatic process (adapting) ff ffi fi ffi ffi PAGE 4 OF 16 WEDNESDAY, OCTOBER 18, 2023 - mood (a ective state) is now lower than usual, so you take drugs to compensate, but the anti-rewarding system is better, so you take even more drugs, etc. - When drugs are taken, it’s simply to feel “normal” because anti-reward process brought you down POSITIVE REINFORCEMENT MODELS Some drugs have mostly positive a ective consequences and mild if no withdrawal 1 INCENTIVE MOTIVATIONAL VIEW - Jane Stewart: incentive stimuli > central motivation state > behaviour - Incentive stimulus: stimulus that is attractive to us - Motivational state increase the saliency of the stimulus - Exposure to cues can attract drug consumption - Pavlovian to operant transfer - If CS is presented from a pavlovian conditioning with another reward, behaviour will increase even if behaviour not related to the CS 1. HEDONIA MODEL: (DA -> PLEASURE) - Motivational system identi es “pleasure” and drives the proper behaviour to get more - drugs are addictive because they produce euphoria - Increase a ective state (pleasure) - Common underlying neuronal activity: mesolimbic DA system - Drugs “hijacking” it and driving it to the extreme - Brain adapts after each use and drugs take control - Involved for every drug - DA junction reresents a synaptic way station where sensory inputs are translated into the hedonic messages we experience as pleasure, euphoria, or “yummies” (Wise) - Without mesolimbic DA = no pleasure, no rewards Evidence # 1 (Fourison & Wise): - Psychostimulants drugs are SA directly into the NAc - DA levels increase in NAc - DA-R antagonists (Pimozide) attenuate behaviours supported by almost all kinds of rewards - Direct electrical current in the brain (medial forebrain bundle), animals will work very hard for it - Train animals to SA the electrical current - After trained, antagonist is injected, less and less responses (extinction-like) as if the current was stopped - Limitation: DA is important for locomotion - DA is not pleasure, they just cannot press the lever - Block access to lever, then open door - SA for a little, but extinction occurs again (spontaneous recovery) - SR: once the reward is taken away, behaviour is stopped, recovery period, behaviour will return (less than before) - Not that they cannot press (locomotion), they just don’t want to ff fi ff ff PAGE 5 OF 16 ** CONCLUSION: DA is critical for intracranial SA Evidence #2 (Fourison & Wise): - train rat to press lever to get food pellets (FR1) - Get injection of DA-R antagonists (Pimozide) - There is an extinction e ect over days (less and less) - Less rewarding, less pleasurable - Remove pellets (extinction) for 3 days, behaviour is extinguished - On 4th day: give food back + Pimozide - Animals behave as if no food was given: low-no response - Food is not rewarding anymore - Limitation: antagonist disallowed any behaviour because of the motor side e ects - Injected Pimozide in their home cage (no access to lever) for 3 days - 4th day: Injected Pimozide and bring back lever: behaviour is recovered (similar to rst day) - If it was accumulation of Pimozide leading to a motor e ect, there would be no behaviour, similar to other condition - For learned behaviours, it takes time to extinguish = results not due to motor e ects ** CONCLUSION: DA is critical for rewards like food Evidence #3 (McFarland & Ettenberg): - using a runway with a start chamber and target, placing animal connected to catheter in start - When animal gets to target, animal gets infusion of heroin in the NAc - Di erent because it’s a single trial - Baseline has a very short time that animal needs to get to target (latency) - Blocking DA transmission using DA-R antagonist (Haloperidol) - Expect: DA will be blocked = heroin will not be rewarding so rats will not run fast - Result: animal still ran very fast - Repeat the experiment without injecting Haloperidol: animal is wandering, no interest, very slow - Maybe Haloperidol was too low, double dose - Animals well trained will still run very fast - Next day without HAL, animal again still wander - Animals remember that the previous day, heroin was not rewarding, so they don’t run - Animals have to experience the heroin without rewards - cannot predict that heroin won’t be rewarding Evidence #4 (Volkow) - In humans, subjective ratings of pleasure correlate with occupancy of DA-R in the striatum - Subjects receive placebo injections or low/high dose of Ritalin (no high since IV) - Not addicts = high density of d2R in striatum - Subjects given Raclopride (DA-R antagonist) - As dose of Ritalin increases, Raclopride becomes less and less bound - Subjects give their impression of their “high” - Immediately after high dose of Ritalin, there’s an increase of the high - Positive correlation with the occupancy of DA-R - Higher levels of DA = higher self-reported high ff ff ff ff PAGE 6 OF 16 ff fi WEDNESDAY, OCTOBER 18, 2023 WEDNESDAY, OCTOBER 18, 2023 CONCLUSION: ** DA seems strongly correlated with subjective concept of high/ pleasure in humans LIMITATIONS: 1. Some degree of reward function is possible even without DA - DA-de cient rats (6-OHDA): - Cannot move (Parkinson’s-like) - If given L-DOPA after training to allow to move, animals will show CPP 2. For opiates, there could be 2 separate DA transmissions (Nader & van Der Kooy): - For DA-dependent subjects - For DA-independent subjects - 2 groups: naive vs chronic use NAIVE - Training for 8 days with morphine, then 7 days of no training (processing what was learned, CPP seems stronger) - Animals received DA-R antagonist or saline - Expect: animals should not show CPP with DAR-A - DAR-Ashowed CPP for morphine - DA is not necessary for morphine CPP CHRONIC - rats given high drug doses of heroin before to induce chronic use - Training for 8 days, then 7 days of no training =withdrawal - Animals received DA-R antagonist or saline - Animals given DAR-A do not show CPP - Animals do need DA for morphine CPP = 2 di erent systems - When chronic use of opiates, drug system shifts - Week of pause is critical: animals have to go through withdrawal 3. Opiates act at 2 points: VTA (modulating DA) and NAc (acting on medium spiny neurons output from NAc) - critical for rewards when animals have gone through withdrawal - If lesioned: animals will not show CPP - Need this to - Then DA system becomes critical for rewards - GABA now becomes excitatory (vs inhibitory) 4. First drug use (opiates, nicotine, alcohol) is often experiences as dysphoric - tolerance develops quickly but rst is unpleasant - Somehow compulsive behaviours develop 5. Under some conditions, electric shock can be reinforcing; and aversive and arousing stimuli result in DA release in the NAc 6. People will work for low cocaine or morphine doses that have no subjective e ects or any kind (no pleasure) - from lowest dose, people will take a lot of it and work very hard to get it - Asked to rate how they liked the injection they got - For 3 lower doses that they worked hard to get, they don’t nd it pleasurable ff fi ff fi fi PAGE 7 OF 16 WEDNESDAY, OCTOBER 18, 2023 - Something else seems to drive the behaviour 7. Drug-taking may increase over time, but “pleasure” is not reported to increase - can actually like the drug less and less - Very common nding 8. DA signal is often associated with cues that predict arrival of reward and not the consumption of reward - DA is a reward prediction error signal? - signalling that a positive/negative event is expected - Signalling indicating whether the reward was better or worse than expected SCHULTZ, 2001 - Reward Prediction Error - Monkeys with implanted electrodes in VTA - Pavlovian conditioning 1. DA res UCS > R (no prediction > Reward) = ring increased shortly after reward - Surprise: positive error - you did not expect but it happened = DA ring 2. DA res to CS/cue (not UCS) > R (prediction > Reward) = ring increased after cue and before Reward - During Pavlovian training, the CS alone triggers the DA release to prepare for the reward and the reward arrives (no increase in DA release) 3. DA red to CS/cue but no R (prediction > no Reward) = ring increased after cue, dip when reward is not presented, and normal ring proceeds - After training, the CS triggers DA release but the reward does not come (negative RPE), so the DA neurons stop ring - If this occurs repeatedly, there’s is an extinction e ect - DA is not a pleasure signal; had it been the shift wouldn’t have occurred DA ring shifts from reward to cue: monkeys learned that cue is predictive to the reward DA represents an error in expectation Rescorla-Wagner: Drugs, because they change DA transmission, override the normal prediction error system/signal and drive an ampli ed learning signal = drive compulsive behaviour - Addiction is an abnormal learning driven phenomenon - But VTA to NAc is not the only pathway 9. Although DA function is important for reward and addiction, it’s not only the mesolimbic DA system (VTA > NAc) function that counts Vanderschurren - 2nd order schedule of cocaine SA - trained rats to SA cocaine (animals have to press 10x to get a light stimulus associated with drugs, and after 15 min they get the drug) - For 15 minutes, they are working drugfree (working for the light) - They then injected non-speci c DA-R antagonist ( upenthixol) into the dstriatum fi fi fi ff fi fi fi fi fi fi fl fi fi fi fi PAGE 8 OF 16 WEDNESDAY, OCTOBER 18, 2023 (target area for nigrostratal pathway) - Partially block DA transmission - When dose of antagonist increases, responses go down - when animal is well trained, the behaviour becomes habitual - When the habit develops, the more the DA transmission occurs in the dstriatum rather than NAc Quinlan - FR1 schedule of cocaine SA - Injections of D1 antagonist into the substantial nigra - See increase in response: when reward is less rewarding = compensation - Not that DA isn’t important, but not only the mesolimbic pathway HEDONIA MODEL: (DA -> PLEASURE) - REVISED VERSION - Normal levels of DA in the brain are important for normal motivation - You need DA to show any reward-related behaviour - Subjective pleasure is strongly correlated with events that cause phasic DA increase - But stressful events can also cause DA elevations - Thus, pleasure is not a necessary correlate of DA elevations (or even reinforcement) - DA rather is important for the learning signal 2. INCENTIVE-SENSITIZATION VIEW (ROBINSON & BERRIDGE) 4 majors points: 1. All potentially addictive drugs share the ability to produce long-lasting adaptations in neuronal systems 2. The brain systems that change are those that are normally involved in the process of incentive motivation and reward 3. Most importantly, addiction makes these brain reward systems more sensitive (“sensitized”) to drugs and drug-associated stimuli/cues - i.e. locomotor sensitization (almost all drugs show this e ect) = hyperactivity - Conditioned reward sensitization which generalizes to other reward - Repeated exposure to morphine facilitates anticipatory response to sexual encounter/cues - More sensitive to reward predicting cues - Sensitization of DA activity (DA release in NAc) - Anecdotal reports in humans 70% with cocaine addictions su er from compulsive sexuality 4. The sensitized brain systems do NOT mediate the “pleasure”/“euphoria” component of reward (“liking”). Rather, they mediate the incentive salience component (“wanting”) - Incentive-salience Hypothesis: rewards have both a ective (liking) and motivational (wanting) consequences - Pleasure and Motivation are distinct psychologically and neurobiologically ff ff ff PAGE 9 OF 16 WEDNESDAY, OCTOBER 18, 2023 DA’S ROLE IN REWARD - DA activation or suppression has no e ect on “liking” responses in animals and humans - Vs the e ects of opiates that can double the “liking” response (mu-opiates R) - But DA mediates “wanting” Leyton - manipulation of DA long term by using a diet APTD (acute phenylalemine/tyrosine depleted) = lower DA baseline - Given participants di erent amounts of cocaines and given subjective measures to report how much they wanted the drug and how much they liked the drug - Controls: want it more and like it more as the doses increased - APTD diet: strained response with rst few doses (lower wanting), no di erence in liking - Reduce DA transmission without a ecting the liking INCENTIVE SALIENCE Attributing Incentive Salience: The making of stimuli and their mental representatives highly salient, attractive, and “wanted” - The most important psychological change that is induced by repeated drug exposure is hypersensitivity to the incentive motivational e ects of drugs and drug-associated stimuli - with repeated exposure to the drug, all the cues around when drug is consumed/under the in uence are becoming very salient = more attractive = increased association wth the drugs - The “incentive sensitization” condition causes a bias in the attentional processing towards drugs and drug-associated stimuli, and pathological motivation to take drugs (“wanting”) - Changes in the brain are sensitizing incentive salience (make cues more attractive) - When undergoing this sensitization process, there is a bias of attention toward drug associated cues = pathological motivation for drug taking - DA is crucial - “Wanting” is the one that goes through sensitization modulated by DA Cues that were neutral are now very salient and powerful in driving behaviours Evidence #1 (in animals) - Robinson & Berridge, 1993 - cocaine sensitization increases the conditioned reinforcing e ects of a cocaine-associated stimulus - When cue (light) is associated with cocaine, it gets assigned incentive properties - Train an animal to respond to the light/cue associated with a drug (press lever = light = cocaine (instrumental learning) - Light now has rewarding/incentive value and can be used to train the animal to do another behaviour - Incentive value of light increases when associated with cocaine - Whole system is being sensitized = cues carry the power to support behaviour - Behaviour are increasing with repeated exposure ff ff ff ff fi ff ff ff fl PAGE 10 OF 16 WEDNESDAY, OCTOBER 18, 2023 Evidence #2 (in humans) - Cox et al., 2006 - PET study with Raclopride Subjects given amphetamine and observed DA release Cocaine SA caused an increase in DA response in the striatum As expected, there is a change of radioactive signal when amphetamine is introduced - Correlation of change DA release with lifetime experience with stimulants - More lifetime experience (not addicts) positive correlated with greater size of the change of Raclopride binding - Previous experience with drugs sensitize the DA system (subject release more DA) - Researchers provide all cues associated with drug use (di than Volkow’s study where cues are missing) - Cues are present and might drive very strong DA release - Volkow also used chronic users vs Cox who use regularly but not addicts - Can cause long-term withdrawal e ects that reduce the DA release Evidence #3 (in humans) - Boileau et al., 2006 THE DA SYSTEM Adaptations in the DA system following chronic exposure: 1. Sensitization of DA release (Boileau et al., 2006) - Self report & PET scan with Raclopride - repeated exposure to psychostimulants (amphetamine) results in an increased DA release in the striatum even a year after the last drug treatment - With repeated with same dose of the drug, e ects are stronger (energetic, con dence) - humans were given 3 doses of amphetamine on day 1-3-5 and response was measure after 14 days and after 1 year - Dose 1 = DA release in striatum - Dose 4-5 shows an increased response supporting sensitization e ects - Sensitization of DA release: less binding (= more DA) - No increase in liking and desire (reported) 2. In addicts, there is an attentional bias towards drug-related stimuli - What we expect is that cues associated with drugs become more and more salient - Recruted alcohol users (light and heavy users) and cannabis users (light and heavy users) - For alcohol users, they see images that includes items associated with alcohol use & change small details between sets) and ask subjects to identify what has changed - Same is done for cannabis users - Measurement of latency: time taken to notice the change - Results: - Heavy users of alcohol: latency for alcohol-related cues is shorter than light users - Same is true for heavy cannabis users - Conclusion: attention is immediately directed towards more salient cues - For heavy users: they waste lot time by looking at drug-related item vs neutral item fi ff ff ff ff PAGE 11 OF 16 WEDNESDAY, OCTOBER 18, 2023 3. In cocaine dependent subjects, drug challenge results in stronger craving compared to controls, but lower high - Volkow - Subjects (controls, cocaine dependent) given Ritalin or placebo - Self-report for cravings is very high for cocaine-depedent vs controls - But the “high” is lower than for controls (“wanting” increases over time but “liking” does not, even goes down) Conclusion: - All the cues associated with drugs/drug e ects give high incentive salience (incentive sensitization procedure) but drug is not liked more - Want it more, like it the same or less CRITIQUE (ESP. OF ROLE OF DA) McFarland and Ettenberg - Robinson & Berridge: wanting goes up, liking goes down, wanting is what drives the behaviour + DA is critical for wanting - animal is in a box with target area, when they get to that area, they get an infusion of heroin - Animals are given Haloperidol - Blocking DA = should kill wanting - However, animals just as fast as before - They are then not injected Haloperidol, and they stop running (because they remember they didn’t feel anything the last time) - Conclusion: DA underlies euphoria, which will modulate the wanting - Animals seem to need to experience the reward at least once under DA- de cient conditions in order to demonstrate reduced motivation THE “LOSS OF WILLPOWER”/DEFICITS IN EXECUTIVE FUNCTION MODEL Antoine Bechara (2000, 2001, 2005): - The choice between optional behaviours is the result of an interaction between the impulsive system and the re ective system - The impulsive system: The critical brain structures are the amygdala and the amygdala- striatum pathway - links a stimulus to a ective/ emotional properties (from the PAG, striatum…) - Associate cues with a ective component attributed by amygdala - Stimuli will gain “value” through learning - i.e. money: people with bilateral amygdala damage show no emotional response to losing or gaining large sums of money \ - Important for value-encoding system: translates di erent experiences with rewarding or aversive values to allow for comparison - with repeated exposure to drugs, the cues associated with the e ects are gaining very powerful a ective/emotional properties - Autonomic responses (HR, BP, skin conduction, etc.) are very high when in contact with cues fi ff ff ff ff ff fl ff PAGE 12 OF 16 WEDNESDAY, OCTOBER 18, 2023 - Abnormal activity in the amygdala-striatum pathway shown when assigning a ective properties: drug- cues acquire very strong a ective properties the creation of “a ective memories” both negative and positive - Pathway works di erently in addicts - Both sensory and executive information get into the striatum - The re ective system: Previous experience with a stimulus results in These memories include knowledge acquired through “learning”, not only self-experience - when having experience with a stimulus and experience positive/negative feeling, creating an a ective memory to it - When thinking about the drug, you bring those stored a ective memories - Memories don’t have to be personally experienced (can be learned through stories, others - When a decision is made (decision making), you consider these memories (almost immediate) - conscious or unconsciously as cues direct us - If is something wrong, we ignore those memories and the potential negative consequences & continue with drug use - Mediated by ventromedial prefrontal cortex (vmPFC) - critical for the function of this memory system - linking relevant memories and emotions - If damaged, control over our behaviour can be lost - in addicts, the balance is tilted: impaired re ective system and/or overdrive of impulsive system DEMONSTRATION OF DEFICIENT DECISION MAKING: PHINEAS GAGE - seemed ne, because walked away but demonstrated personality changes - Short tempered, many wrong decisions, was red - No cognitive impairment but lost control over behaviour - Di culty holding a job - Got better over the years and gained some control - Damage include the vmPFC - Patients that have damage to this area show similar symptoms Bechara suggest that there is a problem with decision making that leads to risky behaviour - But, is addiction caused by vmPFC damage or is it induced by prolonged exposure to drugs? - The Iowa Gambling Test: 67% of addicts show performance similar to vmPFC patients (yet, so do 27% of “normal” people) - Positive reward learning to the extreme - Shows that some people are risk averse - People with vmPFC do not show expected emotional response when risky deck is chosen - Not all addicts would show damage in the vmPFC - Could be caused also by : Impaired re ective system or overactivity of impulsive system - High impulsivity and thrill seeking are considered a risk factor for SUD - Additional possible de cits: - Loss of inhibition of impulsive behaviour - When testing addicts for other impulsive behaviours, they do not do well - Cannot inhibition themselves ff ff ff fi ff fl fl fi ff fi fl ff ffi PAGE 13 OF 16 WEDNESDAY, OCTOBER 18, 2023 - Inability to resist interference from irrelevant information Developmental mechanisms? - functional addicts: addicts that have no-decision-making de cits - Carry on with regular use for many years - PFC (incl. vmPFC) is not fully development until mid-20s - Balance between impulsive vs re ective system may be tilted more in younger adults - When drug taking is done younger, it a ects the brain very strongly - Bechara’s view is that the poor decision making leads to addiction and not the other way around - in other words, it is not that drugs cause poor decision making that subsequently leads to addiction Reduced reward sensitivity and prefrontal cortex disfunction (Volkow) - DA release is critical for the drug reward and the development of drug addiction - But, repeated exposure down-regulates DA receptors and DA release - Reduced DAd2-R in the striatum - After DA-R antagonist (methylphenidate), the response (DA release) is reduced in alcoholics - The repeated exposure to drugs and the over-stimulation of DA pathway create powerful learned associations - Changes in the DA system seem to go together with reduced activity in the OFC - Strongly associated with dysfunction in the PFC - the iRISA syndrome (Impaired Response Inhibition and Salience Attribution) - Repeated exposure to drugs increase strength of input/output of SALIENCY & reduced response inhibition (PFC) - Thickness = stronger = more salient fi ff fl PAGE 14 OF 16 WEDNESDAY, OCTOBER 18, 2023 Demonstration of “innate” compulsive trait: role of mPFC neurons (Chen et al, 2013) - animals trained to SA cocaine for long time (seek-take) - 2 levers and animals have to press seek lever to activate take lever and press it to receive the drugs - Creates very high level of response - After training, 30% of trials resulted in foot shock: uncertainty/risk to get drugs or shock - If foot shock is strong enough = drug seeking starts going down - Reduction of seeking - Animal variability - Some more sensitive to foot shock = drop lever press to 0 - Some resistant to foot shock = slight decrease but not signi cant - Prolonged cocaine SA results in compulsive drug taking is some rats Demonstration of “innate” compulsive trait: role of PFC neurons (Chen et al, 2013) - recording from in vitro brain slices from animals identi ed as sensitive or resistant - In punishment resistant rats (vs naive, sensitive) - neurons needed higher current to re APs - Neurons in PFC are less excitable - Sensitive too, but a little more excitable than resistant - APs ring frequency is reduced - Exposure to cocaine changes neurons in the brains Photoactivation of prelimbic cortex pyramidal neurons suppresses compulsive cocaine seeking in shock resistant rats Identi ed rats that were resistant & infused with ChR2 (blue-light excitable for PFC neurons) - Neurons whose excitability was reduced Trial 1: After shock, the blue light will be activated to excite PFC neurons - Cocaine infusions, latency to seek, average presses, seek lever presses are very similar to controls - Activation of the light does not change drug-seeking behaviour Trial 2: Those who were resistant in trial 1 are given the blue light paired with shock to excite PFC neurons - When only foot shock, there is a certain drug seeking pattern (a little less than baseline) but quite signi cant - When light is activated after shock, there is a signi cant decrease - Rats become more sensitive to the foot shock - Output from the prelimbic cortex inhibits the behaviour/ make them more sensitive to foot shock Reverse: photo inhibition of prelimbic cortex pyramidal neurons suppresses compulsive cocaine seeking in shock sensitive rats Can we make the sensitive rats by manipulating the same neurons - sensitive rats were infused with Halorodopsin (yellow light inhibition) for PFC neurons Trial 1: After shock, the yellow light will be activated to inhibit PFC neurons - Cocaine infusions, latency to seek, average presses, seek lever presses are very similar to controls fi fi fi fi fi fi fi PAGE 15 OF 16 WEDNESDAY, OCTOBER 18, 2023 - Activation of the yellow light does not change drug-seeking behaviour Trial 2: those who were sensitive in trial 1 are given the yellow paired with shock to inhibit PFC neurons - when only foot shock, rats completely stop drug seeking behaviour - When light paired with shock, there’s a signi cant increase - Made sensitive rats into resistant rats - Lack of intput from the prelimbic cortex activates the behaviour/ make them more resistant to foot shock fi PAGE 16 OF 16