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DA (Cravings, Da and Conditioning, Sensitisation, Neural Basis of Reward,…

- - - - 17 crack cocaine users (14 male, 3 female) and 14 comparison subjects (9 male, 5 female) recruited through newspaper ads, paid for participation.
      - Using fMRI, comparisons made between levels of craving/liking and associated regions of activation, with different forms of liking-inducing movie stimuli.
    - - Three films with different content were used:
      - Cocaine film, depicting two men engaged in drug-specific dialogue while smoking “crack cocaine” (which was actually benzocaine made to look like crack cocaine) and drinking “alcohol” (which was water in a gin bottle). The men were experienced cocaine users; the film was made in consultation with, and reviewed by, a number of former and current cocaine users to ensure authenticity.
      - Nature film contained scenic outdoor images.
      - Sex film contained explicit group activity.
    - - In short, procedure was:
      - Rest period
      - Movie (4mins)
      - Working memory task (5mins, ignore hereafter)
      - Self-ratings questionnaire
      - All subjects were shown nature movie first, order of sex and drug movies counterbalanced.
    - - Self-Ratings
        
        Crack cocaine addicts liked a movie about cocaine far more than non-addicts, and in fact more than they liked a sex movie.
        
        Crack cocaine addicts found a movie about cocaine as exciting as a sex movie, not so for controls.
      - fMRI
        
        Cocaine cues tended to activate brain regions only in cocaine users, including medial prefrontal and anterior/posterior cingulate regions.
        
        Brain regions (mostly frontal) of cocaine users were generally more responsive to cocaine stimuli than controls, while many brain regions in controls were more responsive than cocaine users to sex stimuli.
      - Results in a nutshell: craving-induced brain activation is widespread, and drug-related craving is subjectively an intense experience.
    - - No learning involved in the procedure, so it’s rather assumed that when the cocaine group showed a larger neural response to the cocaine video that it was due to learning, rather than some other unknown factor peculiar to that group.
      - Following on from the point above, presumably it was assumed that reactions to the cocaine video were learnt, while reactions to the sex video were innate? Fundamentally different classes of stimluli then, even assuming this distinction to be true.
      - The nature movie was always shown first, only sex/cocaine movies counterbalanced
  - - - Firstly, craving ratings: at the end of each picture block (alcohol, non-alcohol, control), participants briefly rated their craving for alcohol.
      - Alcoholics showed both generally higher levels of craving, and a specifically high level of craving when shown pictures of alcoholic drinks.
      - fMRI
        
        Controls showed no particular response in the VTA to alcohol pictures by comparison with general beverage pictures.
        
        Alcoholics though showed a strong VTA response to alcohol pictures
        
        Controls were similarly unresponsive in more forebrain dopaminergic regions, e.g. accumbens and frontal regions. However, alcoholics showed strong accumbens/frontal response to alcohol pictures.
    - - craving vs. fMRI correlations were carried out, to see the extent to which brain activity occurring in response to alcohol pictures corresponded with subjective craving ratings.
      - Alcohol cravings by alcoholics clearly correlated with activity in the nucleus accumbens.
      - Similarly, the extent of frontal activation in alcoholics also correlated well with their subjective craving ratings.
      - Alcoholics showed widespread brain activation to drink-related images (including, but not limited to nucleus accumbens), which correlated well with subjective craving.
    - - The alcoholic participants showed generally high levels of craving regardless of picture type, presumably as they had been without alcohol for 24h.
      - There was no specific effect of picture type then, consistent with the omission of an interaction effect in the paper for the craving-picture type figure we looked at earlier.
  - - - Earlier work found the medial prefrontal cortex (mPFC) reactive in situations involving implicit (unconscious) value judgements.
        
        Asked the question: How would participants’ conscious evaluation of three smoking campaigns’ effectiveness compare with their unconscious evaluation of the same campaigns, as measured via mpfc activity?
      - Results in a nutshell: Participants’ conscious evaluations did not correspond with campaign effectiveness, while campaign-induced implicit mPFC activity most certainly did!
      - Procedure
        
        Participants watched three advertising campaigns, and two measures were taken of their response:
        
        Their conscious rating of each campaigns’ likely effectiveness.
        
        fMRI measurements of their medial prefrontal cortex while watching each campaign.
    - - Conscious evaluation of the likely effectiveness of anti-smoking campaigns did not track actual campaign effectiveness at all. By contrast, unconscious mPFC activity most certainly did track subsequent campaign effectiveness very well indeed.
      - Participants’ conscious evaluations did not correspond with campaign effectiveness at all, while campaign-induced implicit mPFC activity tracked subsequent campaign effectiveness very well indeed.
  - - - Presented short scripts to smokers, describing the experiences of smoking, and measured their subjective response to the scripts.
      - Asked the participants to give up cigarettes for the next 30 days, and monitored their success.
      - Compared their initial subjective feelings about smoking, with subsequent abstinence success.
    - - Neutral
      - Negative affect-Urge script:
      - Positive affect-Urge script:
    - - Initial levels of craving bore no relationship to subsequent likelihood of relapse (taken from Table 3).
      - no relationship between initial craving for smoking and subsequent success in abstinence from cigarettes.
      - to what extent was the smokers’ feelings generated by the text a valid method for eliciting craving, as normally experienced ‘in the wild’? If not very valid, then the results wouldn’t be meaningful.
      - More work needed then to establish that their method truly generates craving as experienced by most people.
  - - - Used PET and [11C]raclopride as a basic setup for assessing dopamine release, albeit indirectly of course (by seeing how much [11C]raclopride managed to stick to dopamine receptors – the better it did stick, the less dopamine release there must have been to compete with it).
      - Recruited 20 cocaine addicts, and asked them to view two kinds of video: a neutral (nature) video, and a drug-related cocaine smoking video.
    - - Participants were administered either placebo or methylphenidate.
      - Participants then watched either a nature movie or a movie about cocaine.
        
        Placebo followed by nature video.
        
        Methylphenidate followed by nature video.
        
        Methylphenidate followed by cocaine video.
      - The above procedure was repeated twice more, at approximately two day intervals, so participants underwent all of the following permutations:
    - - Firstly, methylphenidate increased dopamine release in striatal regions (whether during nature or cocaine video), as one would expect.
      - However, methylphenidate-induced dopamine release did not result in the subjective experience of craving unless coupled with drug-related cues.
      - “…striatal DA increases (as induced by oral MP) while necessary, by themselves are insufficient to induce craving; craving required exposure to the conditioned cues. …we conclude that an additional pathway(s) is required to induce craving. We hypothesize that these may be prefrontal-striatal, prefrontal-mesencephalic and/or amygdalar-mesencephalic glutamatergic pathways…” p.1269
    - - Where's the placebo followed by cocaine video condition? How do you know there isn't something intrinsically weird about the cued video?
  - - - It's fruitful, because a comprehensive science of addiction will have to account for both craving and drug use; realistic, because craving, despite earnest attempts to wish it away, will not disappear from the researcher's or clinician's ledger. People addicted to drugs will continue to agonize over craving, and they will demand that scientists acknowledge its intrusive, nocuous qualities
    - - consideration of the reliability, stability, sensitivity, specificity, distribution and dimensionality of both the predictor and criterion variables; the content validity (i.e. representativeness) of the evocative cues;
      - the structure of the cue–reactivity procedure (e.g. the optimum number of cue trials, the spacing of trials, the extent to which drug use is possible in the presence of cues, the suitability of the control-cue conditions);
      - the mode of cue presentation (e.g. in vivo, photographs, imagery, virtual reality);
      - the context of the cue–reactivity assessment (e.g. laboratory-based, clinic-based, in the natural environment);
      - the timing of the assessment relative to a quit attempt (i.e. whether the assessment trials are conducted before, during or after a quit attempt);
      - the temporal relationships between cue–reactivity assessment and relapse episode;
      - the nature of the treatment intervention (if any);
      - and key characteristics of the research sample (e.g. abstinence status of the participants, history of drug use, level of drug addiction, stage of change)
    - - we need to examine the network of relationships across the panoply of predictor variables that can be assessed in the cue–reactivity paradigm.
      - That is, cue–reactivity manipulations influence much more than just craving—drug-cue manipulations influence self-report, physiological and behavioral measures representing emotional, cognitive and motivational constructs. The possibility that just one of these variables (e.g. laboratory-based cue-induced craving) might display a weak association with one feature of addiction (e.g. relapse) says little about the overall validity of the cue–reactivity paradigm as a model for studying addictive processes.
      - Indeed, it is hard for us to imagine a mature science of addiction that does not acknowledge the important role of drug-related cues in ongoing drug use and relapse.
    - - the question of whether or not craving (in any of its manifestations) is correlated with relapse strikes us as unnecessarily bounded.
      - A more penetrating exploration of the associations between craving and drug use would take into account the potential moderating and/or mediating effect of the factors listed above
- - - - Social drinkers recruited (at least 15 units/week, 50% male/female), asked to hold and later drink from a glass. Depending on glass colour (orange or green) and flavouring (passion fruit or apricot), the drink might (CS+) or might not (CS-) contain alcohol.
      - Firstly, CS- and CS+ trial each day, for four days (counter balanced):
      - ‘Hold’ Phase: Smelled the drink and filled in an alcohol desire questionnaire.
      - ‘Drink’ Phase: They then drank the solution, waited 5mins then filled in subjective feelings ratings, including feelings of lightheadness.
      - Results Trial 1
        
        Desire for alcohol also became associated specifically with the alcohol-paired flavour after just four days of training.
        
        no alcohol over the first four days - not drugs stimulus
        
        CS- group higher than CS+ until trial 4
        
        Results Trial 2
        
        ‘Drink’ phase: after holding the glass and filling in the alcohol desire questionnaire, participants then drank the solution, waited 5mins then filled in subjective feelings ratings, including feelings of lightheadness.
        
        Results
        
        Euphoria/light-headed feelings became associated specifically with the alcohol paired flavour after just four days of training.
        
        sinsitiveity to alcohol increased with apired stimulus
    - - After these four days of training:
      - Skin conductance was measured during the ‘Hold’ Phase, for the alcohol- (CS+) and control- (CS-) associated drinks.
      - Results – Skin Conductance during ‘Hold’ Phase
        
        After 4 days of training, skin conductance was significantly elevated by CS+ sniffing (‘hold’ phase) vs. CS-, suggesting an arousal/emotional response.
        
        first minute of the whole session
        
        test condition sig higher - increased conductivity = increased sweating
    - - Finally, CS+ and CS- drinks were arranged either side of a computer screen and participants were asked to focus on the screen. However, their gaze shifts towards the two type of stimulus were also surreptitiously measured.
      - Results - Attentional properties of CS+
        
        Gaze shift was also generally more towards the CS+ drinks vs. CS-, suggesting acquired attentional component to the CS+ stimuli.
        
        evidence of drug seeking behaviour - prior association learning of the glass colour & drug effect
    - - Desire for alcohol during the ‘Hold’ Phase appears remarkably suddenly on Day 4, the lack of progression across prior days seems odd.
      - Surely feelings of lightheadness during ‘Drink’ Phase should come directly from the alcohol, and so not build up across days as it seemed to do?
      - Gaze shift seems a bit fragile really, on and off even during the first six minutes.
      - order/temporal effects could affect lightheadedness score
      - gaze shift is desperate basically - not too robust
  - - - Four training days, each with two possible sets of environmental stimulus cues:
      - Pink towel on computer screen, facemask with peppermint teabag, modern guitar music.
      - Stripey towel on computer screen, facemask with spice-scented teabag, Gregorian chant.
      - Pipe routine: then each stimulus set paired either with cocaine (in glass pipe: 25mg cocaine, 6 times every 14mins) or placebo (heated air) while participant blindfolded.
      - Four cocaine and four placebo sessions in all: one of each per day.
      - Measures
        
        Choice: asked to choose which set of environmental stimuli they preferred to spend time with, before training, and afterwards.
        
        Probe: After two training sessions (halfway through training), cocaine- or placebo-associated stimuli were presented and followed with placebo pipe routine, and physiological measures taken.
        
        Extinction: following completion of training, cocaine- or placebo-associated stimuli repeatedly presented without any pipe routine at all.
    - - Choice test: No initial bias to one stimulus set or the other, but after training participants preferred environmental stimuli previously paired with cocaine. “Thus, the CS+ cue had acquired conditioned reinforcing effects.”
      - Probe test, physiological measures: After 2 days of training, stimuli paired with cocaine increased heart rate and skin temperature, while stimuli paired with placebo were less effective.
        
        skin temp related to conductance
        
        suggests significant learnnig
      - Extinction test, physiological measure: stimuli paired with cocaine increased heart rate during extinction (redrawn from Fig. 5).
        
        bad figure - poor presentation: introduce CS+ at time intervals on x-axis
        
        Extinction test, psychological measure: desire for cocaine also greatly increased in extinction.
      - Results in a nutshell: objects in a room where a participants repeatedly took cocaine acquired some of the emotional and physiological properties of the drug itself, and also came to be preferred over control objects.
    - - Critiques 1
        
        The authors talk about “environmental stimuli”: what does this really mean?
        
        p: we're self-described crack addicts before the trial - did not get participants on drugs
        
        drug would have been bought from a drug company so drug-specific factors are controlled for
        
        stimuli we're weak - not actually environmental just sort of contextual
        
        stimuli is still discrete - didn't really answer the question
        
        Well the Procedural details are very confusing, at least to me!
      - Critiques 2
        
        Extinction test, psychological measure:
        
        Effects don’t last very long!
        
        Inappropriate comparisons: between sessions, ought to be with a control condition/group.
        
        extinction section - comparisons between conditions we're used to compare the stimuli - they just compared the same drugs to the same drugs with no control, what are we actually abserving here?
        
        why is session 2 at -30? no reason given, it looks as though they suddenly disliked it - no controls means no comparison
        
        without a control what is the point of the dotted line?
      - Critiques 3
        
        Probe test, psychological measures: After two days of training, stimuli previously paired with cocaine had no effect on psychological measures, despite clear effects on heart rate and skin temperature we saw earlier (above charts redrawn from Figure 4).
        
        conscious awareness = physiological effects, physical awareness occurs before conscious recognition: things go on in the NA but the P isn't aware of it
  - - - Once trained, measurements were taken during exposure to rewarded and neutral trials.
        
        This drug competes with naturally released dopamine to bind to dopamine receptors, so the lower the levels of [11C]raclopride detected by PET, the implication taken was the more natural dopamine had been released.
        
        These were fMRI for nonspecific activity levels, and PET measurements of [11C]raclopride levels to establish dopamine-specific activity.
        
        cocaine effects take conditioning to be more effective - low Da = low cocaine effect
    - - fMRI-derived general activity levels
      - PET-derived specific dopaminergic release
    - - Task was to respond appropriately if number presented was higher or lower than 5, i.e. to press one button if the number presented was between 6-9, alternate button if between 1-4.
      - Participants were trained to associate specific pictures with upcoming reward (50 cents) if they responded to a simple task sufficiently quickly.
    - - Participants were presented with different pictures, which would have no consequences one way or the other for subsequent responses:
    - - Results 1
        
        used a number of D2 Da receptors across the whole brain - the more competitive the drug the more liekly it is to inhibit the maximum amount of faclopride - greater raclopride = lower competition
        
        graph is one p brian across time - measures raclopride concentration - as it decreases DA increases
        
        Data from one participant showing that less [11C]raclopride was detectable in the nucleus accumbens during the rewarded session, implying more dopamine release.
      - Results 2
        
        PET measurements for the nucleus accumbens correlated well with activity changes detected using fMRI.
      - Results 3
        
        fMRI measurements clearly showed widespread activation during reward vs. neutral trials in ventral striatal and surrounding regions.
      - Results 4
        
        PET measurement of [11C]raclopride displacement clearly indicated a specific focus on the nucleus accumbens (left side!).
      - Critiques
        
        Fourteen young (age range 20 –25 years, mean 22.8 􏰎 1.5) healthy vol- unteers participated in the experiment, three of which had to be excluded from analysis due to excessive movement in the PET study (two cases) or not complying with the task instructions (one case).
        
        Why just the left nucleus accumbens? Not mentioned in Abstract, Introduction or Discussion…?
        
        Why the relatively widespread fMRI activation, and on both sides too? Why the obsession with the accumbens?
        
        L-NA has significant release of Da compared to the right, the figure and paper did not acknowledge this, why is only one side affected?
        
        Don’t ignore the lateralisation effects of Da - recurring issue in drug research
  - - - Came back two weeks later and measurements taken again, this time with no amphetamine (‘placebo’ condition).
      - Measurements at each stage (Baseline, 3 days amphetamine, placebo) were subjective ratings (VAS: visual analog scales) and PET data on [11C]raclopride levels.
    - - Results 1
        
        sig placebo condition after 2 weeks
        
        in all response there's a clear subjective association with the drug and its conditioned environment
        
        Subjective ratings during final placebo session were far more similar to those of the drug session than to the original baseline control session.
      - Results 2
        
        Ventral striatal dopaminergic activity tracked subjective ratings, so less [11C]raclopride was detected in both the amphetamine and placebo conditions, implying more dopamine had been released.
        
        Accumbens was the area of greatest activity
      - Results 3
        
        Dopaminergic response in striatal regions to an amphetamine-paired environment was similar to amphetamine itself.
      - Results in a nutshell: pairing amphetamine with a specific environment did indeed lead to conditioned dopamine release in the nucleus accumbens when participants were later exposed to the environment alone.
        
        even if you get off drugs, this learning does not leave, youll feel the effects of the drug as a placebo
    - - the procedure is somewhat lacking some form of control for the order of events being fixed for all participants. This means for example there might have been something funny going on during the final drug-free session to cause the apparent release of dopamine that was not related to conditioning per se.
      - One solution (amongst many) would have been to add a group that were administered the amphetamine in a different environment to the scanner suite, but otherwise experience everything that the conditioning group did.
      - we don't know that the final non-drug session result is because of conditioning - does not answer the research question
      - needs appropriate control
      - we don't know why the placebo session showed increased DA - no evidence its contextual cues so their interpretation is unfounded
  - - - Foundation: Pavlovian learning in addiction (See this lecture). Based on the prediction error in reinforcement learning common hypotheses suggest the Da is used to update the predictive value of stimuli during associative learning - 7
        
        others have argued that the role of dopamine in reward is in attributing Pavlovian incentive value to cues that signal reward, rendering them desirable in their own right - 8
        
        Rationale - it has been difficult to determine whether dopamine mediates the predictive or the motivational properties of reward-associated cues, because these two features are often acquired together. However, the extent to which a predictor of reward acquires incentive value differs between individuals, providing the opportunity to parse the role of dopamine in stimulus-reward learning
      - Procedure
        
        Pavlovian conditioning paradigm - exploit these predictable phenotypes in the selectively-bred rats, as well as normal variation in outbred rats, to probe the role of dopamine transmission in reward learning in individuals that vary in the incentive value they assign to reward cues.
        
        When presentation of a lever-CS was paired with food delivery both bHRs and bLRs developed a Pavlovian CR, but as we have described previously15, the topography of the CR was different in the two groups. With training, bHRs came to rapidly approach and engage the lever-CS (Fig. 1a-b), whereas upon CS presentation bLRs came to rapidly approach and engage the location where food would be delivered
        
        Results - there was a significant effect of session for all measures of sign-tracking behavior for bHRs (a-b; P≤0.0001), and of goaltracking behavior for bLRs (c-d; P≤0.0001). Furthermore, bHRs and bLRs learned their respective CRs at the same rate, as indicated by analyses of variance in which session was treated as a continuous variable and the phenotypes were directly compared.
        
        the CS acquired one defining property of an incentive stimulus in bHRs but not bLRs, the ability to attract. Another feature of an incentive stimulus is to be “wanted” and as such animals should work to obtain it 10. Therefore, we quantified the ability of the lever-CS to serve as a conditioned reinforcer in the two groups (Figure 1f-g) in the absence of the food-US
        
        The NA is responsible for motivated bevaiour and pavlovian learning - if CS-evoked dopamine release encodes the strength of the reward prediction, as previously postulated 5, it should increase to a similar degree in both groups during learning; however, if it encodes the attribution of incentive value to the CS, then it should increase to a greater degree in sign-trackers than in goal-trackers.
        
        Results - During the acquisition of conditioned approach, CS-evoked dopamine release increased in bHR rats relative to unpaired controls (P = 0.003). There was no such effect in bLRs (P = 0.46)
        
        the trial-by-trial correlation between CSFlagel et al. evoked dopamine release and trial number was significant for bHR (P < 0.0001) but not bLR (P=0.54) rats, producing significantly different slopes (P=0.005) and higher CS-evoked dopamine release in bHR rats after acquisition (P = 0.04).
        
        US-evoked dopamine release also differed between bHR and bLR rats during training (P = 0.0003), but for this stimulus dopamine release was lower after acquisition in bHRs (P = 0.002)
      - Results
        
        these data provide several lines of evidence demonstrating that dopamine does not act as a universal teaching signal in reward learning, but selectively participates in a form of stimulus-reward learning whereby Pavlovian incentive value is attributed to a CS.
        
        US-evoked dopamine release in the nucleus accumbens decreased during training in sign-trackers, but not in goal-trackers. Thus, during the acquisition of a goal-tracking CR, there is not a dopamine-mediated “prediction-error” teaching signal since, by definition, prediction errors become smaller as delivered rewards become better predicted
        
        Second, the CS evoked dopamine release in both sign- and goal-tracking rats, but this signal increased to a greater degree in sign-trackers, which attributed incentive salience to the CS. These data indicate that the strength of the CS-US association is reflected by dopamine release to the CS only in some forms of reward learning.
        
        Third, bHR rats that underwent Pavlovian training in the presence of a dopamine receptor antagonist did not acquire a sign-tracking CR, consistent with previous reports24; however, dopamine antagonism had no effect on learning a goal-tracking CR in bLR rats. Thus, learning a goal-tracking CR does not require intact dopamine transmission, whereas learning a sign-tracking CR does.
        
        These findings were specific to bred-rats designed for increased craving. Findings may not translate to out-bred rats
- - - - PET sessions: On same day given a control, then amphetamine injection following [11C]Raclopride infusion.
      - Stress sessions: subjected to psychologically stressful experience, and stress hormone levels measured (cortisol).
      - Comparisons then made between each how stressed a participant became and their dopaminergic response to amphetamine measured separately.
      - PET Measurements
        
        On different occasions (not when doing the stress tests) they were subjected to two PET measurement sessions:
        
        The first was a control session, prior to which they were administered saline.
        
        Participants were also administered [11C]Raclopride before both sessions of course, so that its ability to bind to brain dopamine receptors could be measured, relative to naturally released dopamine in the brain.
    - - The dose of amphetamine was more than sufficient for participants to ‘feel’ its effects.
      - Participant’s stress response also correlated pretty well with their subjective responses to amphetamine.
        
        High stats: r=.48 - p=.016
        
        Rush stats: r=.52 - p=.009
      - Participants’ stress response to stress task correlated well with their LVS dopaminergic response to amphetamine.
      - Results Overall
        
        The bigger a participant’s physiological or subjective stress response, the larger their corresponding release of dopamine in the nucleus accumbens.
        
        People’s stress levels – whether ‘trait’ or baseline, or in response to a stressful situation – correlated well with their dopaminergic response to amphetamine, so the higher their ‘stress profile’ the more reactive their mesoaccumbens dopamine projection.
  - - - Carried out two experiments (they were keen!), here we’ll look at Experiment 2 (Exp.1’s awesome too, but no time here):
      - Ordinary ratties were mildly stressed repeatedly by lightly tweaking their tails for four 1min applications separated by 8-10mins, once a day for 15 days.
      - Control ratties went through the broad procedure, but without the pinchiness.
    - - Locomotor response to amphetamine (24h later)
      - Inclination to learn to self-administer amphetamine (~ 1 week later).
    - - Repeated stress enhanced the locomotor response to amphetamine, and the later acquisition of amphetamine self-administration.
      - Results Overall
        
        Repeated stress seemed to enhance the basic behavioural, and rewarding impact of amphetamine when tested later.
        
        Repeated stress later was found to enhance the locomotor and reinforcing properties of self-administered amphetamine.
        
        NOTE: Experiment 1 used repeated amphetamine instead of stress, and again found sensitisation of animals’ locomotor- and reward-response to amphetamine when tested at a later date.
    - - Amphetamine is a psychomotor stimulant, i.e. it increases activity, and so much of the data presented on self-administration could reflect such activity, rather than response-outcome rewarded behaviour. It is claimed that an inactive hole acted as a control for this, but no data for it are actually presented at any time. Withholding important info is rather a limitation.
      - Fig. 2B (amphetamine self-admin figure) odd: previously stressed group starts high and stay there, controls also start high but die away across days. Neither pattern is what you’d expect for the gradual acquisition of a leverpressing response.
      - Subjective effects of amphetamine exposure. Profile of Mood States (POMS) scores (peak change from baseline) recorded during the drug-free control scan and the 3 amphetamine positron emission tomography sessions at doses 1, 4 (n=10), and 5 (n=7) after amphetamine (0.3 mg/kg by mouth). *P􏰃.05, significantly increased compared with dose 1. Error bars represent SEM.
  - - - Control task = resting in apparatus, no arithmeticiness.
      - Also measured cortisol (stress hormone) production via saliva.
      - Applied rather mean stress task (mental arithmetic, feedback falsely suggesting doing badly) and measured dopamine release indirectly, by measuring brain levels of a radioactive dopamine receptor-specific drug, raclopride using positron emission tomography (PET).
        
        Higher the levels of raclopride found ‘sticking’ to dopamine receptors, by inference the lower the amount of (competing) dopamine that must have been released.
      - Results
        
        Recap result (see Seminar 2): stress greatly increased dopamine release in the ventral striatum (nucleus accumbens), measured as a reduction in [11C]Raclopride Binding Potential.
    - - Additional question, this seminar: Participants also filled in the Parental Bonding Index, which measured:
      - mother care
      - mother overprotection
      - father care
      - father overprotection
      - However, “Because animal studies found dopamine regulation to be affected by differences in maternal care, we used this subscale for subject selection.” p.2826
      - Results
        
        Low maternal bonding in childhood corresponded with higher trait anxiety, and greater stress response in adulthood. [graph above derived from Results text, p. 2827]
        
        Participants reporting low maternal care (bottom 10% on maternal scores) showed a much larger dopaminergic response to a stressor compared with those reporting the highest. [graph above derived from paper’s Figure 2]
        
        Results overall
        
        The lower the self-rated maternal care in childhood, the greater the cortisol and dopaminergic response to stress.
    - - Most obvious issue is the study is correlational, and so you’ve no definite idea whether maternal factors caused high trait anxiety, or e.g. genes caused both.
  - - - Control: baseline PET reading.
      - Doses 1-3: days 1-5 (kind’ve like Piazza et al. (1990) Exp.1 really)
      - Dose 4: 14 days later
      - Dose 5: 365 days after first 3 doses.
    - - Astonishingly really, the subjective effects of just 3 doses of amphetamine were still sensitised when tested an entire year later.
      - Longterm subjective effects were accompanied by equally permanent increases in striatal dopaminergic response to amphetamine.
      - Results overall
        
        just a few doses of amphetamine in humans were sufficient to sensitise their subsequent dopaminergic amphetamine response, for at least a year
    - - Participant selection bias: participants were selected on the basis of scoring highly on the novelty-seeking subscale of the Tridimensional Personality Questionnaire.
        
        This was on the basis of oodles of work in rats showing those who are more active in a novel environment also have a more reactive dopaminergic system. “Whether these findings of sensitization to amphetamine can be generalized to other nonclinical or clinical populations is unknown, although plausible.”
      - All drug exposure took place in the PET environment “to facilitate the expression of behavioral sensitization.”
        
        Results then are a mixture of unknown proportions of conditioning and basic molecular sensitisation effects. “Until further experiments designed to test for conditioning are completed, the possibility that this effect may have contributed to an enhanced response to stimulant cannot be discarded.
  - - - apomorphine susceptible (APO-SUS) and apomorphine unsusceptible (APO-UNSUS) rats. were recently found to be genetically different in the number of gene copies of a component of the γ-secretase complex called Aph-1b. Whereas APO-UNSUS rats have three copies of the gene, APO-SUS rats have either 1 or 2 copies
      - Risk Factors of Addiction
        
        Genetics
        
        Alcohol - High risk and twin studies have further underlined the significance of genetic factors in addiction. Thus, in twin studies for cocaine, marihuana, opiates, sedatives and stimulant
        
        The single most often reported association is between substance abuse disorder and the TaqI A1 allele of the dopamine D2 receptor. Following the original positive report for alcoholism, many positive reports followed, including associations with cocaine addiction and tobacco smoking (Noble, 2000) - association studies have not yielded consistent results, and many negative studies have also been reported (see (Merikangas, 2002)
        
        Early Life Events
        
        concordance studies in monozygotic twins have consistently shown rates well below 100% (Kendler and Prescott, 1998b), a clear indication that non-genetic factors are also important in determining drug addiction.
        
        have reported an increase risk of developing addictive behaviour after early childhood abuse (Marcenko et al., 2000, Wilsnack et al., 1997). This is corroborated by other studies that found that addiction is strongly related to several categories of adverse experiences during childhood, such as emotional or physical neglect, mental illness in the household, battered mothers and other household dysfunction (Dube et al., 2003)
        
        Late Environmental Factors
        
        several reports have recently pointed to a gene * environment interaction. Thus, it was recently found that the occurrence of alcoholism could best be predicted by low socio-economical status combined with the occurrence of the TaqI allele of the D2 receptor, but not by either of these factors alone (Madrid et al., 2001).
        
        Animal Model of Addiction
        
        addictive behaviour can be measured in animals using the self-administration procedure. Moreover, there is strong evidence that rats from the same strain show a lot of variety in drug self-administration
        
        rats with a high response to novelty show a larger propensity to self-administer cocaine (Kabbaj et al., 2001) or amphetamine (Piazza et al., 1990). On the other hand, a reduced consumption of alcohol was reported in high responders to novelty (Gingras and Cools, 1995), though this may be dependent on the specific set-up to measure self-administration (Nadal et al., 2002).
        
        This is interesting in view of the fact that in humans the novelty seeking character trait has been linked to the occurrence of addiction (Le Bon et al., 2004
        
        Procedure & Results
        
        Individual Variables
        
        focussing on the underlying mechanisms of addiction. Although many aspects of addiction are still far from elucidated, it is well known, from both clinical and preclinical studies that dopamine plays a crucial role in the acquisition of drug-taking behaviour and in the craving for drugs of abuse (Volkow et al., 2004
        
        select Wistar rats on the basis of their response to the dopamine D1/D2 receptor agonist apomorphine, injected subcutaneously in a standard dose of 1.5 mg/kg. Using the modified Ungerstedt box (Ljungberg and Ungerstedt, 1978), we found a bimodal shape of variation with approximately 40–45% showing a weak gnawing response and 40–45% showing an intense gnawing response (Cools et al., 1990, Ellenbroek et al., 2000).
        
        research was devoted to the phenotypical characterization, and we could show that the APO-SUS and APO-UNSUS rats differed in many aspects of the central nervous system, the neuroendocrine system as well as the immunological system
        
        We first focussed on alcohol consumption and found that when rats were given a free choice of either an ethanol solution of water in their home cage, the APO-UNSUS rats drank significantly more of the ethanol solution than APO-SUS rats (Sluyter et al., 2000). Moreover, this increased consumption of the APO-UNSUS rats was seen at alcohol concentration from 4% up to 10% (higher concentrations were not tested)
        
        APO-UNSUS rats also more readily self-administered cocaine than the APO-SUS rats (van der Kam et al., 2005b). Thus, under normal conditions, the APO-UNSUS rats seem to be more prone to develop addiction
        
        Gene-environement Interactions - largely support the three-hit model
        
        This variety of substrates, many of which are critically involved in various aspects of development may explain why APO-SUS and APO-UNSUS rats show such fundamentally different properties in the nervous, endocrine and immune system
        
        The minimal molecular composition of the γ-secretase complex has recently been resolved, namely, presenilin (either PS1 or PS2), nicastrin, presenilin enhancer 2 (PEN-2) and anterior pharynx defective 1 protein (Aph-1aS, Aph-1aL or Aph1b). Thus, at least six different configurations of the γ-secretase complex are possible
        
        selectively bred rats with 1, 2 or 3 copies of the Aph-1b gene - rats with 1 or 2 copies had a significantly higher gnawing response than animals with 3 copies of the Aph-1b gene
        
        Early Life Events
        
        a single 24 h period of maternal deprivation at postnatal day 9 (birth being postnatal day 0) significantly enhanced the apomorphine-induced gnawing response in the APO-UNSUS, but not in the APO-SUS rats. Conversely, cross fostering APO-SUS pups to APO-UNSUS rats decreased the apomorphine-induced gnawing response in these pups.
        
        Cross fostering APO-UNSUS rats to APO-SUS mothers did not affect the apomorphine-induced gnawing response. Likewise, cross fostering APO-SUS pups to other APO-SUS mothers (a procedure generally referred to as in-fostering) did not affect the apomorphine-induced gnawing response in the pups (Ellenbroek et al., 2000).
        
        maternally deprived APO-UNSUS rats showed a self-administration profile very similar to that of APO-SUS rats, namely a reduction in cocaine self-administration under normal, non-challenged conditions
        
        Late Environemental Factors
        
        APO-SUS and APO-UNSUS rats show a different response to mild stressors, often opposite to each other. Thus, whereas the basal levels of corticosterone are lower in APO-SUS rats, after stress, the levels are higher compared to APO-UNSUS rats (Rots et al., 1995).
        
        self-administration of cocaine and alcohol is strongly dependent on environmental stressors. As discussed above, under non-challenged conditions APO-SUS rats drink significantly less alcohol than APO-UNSUS rats. However, after a single stressful experience, the APO-SUS rats showed a strong and prolonged increase in drinking behaviour, whereas the APO-UNSUS rats only showed a small and short-lasting increase
        
        APO-UNSUS rats rapidly learned to self-administer cocaine, after these animals were shaped (by giving them one forced nose-poke upon placing the animals in the cage, see Fig. 1). When subsequently the light stressor was applied, the APO-SUS rats also readily learned to self-administer cocaine.
    - - alcohol and cocaine self-administration behaviour in APO-SUS and APO-UNSUS rats results from an interaction between genetic factors, early life events and late environmental factors. The important question is of course, how these factors interact to shape the brain (and body) of these animals
        
        in relation to dopamine, it has been shown that APO-SUS rats have an increased mRNA activity for tyrosine hydroxylase, and an increase in tyrosine hydroxylase-immunoreactivity in the nucleus accumbens when compared to APO-UNSUS rats (Rots et al., 1996,
        
        APO-SUS rats also have more D2 receptors (Rots et al., 1996) and dopamine transporters (Van der Kam et al., in preparation) in the dorsal striatum. When challenged with a mild stressor, APO-SUS rats show a stronger and more prolonged release of dopamine in the nucleus accumbens (van der Elst et al., 2005b)
      - whereas cocaine increased in tyrosine hydroxylase-immunoreactivity in the nucleus accumbens of the APO-UNSUS rats, it increased it in the medial prefrontal cortex of the APO-SUS rats, indicating that cocaine affected different brain circuitries in both rat types
      - maternal deprivation affects only the APO-UNSUS rats, whereas cross fostering affects only the APO-SUS rats. It is important to realise that not only the nature of these early life events is different, but also the timing.
        
        Using systemic injections of clonidine and saline as early life events, we found that injections in the first few days after birth affected the apomorphine induced gnawing response only in the APO-SUS rats, whereas injections around postnatal day 9 affected the apomorphine-induced gnawing response only in the APO-UNSUS rats (Degen et al., 2004
        
        This has led us to propose a more general model explaining the gene * early environmental interaction.
        
        This model proposes that (1) the general speed of development is primarily determined by the genetic background of rat and (2) that an early life event primarily affects brain structures (and thus function) that are currently developing.
        
        This explains why manipulation A in Fig. 2 affect rat strain I but not II or III, whereas manipulation C affect strain III, but not strain I. Given the importance of γ-secretase in development, and the fact that our rat lines with I, II, or III copies show a strong reduction in γ-secretase cleavage activity during development
        
        Summary present data suggest that the acquisition of cocaine and alcohol self-administration in APO-SUS and APO-UNSUS rats is the result of a complex interaction between genetic factors, early life events and late environmental factors. Although the precise interaction between these factors remains to be investigated, we have proposed a testable hypothesis that the genetic difference in Aph-1b activity determines the speed of development, and thereby when an early stressful life event will have a long lasting effect.
- - - - mPFC = mesocortical Da projection - VTA - NA (short jump)
      - Mesolimbic dopamine system - passes through medial forebrain bundle (mfb) between VTA and nucleus accumbens.
    - - Bishop et al. (1963): “It is of interest that the introduction of an attractive tray of food produced no break in responding, although the subject had been without food for 7 hours, was noted to glance repeatedly at the tray, and later indicated that he knew he could have stopped to eat if he wished. Even under these conditions he continued to respond without change in rate …until finally instructed to stop, at which point he ate heartily.” (p.395)
      - Similar findings in people and rats with similar methods
      - Days worth of recording - quote: P feels as though he could have stopped whether he would or not is unclear
    - - Procedure
        
        Heterogeneity within the midbrain tegmentum
        
        The heterogeneity of neurons in the midbrain tegmentum is reflected not only by their regional distributions and cytological features, but also by the coexisting proteins and peptides found in subpopulations of dopaminergic neurons and by the presence of many nondopaminergic neurons that have both mesocortical and mesolimbic projections.
        
        Regional and cellular heterogeneity
        
        The A10 region comprises several nuclei: parabrachial pigmented nucleus (PBP), paranigral nucleus (PN), caudal linear nucleus (CLi), interfascicular nucleus (IF), and rostral linear nucleus of the raphe (RLi). While there is general agreement that the PBP and the PN (lateral nuclei of the A10 region) are subdivisions of the VTA, there is a lack of consensus on which of the medial subdivisions of the A10 region (the RLi, the Cli, and the IF) are part of the VTA
        
        recent electrophysiological, biochemical, and anatomical evidence indicates a differential cellular composition between the lateral and midline nuclei of the A10 region.17–27 Thus, when available, we will include information on the specific subdivision of the A10 region under consideration.
        
        ultra structural analysis
        
        Synaptic inputs to VTA neurons from intrinsic and extrinsic sources
        
        ultra structural analysis
        
        Synaptic structure and function - immunoelectron microscopy approach - measures interactions among different brain structures; however, information on the synaptic connectivity requires ultrastructural analysis
        
        the symmetry and asymmetry of synapses are consistent with, but not unequivocal proof of, excitatory or inhibitory transmitter content within presynaptic axon terminals in asymmetric or symmetric synapses, respectively
        
        The 5-HT as well as other monoaminergic terminals can form either asymmetric or symmetric synapses, whereas others, including those of dopaminergic neurons, form either thin punctuate symmetric junctions or lack any recognizable synaptic specializations
        
        Those axonal varicosities without recognizable synapses are said to operate in a more global volume mode of transmission - Agnati, L.F. et al. 2010
        
        Both dopaminergic and nondopaminergic neurons in the VTA receive input from serotonin (5-hydroxytryptamine, 5-HT)-containing axon terminals44 consistent with a postsynaptic distribution of 5-HT receptors in these neurons
        
        Mesocortical projections and their prefrontal cortical targets
        
        animal models suggest that dopaminergic afferents within the PFC play a role in the rewarding effects of drugs of abuse.70 Additionally, it has been hypothesized that the PFC is a neuronal substrate for drug-induced neuroadaptations that in turn maintain drug seeking
        
        These neuroadaptations occur differentially in the dorsal and ventral medial PFC, such that there is a resulting increase and decrease in the respective glutamatergic outputs from these regions. The increase in dorsal medial PFC glutamatergic output may enhance and induce drug seeking, while the reduction in these outputs from the ventral medial PFC could impair response inhibition upon exposure to drug-conditioned stimuli.
        
        Mesocortical dopamine projections
        
        In monkeys (Goldman-Rakic et al, 1989) dopaminergic afferents make asymmetric synapse with the shafts and spines of glutamatergic pyramidal projection neurons. Some of these pyramidal neurons innervate the nAcc or the contralateral PFC. It is through these synapses that dopamine is likely to modulate both corticoaccumbal and interhemispheric communication. Dopamine modulation of cortical neurons that project to the nAcc appears to play a role in the rewarding effects of drugs of abuse and drug seeking (Carr & Sesack, 2000)
        
        localization of D1 receptors in dendritic spines receiving asymmetric synapses has led to the suggestion that a primary role of D1 receptors is to enable dopamine modulation of glutamatergic transmission in cortical pyramidal cells
        
        presynaptic and postsynaptic activations of D1 receptors in synapses established among cortical pyramidal neurons
        
        These distributions indicate that dopamine D1- and D2-like receptors play a complex role in modulating synaptic activity in the PFC
        
        Mesostriatal projections and their striatal targets
        
        The striatum is traditionally divided into dorsal (caudate–putamen) and ventral divisions (nAcc). The ventral striatum is further subdivided into shell and core, and although GABAergic MSNs are the main type of neurons in all compartments of the striatum, these neurons are different in the core and the shell.
        
        morphological differences, site-directed pharmacological behavioral studies show that in drug reward, the shell portion of the nAcc appears to be more important than the core for the reinforcing effects of cocaine
        
        The dopaminergic nature of the mesostriatal pathway and its ultrastructural association with striatal MSNs are well established. However, emerging evidence indicates that in addition to VTA dopaminergic innervations, the nAcc receives inputs from both GABAergic64,106,107 and glutamatergic33 neurons in the VTA
        
        Mesostriatal dopamine projections
        
        Within the dorsal and ventral striatum, the major recipients of dopaminergic terminals are MSNs.108–112 In contrast, dopaminergic terminals rarely contact striatal interneurons containing acetylcholine
        
        Serial reconstruction of striatal dopaminergic axons shows that only 30–40% of these axons form synapses.114,115 These findings indicate that dopaminergic fibers mediate actions by nonsynaptic mechanisms involving volume transmission
        
        findings lead to the hypothesis of distinct subpopulations of core- and shell-projecting mesencephalic dopamine neurons.118 In support of this hypothesis, neurotoxicologic data show that dopamine innervations to the core are more vulnerable to neurotoxins than innervations to the shell
        
        As the shell appears to be more important than the core for drug reward,11,39–41 knowledge of the molecular differences between the postulated core- and shell-projecting mesencephalic dopamine neurons potentially will be useful in our understanding of the molecular and cellular bases on drug reward.
        
        take into consideration ultrastructural evidence indicating the presynaptic and postsynaptic distribution of dopamine receptors within the striatum.
      - Results
        
        Drugs of abuse can enhance mesolimbic dopamine transmission by multiple direct and indirect mechanisms. Cocaine and other psychostimulants that bind to the plasmalemmal dopamine transporter prevent reuptake, thus enhancing extracellular levels of dopamine, a mechanism that accounts for some, but not all of their rewarding and aversive actions - 158
        
        In contrast with psychostimulants, cannabinoids increase the bursting activity of mesolimbic dopamine neurons by modulating the presynaptic release of GABA and glutamate present in axon terminals providing input to the dopamine as well as nondopamine-containing neurons in the VTA - 159
        
        Opiates also enhance the activity of midbrain dopamine neurons indirectly through disinhibition, which results from the activation of Gi-coupled μ-opioid receptors located in GABAergic neurons that provide synaptic input to dopaminergic neurons in the VTA - 160
        
        In addition, whole-cell recording of retrogradely labeled VTA dopaminergic neurons indicate that opioids differentially inhibit mesolimbic dopaminergic neurons depending on their projection fields - 107
        
        The drug-induced activation of the mesocortical output system can have a significant reciprocal impact on VTA glutamatergic transmission,163–165 which results in neuronal plasticity within the mesocorticolimbic DA pathway.3,166–171 Drugs of abuse induce molecular, functional, and possible structural changes on synapses formed between glutamatergic inputs and dopaminergic neurons.3,168,169
        
        Electrophysiological, behavioral, and cell biological studies have led to the hypothesis that changes of excitatory synaptic transmission in the mesocorticolimbic DA system are important for the neural adaptations underlying some of the long-lasting behavioral effects of drugs of abuse
        
        electrophysiological studies have shown that drugs of abuse induce changes in the function of ionotropic glutamate receptors in the VTA dopaminergic neurons - 3
        
        Initial autoradiographic and immunocytochemistry studies addressing AMPA receptor subunit expression after repeated administration of either methamphetamine or cocaine did not detect changes in the regional expression of these molecules.180 However, there is now evidence that cocaine, morphine, and other drugs of abuse elicit changes in the synaptic composition of these receptors in both dopaminergic and nondopaminergic neurons within the VTA. - 3
        
        Drug-induced changes in the function of glutamatergic synapses in the VTA have many analogies with those occurring in the nAcc173,181–186 and PFC.187 These regions are key portions of the neural network mediating goal-directed behaviors, including those related to drugs of abuse.188 Moreover, changes in this circuitry are suggested to play a critical role in drug addiction
        
        This plasticity is consistent with evidence that dopaminergic inputs converge with glutamatergic inputs in the nAcc. This illustrates the great potential of using quantitative electron microscopic immunogold labeling of receptors in conjunction with immunoperoxidase detection of other functionally related antigens in order to precisely define the in vivo synaptic circuitry targeted by addictive substances.
  - - - “I applied a brief train of 60-cycle sine-wave electrical current whenever the animal entered one corner of the enclosure. The animal did not stay away from the corner, but rather came back quickly after a brief sortie which followed the first stimulation, and came back even more quickly after a briefer sortie which followed the second stimulation. By the time the third electrical stimulus had been applied the animal seemed indubitably to be “coming back for more”.
      - Thought they were stimulating the hindbrain but actually stimulated the VTA-NA mesoaccumbens pathway
        People conducting this had no brain stimulation training prior to testing in the 50s
        
        Mispositioned electrode was probably located in the region of the hypothalamus, through which passes the medial forebrain bundle (mfb).
        
        The mfb is a major highway from ascending and descending neural tracts, including the mesoaccumbens dopamine projection from the VTA to the nucleus accumbens.
        
        Subsequent studies allowed rats to induce electrical current in the region of the mfb themselves - hence ‘intra-cranial self-stimulation’, or ICSS.
        
        ICSS in the mfb is EXTREMELY reinforcing:
        
        Critiques
        
        Drug addicts don’t have wires inserted into their heads, so the relevance of electrical self-stimulation to drug addiction isn’t entirely clear.
        
        OK, electrical self-stimulation seems to have the ability to motivate continuing self-stimulatory behaviour, but how is this relevant to the patterns of drug addiction often seen? For example, how is this relevant to someone who relapses back into drug taking six months after they last sample a drug?
        
        In short, while not to cast aspersions entirely, electrical self-stimulation is rather artificial and not obviously equivalent to the usual drug experience.
    - - steep = rapid pressing of the lever
      - no change in NOON trial - no pauses
      - No pauses for basically 24 hrs (few pauses)
      - When the rat stopped he wasn't bored he just fell asleep from exhaustion - if he could press it more he would
  - - - Double-blind within-subject design (3 sessions each a week apart):
        
        Placebo
        
        Levodopa (dopamine precursor, used by dopaminergic neurons to synthesise dopamine).
        
        Risperidone: dopamine receptor blocker (mainly of the D2 family).
      - Measures taken after songs (participant- and experimenter-selected):
        
        Subjective emotional responses
        
        Physiological skin conductance
        
        Motivation to access song.
        
        skin conductance = sweat
        Asked about motivation toward the songs to separate motivation from pleasre
    - - Music: Participants self-selected 5 musical excerpts they really liked. For each of the 3 sessions, they listened to these excerpts intermixed with 10 experimenter-selected excerpts that had been in the Spanish Top 40 in the last three years.
      - Each experimenter-selected list was matched we matched them according to different features computed by Spotify’s algorithms, namely bpm, energy, danceability, valence, and popularity using using the Spotify application “Sort your Music”
      - Motivational ratings: Auction paradigm - for each experimenter-selected song, participants indicated how much from a set budget how much they were willing to pay. At the end of each session, one excerpt was randomly selected. If their bid was the same or higher than the real price of the song (randomly assigned at the beginning of the experiment), they would get a legal copy of the song at the end of the experiment.
        
        Not just about how they feel about the music (difficult to get objectively) but also what theyre willing to do to get that music again
        
        Results
        
        Subjective Ratings - See slide 22
        
        measures above are vs. the placebo condition. Levodopa increased Chills and High Pleasure responses to music, while Risperidone resulted in the opposite pattern, and also increased the Low Pleasure musical response.
        
        Skin coductance & Wanting scores (money)
        
        measures above are again vs. the placebo condition. Levodopa increased both the skin conductance response to music and and motivation to spend money on future experimenter-selected song access. Risperidone resulted in the opposite pattern.
        
        Results in a nutshell: Yes it is! Risperidone was used to block dopamine receptors and it indeed reduced musical pleasure measures (subjective ratings and skin conductance), while another drug that increased dopamine availability increased the same ratings.
        
        General motivation to access experimenter-selected songs was also affected in the same way.
        
        pleasure is dependent on Da activity - drugs we're significant factors in altering pleasure response
    - - Specificity issues:
        
        Drugs: The paper claims that the drugs Risperidone and Levodopa are selectively affecting dopaminergic activity, indeed the word “Dopamine” begins even the paper’s title. However, neither drug has a particularly selective action on brain dopamine:
        
        Risperidone prefers to bind to the serotonin 5-HT2A receptor TWENTY times more than to the typical dopamine D2 receptor subtype.
        
        Levodopa is not just a precursor for manufacturing dopamine, it’s also a precursor for noradrenaline and other neural substances!
        
        Music: what exactly is the nature of a musical stimulus? It’s pretty much undefinable in the necessary level of detail, so we’re not enlightened by the findings are much as one would like.
        
        The absence of a -ve music condition could be further problematic as P might not like any of the music selected - poor definition and selection of varied music
        
        Direction of causality - stress could have caused the Da not the music
  - - - Within an fMRI procedure, stimuli were presented (various symbols) that were predictive of small vs. large monetary rewards if participants responded to a rapidly presented target stimulus quickly enough, or varying punishments if they didn’t.
      - NA activity and nearby regions
      - reward vs punishment in addition
    - - reward vs punishment in addition
        
        fMRI Nucleus accumbens activation can be clearly seen when comparing large vs. small monetary reward conditions.
        
        Anticipation of large financial reward increased signal in nucleus accumbens.
        
        0 - control level
        
        -ve numbers = punishments
        
        Increased signal change in punishment condition - Da is responsible for anticipation in general?
        
        NOTE: anticipation of possible punishment also increased signal somewhat, and to a statistically significant degree in the overlying caudate region (dorsomedial striatum).
      - Large vs. small reward – Dorsomedial striatum
        
        Dorsomedial striatal activation (caudate) also very clear, when comparing large vs. small monetary reward conditions.
        
        Anticipation of large financial reward increased signal in nucleus accumbens.
        
        similar response to punishment and reward (supports Na findings)
        
        Need a -ve stimuli condition to evaluate role of Da in NA
      - Results in a nutshell: activity in the nucleus accumbens and nearby regions increased with bigger rewards as you’d expect, but also increased somewhat to increasing punishment!
        
        Critiques
        
        We’re supposed to be focusing on the nucleus accumbens, but here the overlying dorsomedial striatum was at least as responsive to reward, and also to punishment, hmm!
        
        This indicates that the true situation is likely to be a lot more complicated that simply “it’s the nucleus accumbens”, and we’ll see some hints at least of this later in our craving seminar.
  - - - Measured dopamine release indirectly, by measuring brain levels of a radioactive dopamine receptor-specific drug, [11C]Raclopride using positron emission tomography (PET). Higher the levels of raclopride found ‘sticking’ to dopamine receptors, by inference the lower the amount of (competing) dopamine that must have been released.
      - Participants carried out a stressful task while levels of [11C]Raclopride in the brain were measured.
        
        Da competes for receptors with raclopride - increased raclopride tha disappears means that is has been removed from receptors by Da, findings more Raclopride means less dopamine was there to block the receptors
        
        decreased raclopride = increased Da
      - Applied a (mental arithmetic) stress task
        
        In the PET session, the time constraint was adjusted to be slightly above each individual’s abilities. Subjects were told that the average college student reaches 80–90% correct answers. Because of the manipulation of the difficulty level, the average performance of the tested subjects was 20–30% correct answers.
        
        Subjects were also given negative verbal feedback by the investigator for ~2 min after each 6 min session, telling them that they needed to improve their performance to reach minimum performance requirements.
        
        Control task was essentially as above, but no mental arithmetic, ‘resting’.
        
        Also measured cortisol (stress hormone) production via saliva.
      - Results
        
        Stress greatly increased dopamine release in the ventral striatum (nucleus accumbens), measured as a reduction in [11C]Raclopride Binding Potential.
        
        Changes in [11C]Raclopride Binding Potential correlated nicely with levels of stress hormone measured in saliva.
        
        Increased success = increased Da release
        
        increased Da release = increased stress
        
        Results in a nutshell: yes, an unambiguously aversive task released dopamine in the nucleus accumbens of human participants!
    - - The main measure of brain levels of [11C]Raclopride is very nice, but really it’s a very indirect measure of dopamine release. For example, just how specific is [11C]Raclopride to dopamine receptors (and which kinds?), compared with for example serotonin or noradrenergic receptors?
      - To what extent did the findings reflect subjective stress per se, by comparison with less emotional factors such as concentration, attention etc?
      - Correlational issues
        
        Raclopride as a measure of Da expression? how specific and valid is this - pretty specific but not perfect
        
        Raclopride can bind to other receptors and other molecules can bins to Da receptors - no drug is perfect
      - How do you know the stress condition changed the brain - the resting control condition does not control stress in particular, the task itself requires focus nad other cognitive abilities which sould explain Da alterations, how valid are these measures?
        
        participants - 10, 9 were male - sex differences
        
        stress is subjective - individual differences
  - - - Measured accumbens dopamine release in the nucleus accumbens of rats using fast cyclic voltammetry, which had been trained to know what to do when a footshock was applied.
      - If dopamine release simply=pleasure, one wouldn’t really expect much to happen here, would one?
      - Avoidance procedure: footshock could be avoided by pressing a lever during a 2 second presentation of a light.
    - - Large dopamine release during signal for footshock!
      - Associates light (unconditioned) with the onsoming pain triggering Da release
      - Results in a nutshell: yes, an aversive footshock released dopamine in the nucleus accumbens!
      - Critiques
        
        Well the ‘participants’ are rats for a start. Not the end of the world, but worth a note of caution.
        
        The main measure was an electrical signal, which was interpreted as indicating dopamine release. How confident can one be though that this signal really did fully reflect dopamine release?
        
        Not a measure of Da - jumped through hoops to justify signals reflecting Da release
- - - - Analysed the data from 732 heroin addicts taking part in a long-term study called the Amsterdam Cohort Study begun in 1985.
      - Looked at relapse rates following increasing numbers of prior attempts, and when also using cocaine.
      - Methadone is a weaker version of heroin - activates the same neurons with a diminished psychedelic effect
    - - First trial is the lower line
      - ½ of N relapse within two years
      - Repeat abstinence barely improves relapse rates
      - Even the highest doses of methadone were only moderately effective, regardless of the amount of cocaine concurrently used by addicts.
        
        Minor changes in relapse effects of increased methadone dosage
      - Results overall - People found it extremely difficult to stay off heroin, even when also using methadone (blocks the ‘high’ from heroin) or even cocaine.
    - - 1. Participant Bias: “Since January 2001, only young participants (≤30 years of age) enter the study, but data collection continues for those enrolled before that date. ACS participation is voluntary, and written informed consent is obtained prior to data collection…. recruited mainly from “low-threshold” methadone maintenance programs (including a weekly STD clinic for drug-using prostitutes) and by word of mouth. Follow-up involved visits every 4 months for which 12 Euros was reimbursed.”
  - - - Drug conditioning on rats
      - Could you take the addict and show them the related stimuli to drugs without the actual high to cause extinction???
      - This is context dependent extinction - move conditioned stimuli into an unconditioned context to decrease the stimulus conditioning effect
      - In second trial you might expect a continuation of the first trial but conditioned effect still exists just slightly lower - N has not forgotten the learning they did in the first place even if its diminished
      - Instead they learnt to inhibit the response a second time
  - - - Rats were trained to associate a particular kind of floor and context with cocaine (Experiment 1) or morphine (Experiment 2)
      - Then exposed repeatedly to the floor alone (extinction) either in the same drug context or a different context.
      - Preference for the drug-paired floor in the original drug context was then tested.
    - - Here are the important steps and conditions (for simplicity I’m missing out the various alternates needed to fully counterbalance the study):
      - Drug floor-context preference training (6 sessions):
        
        Cocaine + Floor A + Context A
      - Context-specific extinction:
        
        Floor A + Context A (SAME context) OR Context B (DIFFERENT context)
      - Preference test (SAME):
        
        Floor A + Context A
    - - Experiment 1 - Preference for a cocaine-paired floor could only be extinguished if extinction treatment occurred in the same environment (simplified Figure 1 from paper).
      - Experiment 2 - While extinction of preference for the morphine-paired floor was a bit more resistant than cocaine, it was still found to be as context-dependent.
      - Results overall - extinction of either cocaine- or morphine-associated place conditioning was very much context-specific.
    - - Generalisability: Rattie participants, not humans.
      - Exactly how does place preference translate to addiction per se?
      - Morphine gave them some trouble really, less straightforward than cocaine.
      - But really, this is a particularly well carried out set of studies, all obvious bases covered with counterbalancing galore. An object lesson really in how things should be carried out.
  - - - Training
        
        Ability of tone presentations in the original, Context A to initiate nosepoking again assessed.
      - Context-specific extinction
        
        AAA Group: Nosepoking during tone extinguished (no cocaine) in the same context.
        
        ABA Group: Nosepoking during tone extinguished (no cocaine) in a different context.
      - Test
        
        rats were trained to nosepoke for cocaine during tone presentations, and to withhold nosepoking in the absence of the tone, in Context A (particular floor, lighting, background noise).
    - - After subsequent extinction training with the tone, its ability to support nosepoking was only extinguished in the AAA group.
      - Results overall - just like place preference in the last study, here extinction of preparedness to work for cocaine was also context dependent.
    - - Procedure
        
        Pre-test Trial: All groups, Spider in Context A.
        
        Training (Warning: Spiders!):
        
        ‘Single Contexts’ – repeatedly exposed to a spider picture in Context A every time.
        
        ‘Multiple Contexts’ – repeatedly exposed to a spider picture in Contexts A, B or C.
        
        Controls – just exposed to a Context A without the spideriness.
        
        Test 1: Spider in Context A.
        
        Test 2: Spider in a NEW context: Context D.
        
        Would spider extinction training in multiple contexts generalise somewhat to Context D?
        
        Procedure 2: household context picture
      - Results
        
        Sweatiness - Exposure to the spider cue in multiple contexts did reduce skin conductance response when later tested in a new context.
        
        Fear - Spider cue exposure in multiple contexts also reduced fear response when later tested in a new context.
        
        Results overall - oh yes, exposure to the spider cue in a range of contexts did indeed generalise to a final, new context, so those participants who’d got used to/bored with seeing the spider in multiple contexts also showed a greatly reduced emotional response to the spider picture in a novel context too.
      - Critical Evaluation
        
        Not hugely practical as a therapeutic tool?
        
        No control group for the multiple contexts-spider group. i.e. contexts A, B and C without the spider pics. Multiple context results might be nonassociative then.
    - - Generalisability: Rattie participants, not humans.
      - But again, the procedure section is one to die for compared with a lot of studies.
  - - - Results: It certainly is! Reawakening a drug-associated set of memories a short while before extinction treatment with addicts abolished the ability of those associations to elicit craving in those addicts, apparently forever!
        
        In other words, reawakening those memories made them vulnerable for a short time to new learning (in this case, extinction) that therefore abolished in a context (temporally)-independent fashion the ability of these drug-associated cues to reestablish craving.
      - Procedure - Heroin addicts were tested under three conditions
        
        Day 1 - Baseline heroin craving cue context
        
        Day 2/3 - retrieval and extinction trial - 10m, 10m, 6hrs
        
        Day 4/34/184 - cue induced craving
      - Results
        
        Initially, abstinent heroin addicts showed a large craving response to the heroin-related cues.
        
        Activating the heroin cues 10mins before extinction training eliminated craving to the cues when tested the next day.
        
        Activating the heroin cues 10mins before extinction training eliminated craving to the cues even when tested a month later!
        
        Activating the heroin cues 10mins before extinction training eliminated craving to the cues even when tested six months later!!!
      - Critical Evluation
        
        Procedural information sparse, even when including the Supplementary Materials document. Rather a lot to be taken on trust then…
        
        Temporal context only: all testing carried out in the same environment. No idea whether these effects would generalise spatially in the manner one would anticipate being therapeutically useful.
  - - - Two levels of description and analysis are used to describe the consolidation process. Synaptic consolidation involves the activation of intracellular signaling cascades, modulation of gene expression, and synthesis of gene products that alter synaptic efficacy - this occurs within hours of initiation
        
        Systems-level consolidation refers to the reorganization of LTM over distributed brain networks.
        
        sleep optimizes the consolidation of some types of newly encoded information in memory
        
        noninvasive brain stimulation (NIBS) [20] has recently provided a powerful approach for studying brain function in humans. Indeed, transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) [20] have been used in the past few years to reveal the mechanisms underlying consolidation and reconsolidation of human memories.
        
        Combining NIBS with neuroimaging [21] through interdisciplinary efforts
        
        demonstrates that modification of previously consolidated human motor skill memories is possible, and shows that processing in primary motor cortex (M1) during memory reactivation is essential for efficient reconsolidation of the memory [24].
        
        In addition, correlated coactivations of M1 and dorsal striatum are altered following interference with a consolidated motor memory, revealing a network in which both regional activity and inter-regional functional connectivity are involved in the reactivation–reconsolidation process 22
        
        studies that used NIBS to modulate prefrontal cortex (PFC) function 25, 26, 27, and demonstrate its causal role in the reconsolidation of episodic memories
      - Animal Studies
        
        The classical interventions used to modify memory strength through reconsolidation were electroconvulsive shocks [5] and the administration of amnesic agents such as protein synthesis inhibitors [4].
        
        For instance, in a study using the auditory fear-conditioning paradigm [4], a neutral stimulus (conditioned stimulus; i.e., a tone) was paired with an aversive outcome (unconditioned stimulus; i.e., a footshock). After the memory was consolidated, the protein synthesis inhibitor anisomycin was infused into the lateral basal nucleus of the amygdala shortly after the memory for fear was reactivated by the presentation of the tone alone.
        
        In the control group, a vehicle (i.e., inactive variant of the drug) infusion was administered after the reactivation of the fear memory. Memory for fear was tested 24 h later by presenting only the tone. Immobility of the animal (freezing) was used as a measure of the retention of the fear response.
        
        The results showed that memory for fear was disrupted in the experimental group, whereas in the control group fear conditioning was still present – as well as in another control group in which the drug was infused without memory reactivation (no tone) – suggesting that indeed the reactivation rendered the fear memory unstable again.
        
        Moreover, if the drug was infused 6 h after memory reactivation, there was no effect on memory tested the following day, suggesting a limited time-window during which the memory is unstable following its reactivation
        
        intra-hippocampal infusions of the protein synthesis inhibitor anisomycin blocked hippocampus-dependent contextual fear memory, but only if the memory was reactivated before infusion [29]
        
        Existing memories can be not only weakened but also strengthened through reconsolidation. Some studies have shown memory enhancement during reconsolidation by using different pharmacological agents or modulators that affect the re-stabilization phase 30, 31. Other studies have addressed the strengthening function of reconsolidation by simply triggering this process without any treatment 28
        
        Overall, these studies indicate that memory modification through reconsolidation may include changes in memory strength. However, there is also evidence of changes in content. Existing memories can also be updated by the inclusion of new information 16, 17, 18. This approach capitalizes on reconsolidation as an update mechanism
      - Modifying Human Memories
        
        pharmacological or behavioral interventions - administering propranolol (a β-adrenergic antagonist) to understand how fear memory strength can be modified [35]. Subjects were fear-conditioned and the memory was reactivated by the presentation of a conditioned stimulus 24 h later.
        
        The authors found that the pharmacological intervention before memory reactivation disrupted the behavioral expression of the fear memory 24 h later and prevented the return of fear. Importantly, propranolol without memory reactivation, as well as the combination of a placebo pill and memory reactivation, did not alter the memory.
        
        fMRI) study found that impairments in emotional episodic memories induced by propranolol during reactivation were associated with altered amygdala and hippocampus activation [41]. Most interestingly, the same structures were active during memory reactivation, suggesting that the brain areas recruited during reactivation undergo changes in activity that are associated with subsequent changes in memory strength
        
        Conclusion: animal and human evidence reveals that reconsolidation allows changes of the memory strength or mediates updating of the memory content. The idea that memories can be updated by the inclusion of new information through reconsolidation could explain the malleable nature of memory after retrieval that has been extensively documented by cognitive psychology [65].
        
        Memory distortions, such as the misinformation effect (i.e., recall of episodic memories becomes less accurate because of post-event information) [65], illustrate that memories can be modified. Thus, reconsolidation seems to link cognitive findings in memory research with novel mechanistic insights emerging from systems and basic neuroscience [66]
    - - new strategies and tools have uncovered systems-level dynamics of human memories by modulating memory reconsolidation. This exciting new framework of understanding is leading to the development of neuromodulatory strategies for reshaping human memories in health and disease
      - strategies are geared to facilitate or inhibit target brain regions or networks, thus enabling enhancement of memory functions or downregulation of maladaptive memories (Box 2).
        
        In turn, this would enable the development of mechanism-based modulation of reconsolidation using noninvasive brain stimulation, including emerging techniques geared to entrain in a frequency-specific fashion the underlying oscillatory activity in cortical networks
        
        For this to occur, several outstanding questions remain to be addressed. There is a need to better understand the systems-level correlates of memory reconsolidation across memory modalities (Box 3).
        
        Future - a window of opportunity is opening to modulate memory reconsolidation, with the potential to facilitate neuroplasticity and learning in healthy individuals, and in patients with brain and memory disorders, as well as to mediate the forgetting of negative memories such as in post-traumatic stress disorders.
- - - - A variety of species will self-administer drugs in the absence of withdrawal symptoms.
      - Many drugs have withdrawal syndromes, but are not addictive.
      - ‘Priming’ – a small dose of drug increases, rather than reduces craving during withdrawal.
      - Relapse after a prolonged period of abstinence.
    - - Problem 1
        
        what effect does giving free shots of cocaine or stimuli associated with cocaine have on responding, ostensibly during withdrawal?
        
        Responding was then extinguished (no cocaine).
        
        On different occasions, animals were presented with the light stimulus, cocaine or the two together.
        
        Squirrel monkeys learned to self-administer cocaine, with each delivery paired with a light stimulus.
        
        Self administration phase saw massive spike in Da responses
        
        Ext, stim and priming phases saw slow increases in Da responses over time
        
        Prime and stim phase refelcts the self-admin spike in Da
      - Problem 2
        
        to what extent are the priming effects of cocaine dose-dependent?
        
        Squirrel monkeys learned to self-administer cocaine, with each delivery paired with a light stimulus.
        
        Responding was then extinguished (no cocaine).
        
        On different occasions, animals were presented with the light stimulus, cocaine or the two together.
        
        Following essentially the same training and extinction as previously, animals were presented with varying doses of cocaine plus cocaine-paired stimulus.
        
        the larger the ‘taster’ dose of cocaine, the bigger its reinstatement effect.
      - Summary Inclination to work for cocaine or cocaine-related cues grew progressively as free cocaine dose increased, i.e. not well explained by negative reinforcement (avoidance of withdrawal).
  - - - After 10 days, withdrawn from cocaine for 1, 2, 4, 7, 15, 29 or 60 days.
      - For Experiment 1, the houselight was turned on again, and the lever was inserted.
      - There were six such extinction sessions (no CS+), and the total number of responses recorded.
      - Rats lived in experimental chambers, where they could earn cocaine (0.5mg/kg/dose) during 2 x 3h sessions per day (red light on, lever inserted, 5sec tone-light CS+ with each infusion).
    - - Results the ability of a cocaine CS+ stimulus to reinstate leverpressing only grew to maximal levels once the withdrawal period was over.
    - - “Our results are consistent with clinical observations in humans and suggest that a delayed-onset craving syndrome develops or ‘incubates’ during the first 2 months of cocaine abstinence, and probably lasts for longer....
      - …develops over a period when most of the neuroadaptations that accompany withdrawal from chronic cocaine addiction are in progressive decline. The time course of this intensified drug seeking is similar to that of psychostimulant sensitization, which becomes progressively stronger with increasing abstinence for periods of up to several weeks…
      - …It suggests instead that the individual is most vulnerable to relapse at times well beyond the acute phase of drug withdrawal.”
  - - - Degree of harm induced by addiction often so severe as to be completely out of proportion to any positive subjective effects.
      - Lack of clearcut relationship between craving and relapse (see Seminar 5).
      - Effects of drugs often context-dependent (see also Volkow et al. (2008), Seminar 4).
      - Relationship between drug euphoria and addiction weak: e.g. nicotine.
    - - In short, they injected students with adrenaline without necessarily telling them, and then examined how much their subsequently strong emotions could be manipulated artificially to be very happy (or very angry – we’re ignoring this side of the study).
      - Procedure 1
        
        Injected with placebo or adrenaline (epinephrine):
        
        “In this experiment we would like to make various tests of your vision. We are particularly interested in how certain vitamin compounds and vitamin supplements affect the visual skills. In particular, we want to find out how the vitamin compound called 'Suproxin' affects your vision.
        
        What we would like to do, then, if we can get your permission, is to give you a small injection of Suproxin. The injection itself is mild and harmless; however, since some people do object to being injected we don't want to talk you into anything. Would you mind receiving a Suproxin injection?”
      - Procedure 2
        
        2 groups:
        
        Epi-Inf: informed of symptoms.
        
        Epi-Ign: simply not told anything
        
        Left for 20 minutes with stooge who performed a ‘happy’ script, while secretly observed:
        
        “…[the stooge] notices, behind a portable blackboard, a pair of hula hoops which have been covered with black tape with a few wires sticking out of the tape. He reaches for these, taking one for himself and putting the other aside but within reaching distance of the subject. The stooge tries the hula hoop, saying, "This isn't as easy as it looks.”
        
        Stooge twirls hoop wildly on arm, saying, "Hey, look at this - this is great.””
        
        Participants filled in questionnaire on emotional state.
        
        Results - Euphoria
        
        Participants were very much more influenced by the happy stooge when not told of the physiological effects of the ‘Suproxin’.
  - - - Each day, sat in front of panel: pressing the left lever illuminated a green light and started the session.
      - Every 100 presses on the right lever turned off the green light and turned on a red light for 1 second.
      - After 30 such presentations, the red light stayed on for 15mins and the nurse administered an i.m. injection.
      - Participants were told the dose of morphine in injections might change from week to week.
      - Subjective ratings were taken 1.5h after the end of each session.
    - - Drug Liking Firstly, all doses above zero supported responding in 4/5 subjects.
      - Drug strength Similarly, participants judged the lowest dose of morphine to be no different to placebo.
      - Drug value Finally, they figured the value of the lowest dose of morphine to be effectively zero too, not really that surprisingly.
  - - - In brief: mesolimbic dopamine activation is extremely rewarding and so one might suppose dopamine=pleasure.
      - BUT aversive stimuli also release dopamine. So…..
    - - BUT aversive stimuli also release dopamine. So….. we covered studies showing dopamine release actually occurs very commonly in response to stimuli associated with drug-taking and other unconditioned stimuli, which can therefore be either positive or negative in affective tone. Dopamine is released in prediction of these upcoming stimuli then.
    - - In brief: repeated stimulation of mesolimbic dopamine systems permanently increases its responsiveness to appropriate stimuli (independently of any short-term tolerance).
    - - In brief: conscious emotional experience of drugs may seem a powerful phenomenon at times, but studies show it isn’t at all important in predicting drug-taking or relapse potential.
    - - In brief: a number of studies will show that drug-seeking behaviour can occur independently of conscious awareness of the drug state, and long after any initial withdrawal symptoms. Neither affective pleasure nor withdrawal symptoms play a significant role in drug addiction then.
    - - Firstly, addiction involves the important role of dopamine in rewarded behaviour (Seminar 2) and particularly conditioning (Seminar 3) as well as other forms of learning.
      - Secondly, sensitisation of dopaminergic systems (Seminar 5) is said to enhance permanently the ‘addictive’ properties of drug-associated stimuli (incentive value).
      - Thirdly, addiction is NOT thought to depend directly on conscious emotional states such as drug craving (Seminar 4) or any subjective pleasure derived from a drug experience (e.g. Seminar 7).
      - Cure would therefore involve tackling both the learning component of addiction (Seminar 6) and the sensitisation aspect (?).
  - - - We argue that traditional negative reinforcement, positive reinforcement, and hedonic accounts of addiction are neither necessary nor sufficient to account for compulsive patterns of drug-seeking and drug-taking behavior.
      - Four major tenets of the incentive-sensitization view are discussed. These are:
        
        (1) Potentially addictive drugs share the ability to produce long-lasting adaptations in neural systems.
        
        (2) The brain systems that are changed include those normally involved in the process of incentive motivation and reward.
        
        (3) The critical neuroadaptations for addiction render these brain reward systems hypersensitive (“sensitized”) to drugs and drug-associated stimuli.
        
        (4) The brain systems that are sensitized do not mediate the pleasurable or euphoric effects of drugs (drug “liking”), but instead they mediate a subcomponent of reward we have termed incentive salience (drug “wanting”).
      - We also discuss the role that mesolimbic dopamine systems play in reward, evidence that neural sensitization happens in humans, and the implications of incentive-sensitization for the development of therapies in the treatment of addiction.