Theories of Addiction (2).pdf

Theories of Addiction (2) 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 incen...

Theories of Addiction (2) 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 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 ff ff ff ff ff ff fi ff ff ff 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 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 ff ff ff fl 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 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 fi ff ff ff - 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 - 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 ff ff fi ff ff ff ff ff ff fl ff ff fl ff 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 - 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 fi fi fl ff fl fl fi fi ffi 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 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) fi fi fi fi - 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 - Activation of the yellow light does not change drug-seeking behaviour fi fi fi fi 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