Module 1: Drug Craving and Neural Basis Flashcards
1. Incentive-sensitization theory 2. lecture 3. brain disease model 4. module background
1
Q
Berridge and and Robinson’s article presents an overview of the
A
incentive-sensitization theory of addiction
2
Q
What kind of drug taking behavior is categorized as addiction? (6)
A
- pathological, compulsive pattern or drug taking
- pathological, compulsive pattern of drug seeking
- an excessive time and thinking is spent on these behaviors (1&2)
- these activities and persistent thoughts persist despite adverse consequences
- difficulty cutting or controlling drug intake even when there is a desire to do so
- highly vulnerable to relapse well after withdrawal
3
Q
What is thought to be behind the transition from casual experimental drug use to addiction?
A
There has been increasing recognition that drugs themselves change the brains of susceptible individuals in complex ways
-> these changes in the brain contribute to the transition to addiction
4
Q
Changes related to the mesolimbic sensitization
A
are persistent and far outlast other changes associated with tolerance and withdrawal
5
Q
How are multiple symptoms of addiction explained?
A
Drug-induced changes in the brain alter a number of different psychological processes at the same time -> symptoms are heterogenous
6
Q
The incentive sensitization theory of addiction
A
most important psychological changes that underlie addiction is:
a persistent sensitization or hypersensitivity to the incentive motivational effects of drugs & drug-associated stimuli
–> it means that there is a bias of attentional processing towards drug-associated stimuli AND a feeling of “wanting” towards the drug itself
7
Q
the intensified “wanting” or incentive salience is partly explained by
A
Pavlovian associative mechanisms.
Addictive drug is a stimulus that 1) potently activates the mesolimbic brain system and 2) initiates neurobiological events that persistently sensitize that system
8
Q
Intensified “wanting” is not the same as intensified “liking” ?
A
This is explained by the fact that “liking” mechanisms are somewhat separable from “wanting” mechanisms, even for the same reward
+ only the “wanting” gets sensitized (aka. wanting gets more intense) so -> wanting can increase without the individual necessarily liking the drug more after repeated usage
9
Q
After sensitization of brain’s mesolimbic systems, “wanting” can be triggered by
A
- drug-associated cues
- drug-associated mental representations
- Additionally specific contexts, stimuli or mood states facilitate the expression of wanting
-> therefore the drug-induced prefrontal cortex dysfunction (aka. incentive sensitization) culminates in the core symptoms of addiction
10
Q
When measured neurobiologically, sensitization is associated with
A
Increased dopamine neurotransmission, particularly in regions that receive dopamine inputs such as the nucleus accumbens
11
Q
When measured psychologically, incentive sensitization is associated with
A
increases in “wanting” for specific rewards triggered when the individual encounters cues related to rewards
- wanting is expressed in behavioral seeking and subjective ratings of rewards
12
Q
Individual susceptibility to sensitization is determined by many factors
A
- genetic
- hormonal
- previous experiences with major stresses in life
- factors related to the drug itself (e.g., heroin induces sensitization more than nicotine)
-> once induced, the sensitization can cross over to other drugs too - Factors surrounding exposure to drugs
-> sensitization can cross over to other drugs
-> more sensitization is produced by exposure to high doses of drug than low doses
-> Repeated but intermittent use induces greater sensitization (e.g., drinking alcohol only during weekends but abstaining at other times) - speed with which drug reaches brain (related to route and administration)
-> facilitated by drug’s ability to have extended access to drugs that leads to increased intake
13
Q
Traditional withdrawal-based explanations of addiction (also called: pleasure-pain; positive-negative reinforcement; opponent processes; hedonic homeostasis; hedonic dysregulation; reward allostasis etc.)
A
Drug is taken first because its pleasant “highs” and then after repeated drug use, they are taken also to avoid the unpleasant “low” withdrawal symptoms that surface when drug use is halted
14
Q
The traditional withdrawal-based explanations of addiction is considered incomplete. What is the first problem associated with it?
A
The first problem is that withdrawal may be much less powerful at motivating drug-seeking behavior
15
Q
What kind of study was done to study this?
A
Stewart and colleagues studied “relapse” rates in rats that were previously addicted to heroin or cocaine but have been drug free for a while
- To activate the mesolimbic systems (in order to produce a resurgence of incentive salience) rats were given a small injection of the drug they were previously addicted to -> called a priming injection
- To induce a negative withdrawal state, rats were given naltrexone
-> negative withdrawal state is a negative state so it is expected that animals will try to escape from it (usually by taking drugs)
(this drug blocks opioid receptors and induces “precipitated withdrawal” symptoms in those that have recently been addicted to heroin / cocaine)
16
Q
what were the results of the study and what do results imply
A
Priming injection of cocaine or heroin was more effective at reinstating drug-seeking behavior than naltrexone administration
= incentive salience better at predicting drug-seeking behavior than withdrawal symptoms
! other studies show withdrawal to be effective if participants learn that they can escape withdrawal by taking drug
! accounts from addicts also aligns with this framework showing that craving a drug and the withdrawal of a drug are separate feelings
17
Q
What is the second problem for withdrawal theories?
A
The fact that after only a few weeks of drug abstinence, the symptoms of withdrawal dissipate and they therefore lose their ability to be a motivating factor. YET addicts relapse even after long periods of abstinence and no withdrawal symptoms
- this contradicts what the withdrawal theories propose; that drug-seeking behavior (which can persist for a long time) maintains due to withdrawal symptoms (which do NOT last for a long time)
18
Q
how do withdrawal theorists explain away the second problem? and how is this not sufficient
A
Conditioned opponent theories: associative conditioning causes drug cues to elicit conditioned tolerance and conditioned withdrawal symptoms.
- e.g., person encounters a drug-associated cue after real withdrawal symptoms are long gone and the cue elicits withdrawal symptoms as a conditioned response to the cue -> withdrawal now has come back and causes relapse
Not sufficient because: 1. cues often fail to elicit conditioned withdrawal
2. cues often elicit quite different effects (e.g., drug high or drug craving)
19
Q
how does the incentive sensitization explain the first and second problem of withdrawal theories?
A
Distinguish between mechanisms underlying “wanting” and “liking”. Repeated drug use due to “wanting” gets stronger -> thus drug-seeking behavior stronger
but “liking” is governed by a different mechanism, hence it doesn’t get affected by amount of drug taken.
It also explains the first problem: withdrawal not being enough of a reason for drug-seeking behavior after some time
-> addiction is not solely driven by the negative affect that follows cessation of drug usage
20
Q
Aberrant learning as an explanation of addiction?
A
the idea that drugs alter learning processes particularly aberrant learning, to somehow cause the transition to addiction
21
Q
Which circuitry in the brain are involved in reward learning (2) which types of cues can activate these circuits to facilitate learning processes
A
nucleus accumbens (NAcc) and dopamine-related circuitry
For example cues that PREDICT availability of a reward activate the NAcc-related circuitry sometimes better than the reward itself
22
Q
Learning accounts of addiction (approaches that label addiction as a learning disorder) posit that compulsivity arises in addiction due to
A
drugs facilitating the learning of strong automatic stimulus-response (S-R) habits
23
Q
what are some problems that arise with thinking that strongly learnt S-R habits are behind the compulsions in addiction?
A
- A pure habit is performed autonomously when one is thinking about something else
- they happen when there is no countervailing purpose to act otherwise
- in addicts its not an accurate account that they take a drug absentmindedly and then are surprised of its effects (they are usually actively conscious of the fact that they are taking a drug - No matter how many times an action is performed, repetition or “stamping” cannot by itself be a compulsion.
- e.g., we brush our teeth every day but it isn’t a compulsion
- a compulsion requires motivation like in OCD where the compulsion is motivated by a need to calm an obsession
- a regular S-R is not a compulsion - Addictive behavior is flexible, whereas the S-R habits are rigid
- addicts do what they have to do and go where they have to go in order to procure a drug
- this doesn’t fit in with the idea of S-R habits that would require you to automatically engage in the same behaviors to get a drug
24
Q
In which situations can S-R associations however be responsible for automatized habits and rituals?
A
- When consuming drugs
- Treatment with drugs facilitates the development of S-R habits in animals
- Habits are especially prominent in self-administration animal models when only a single response is available to procure a drug (e.g., pressing a lever)
25
How does the incentive sensitization interact with learning?
1. The focus on drugs in addicts is from an interaction of associative learning mechanisms (direct motivation to specific and appropriate targets) and incentive-salience mechanisms
- learning that drug is pleasant
- learning the environmental context in which drug is taken
2. Incentive sensitization sometimes "spills over" to other targets (food, sex, gambling etc)
26
Can incentive sensitization apply to other forms of addictions beyond drugs?
Overactivation of brain dopamine circuits can power excessive "wanting" to have sex, binge eat and most clearly use drugs.
But what is not known is whether sensitization-type states emerge on their own in the absence of the person having taken any drugs or medication
27
What finding supports the notion that sensitization-type states can emerge on their own?
When rats are exposed to patterns or alternating periods of dieting with periods of access to sugary treats their brains undergo changes that overlap with drug sensitization
-> hypothesis: excessive wanting might power episodes of binge eating in the same manner that environmental cues or genetic factors may (however no evidence of that to date)
28
Relation of incentive sensitization to cognitive dysfunction
impairment in executive control plays an important role in making bad choices about drugs
+ especially when combined with the pathological incentive motivation for drugs induced by incentive sensitization
29
The nature of incentive salience as a "wanting" module
Here the article argues that the "wanting" that arises from incentive sensitization is distinct from other known variants of wanting such as
- cognitive wanting
30
what is cognitive wanting and how is incentive salience "wanting" different from one another?
Cognitive wanting: declarative goals, explicit expectations of future outcomes.
Incentive salience "wanting": has causes and targets without explicit goals (except to degree that incentive salience can color cognitive desires)
31
Another way to distinguish among modules of desire / wanting
through the concept of reward utility which can be:
1. predicted utility,
- expectation of how much a reward will be liked
2. decision utility,
- what we actually decide to do (choices)
3. experienced utility
- pleasant impact of experienced reward gain
4. remembered utility
- memory of how good a previous reward was in the past
32
How is incentive salience "wanting" different from these forms of utility)? and how does this make "wanting" different from cognitive wanting?
it is a pure form of decision utility (what we actually decide to do)
in cognitive wanting, decision utility combines with predicted utility --> therefore cognitive wanting involves two forms of utility while incentive salience "wanting" is just pure decision utility
33
Incentive salience "wanting" characteristics
1. bound to percepts
2. triggered as a phasic pulse or a brief peak when cue reminders of the reward are encountered
3. doesn't require a clear cognition of what's wanted and what isn't
4. can be an unconscious experience of wanting in some cases
5. can considerably intensify feelings of desire
--> all these could be due to the fact that incentive salience is mediated chiefly by subcortical brain mechanisms while cognitive wanting requires higher cortex-based brain systems.
34
how could incentive salience have evolved as a distinct "wanting" module
for example to guide our behavior in the right direction toward appropriate rewards and cues in advance of experiencing the goals
35
how can you tell if a stimulus is attributed with incentive salience
1. the stimuli has a "motivational magnet" property
- it has the power to make ordinary stimuli especially attractive and elicits approach towards the stimuli
2. the stimulus is "wanted"
- animals and people work to get the stimulus even when you need to learn something new to acquire them (conditioned reinforcers)
3. triggers momentary peaks of intense motivation obtain the cued reward (which is presumed to follow from incentive cue)
36
Can "wanting" be compulsive?
The article presents a definition from Stephens and Graham (2009): something is only a compulsion if it is externally forced (aka. the person has no choice because of an outside force)
Yes, incentive salience "wanting" can be compulsive because its distinction from cognitive wanting allows a compulsion to come internally. The internally induced "wanting" is so strong that it overrides the cognitive wanting
- e.g., an addict may cognitively want to stop using drugs but still resort to use the drug if drug cues are dangled in the right context to elicit incentive sensitization "wanting"
37
The expression of "wanting" is a top-down process what does this mean and what implications does it have
Although "wanting" can come internally to lead to a compulsion, it can sometimes be controlled by top-down processes. This is essentially how addicts can recover.
--> it can offer a way to win many battles over compulsions; but a single loss can corrupt the dominant cognitive desire and lead to relapse
--> this illustrates one way in which it can take over compulsive properties
38
What suggestive evidence do we have for the idea that "wanting" competes with and overrides over a dominant cognitive desire without necessarily changing it
1. Animal neuroscience studies
- administration of a dopamine-blocking drug to a rat prevents the occurrence of cue-triggered "wanting" but doesn't seem to have any effect on the rat's cognitive desires
- proves that "wanting" is independent of cognitive wanting
2. Cue-triggered "wanting" is transient in nature and rests on a stable baseline of cognitive wanting
- rats receive an injection of amphetamine directly into their brain to activate increased dopamine transmission --> their brain is dopamine activated --> their dopamine activated brain wants sugar (the reward used in the experiment) at a normal level
**a hyper-"wanting" state is induced only when a reward cue is presented **
- this state goes away after the cue ends -> "wanting" is transient but strong
--> **cue triggered bursts of "wanting" do not always lead to a shift in dominant cognitive desire but rather can overlay and override the stable desire at special moments**
39
From use to abuse
1. recreational use is driven by positive effects
- escape negative feelings
- feeling energized or relaxed
2. repeated use eventually results in involuntary intake
- "drug misuser" -> "drug abuser"
- characterized by relapse after a period of abstinence
40
Risk factors
1. Familial
- lack of parental supervision
- lack of attachment to parents
- exposure to substance abuse in family
- lower socio-economic status
2. Genetic disposition
3. Individual factors
- early aggressive behavior
- personality traits: sensation seeking, impulsivity, difficulty with self-regulation
- early drug use
4. Mental health issue
- PTSD, ADHD, depression
5. Peer pressure
6. Poor academic achievement
7. Substance availability at school
8. Community poverty
41
in what phase are you more at risk for developing an addiction? what implication does this have?
during adolescence
--> drugs have a profound negative effect on the developing brain which is why prevention is better than a cure
--> during adolescence, risky behavior increases which is why it becomes that much more important to focus on prevention at this point
42
Protective factors
1. Familial
- parental monitoring
- parental support
- financial stability
2. Protective relationships
3. Skills
- refusal skills
- self-efficacy
- social skills
3. Recreational activities
4. Good academic achievement
5. School anti-drug policies and connectedness
6. Neighbourhood resources
43
For who does drug use become an addiction?
* No single factor can predict whether a certain individual will
develop substance abuse.
* The interplay between genetic, environmental, and
developmental factors influences risk for addiction.
* The more risk factors, the greater the chance that alcohol/drug
use spirals out of control.
* The more protective factors, the greater the resilience of the
individual against developing an addiction.
44
According to NEMESIS study, those with a substance abuse disorder make least use of mental health services compared to other disorders, what are barriers to seeking treatment?
1. Attitudinal
- I thought it would get better
- I thought I could handle it better
2. Readiness for change
- I thought the problem wasn't that serious
3. Stigma
4. Financial/Cost
5. Structural
- I didn't know where to go or how to get there
45
Treatment efficacy
High relapse rates (40% - 60%; NIDA) due to 3 common triggers
1. returning to a particular place or seeing a person associated with drug use
2. Stressful circumstances that trigger drug or alcohol use
3. Pre-existing emotional or mental health challenges
46
Why do we need to understand addiction better?
* Substance and alcohol abuse are prevalent...
* they have a destructive impact on individuals' wellbeing and
physical and mental health, social relationships, financial and legal status and professional functioning.
* Society as a whole pays a price for substance abuse.
– costs involved with healthcare resources,
- lost productivity,
- the spread
of diseases,
- crime, and homelessness.
* most importantly in order to improve prevention and treatment
47
Understanding addiction is complicated because
There are multiple pathways leading to recreational use and further to escalation and development of an addiction
- it is a heterogenous phenomenon
48
What do dominant theories of addiction still propose?
that there are commonly shared psychological / neurobiological processes underlying the development and maintenance of addiction
49
The brain disease model of addiction
Views addiction and the treatment of it as a disease of the brain
Core ideas:
1. Addiction is a chronic, relapsing disease
2. Addiction is a chronic relapsing BRAIN disease
3. Characterized by compulsive drug seeking and use, despite harmful consequences
50
1. Addiction is a chronic, relapsing disease
Addiction is a CHRONIC RELAPSING disease akin to other chronic diseases such as diabetes, cancer and cardiovascular disease
- they all have similar relapse rates
51
2. Addiction is a chronic, relapsing brain disease
Empirical basis shows deficits in the brains of those with drug abuse
- similar to deficits in the hearts of those with a hear disease
52
3. Characterized by compulsive drug seeking and use, despite harmful consequences
Central in the brain disease model are
* Hyperactive reward system, sensitized to drug
reward:
– Craving (literature & lecture Module 1)
– Habits (literature & lecture Module 2)
* Cognitive dysfunction (knowledge clip Module 2)
53
Addiction then is a complex disease with contributions from which factors
1. genetic
2. neurobiological
3. psychological
4. environmental
5. social
54
What effect is there in framing addiction as a disease deserving of treatment?
Calling it a disease allows to put the guilt [and stigma] aside
55
Criticisms of the brain disease model
1. Addiction: a disorder of choice (2009) Gene Heyman: people take heroin out of choice, ultimately, and so can stop out of choice
2. Theodore Dalrymple: addicts are not blameless victims of some terrible illness they have no control over
3. Marc Lewis: Most people beat addiction by working really hard at it. If only we could say the same thing about medical diseases
- addiction cannot be completely seen as a medical disease because it can be defeated with hard work whereas a medical condition cannot go away with just hard work
56
1. Which statement is false according to NIDA’s brain disease model of
addiction?
A. The brain disease model alleviates the stigma attached to addiction.
B. Addiction is characterized by compulsive drug seeking.
C. The contribution of psychological and social factors to the development of
addiction is negligible.
D. Pharmacological and behavioral interventions offer the most promising
avenues for treatment
C
57
Craving in addiction
Strong craving is common across substance use disorders, and is thought
to play an important role in relapse.
It is divided into 3 classes:
* Anticipation
- e.g., a feeling of approaching something good
* Sensory experience
- e.g., in alcohol use disorder it could be the taste of a certain brand
* Me, there and then imager y
- e.g., imagining you on the sofa with a glass of wine and this happy smile
58
Craving can be accompanied by
repetitive intrusive thoughts
- pose a further risk to recovery
59
Several self-report measures have been developed to measure craving:
E.g., the Questionnaire on Smoking Urges; and the Obsessive-Compulsive
Drinking Scale: – If you don’t drink, how much of your time is taken up by thoughts, ideas, impulses
or images related to drinking? – If you don’t drink, how much effort does it take to counter or ignore these
thoughts or to raise your thoughts elsewhere when they come to mind?
60
Craving explained neurobiologically: dopamine transmission
substances of abuse increase extracellular dopamine MUCH MORE than natural reinforces
- drugs hijack the brain's natural reward system to increase dopamine transmission in an exaggerated manner
- could explain how craving is so overwhelming in addiction
61
Evidence for this comes from Microdialysis studies that show
Normal rewards (e.g., food) lead to increased release of dopamine levels in the nucleus accumbens
- Nucleus accumbens is a dopamine input receiving system
Substances of abuse however lead to an increased release of DA in the nucleus accumbens but its much more than natural rewards
- DA release from effects of drugs increase 100% above baseline levels
62
Not only drugs themselves, but also drug-associated cues evoke a strong dopamine response
Exposure to drugs and drug-associated cues -> dopamine release in Nacc -> craving
63
Mesolimbic pathway: the brain's reward system, specifically the Striatum is a
small group of subcortical structures in the basal ganglia including:
1. Caudate
2. Putamen
3. Nucleus Accumbens / ventral striatum
! know where these are located in the brain
64
Mesolimbic dopamine pathway
Dopamine neurons in the ventral tegmental area (VTA) project to the nucleus accumbens (Nacc / ventral striatum)
65
Structural differences in the dopamine system
PET studies show lower density of dopamine (DA) D2 receptors in the striatum of addicted individuals, relative to controls
66
The first proposed reason for these structural differences in the dopamine system of addicted individuals
Homeostatic account: changes are a result of homeostatic compensatory brain changes after chronic drug use in order to lower dopamine (DA) transmission: balance is established through down regulation of D2 receptors
- in order to restore the balance following the intense increase in dopamine transmission from drugs
D2 receptor down-regulation may also underlie decreased reward sensitivity to natural rewards in addiction and to tolerance of them
- anhedonia
- dysphoria
-> natural rewards are too weak
67
with animal studies, causal relationships can be studied and they show
evidence in favor of the homeostatic account of structural changes in the dopamine system, namely:
- chronic cocaine use can indeed cause D2 receptor downregulation
68
Another piece of evidence in favor of the homeostatic account
D2 receptor density can recover (increase) following a period of abstinence
69
the second reason for these structural differences in the dopamine system of addicted individuals: Reward deficiency syndrome
Number of D2 receptors relates to INDIVIDUAL DIFFERENCES in reward sensitivity: less receptors mean lower reward sensitivity and higher vulnerability for addiction
- natural rewards such as food are not sufficient
in conclusion, there is evidence for both directions
70
The role of drug/alcohol-associated cues; relapse triggers
e.g., returning to a particular place or seeing a person associated with drug use
71
How do drug/alcohol associated cues induce craving? + example
through Pavlovian learning mechanisms
A drug example of Pavlovian learning: while drinking beer you see the label on the bottle
CS = seeing the label of beer
US = drinking beer
CR = 1) salivation, craving or 2) mental imagery / expectation of US
Cues (CS) evoke expectation and craving
72
How do we investigate the triggering of cues?
Cue reactivity fMRI studies:
1. participants are shown images of alcohol or drugs and neutral images
2. Blood-oxygenation-level-dependent signals from drug-associated cues (images) and neutral images are compared
73
# Cue reactivity fMRI studies
What do these studies show?
* When drug users are exposed to images of drugs/alcohol and
associated stimuli in cue reactivity studies, this tends to ‘activate’ quite consistently the nucleus accumbens relative to neutral images
- and next to other regions, including ventromedial prefrontal cortex/orbitofrontal cortex, dorsolateral prefrontal cortex, anterior cingulate
cortex
* Studies show that this correlates with cue-induced self-reported craving
74
What is another way to study Pavlovian learning in regards to cues?
Single cell recordings in monkeys to Pavlovian cues
Learning paradigm:
Monkeys learn to predict delivery of fruit juice (US) based on visual icons (CS)
Procedure:
extremely thin electrodes are implanted into animal's midbrain & substantia nigra nearby or inside DA neurons to detect action potentials
75
What were the results?
At the start of CS-US training there is an increase in DA release as a response to unexpected reward
! response to reward itself, not the CS
At the end of CS-US training, the DA release has transferred over to cues predicting reward
! now its the CS that is unexpected, hence response is from the CS, not US anymore
76
# Single cell recording study
Explanation of these results
1. when prediction of reward is still inaccurate (start of learning), receiving a reward is unexpected -> leads to a surprise and a reward prediction error occurs
2. midbrain dopamine neurons encode this prediction error (current reward value does not match expected value -> teaching signal)
- this is when you start learning to expect the reward as the CS-US pairing is repeated
3. Once the CS-US rleationship is learned (end of training), the predictive cue (CS) will alone evoke a dopamine response
- the new unexpected stimuli is now the presentation of the CS not the US (because the US is predicted)
77
# Single cell recording studies
If instead of fruit juice, the reward was a drug, how would the results look like?
Temporal difference (aberrant learning) account of dopamine function in addiction hypothesis:
unlike normal reinforces, drugs continue to invoke dopamine responses trial after trial even when they have been predicted (slide 53) --> continuous stimulation of the dopamine system --> aberrantly strong levels of anticipation and craving -->
78
Interim summary
* The mesolimbic dopamine pathway (Ventral Tegmental Area -> Nucleus Accumbens) plays a role in craving and is hijacked in addiction, as reflected in multiple ways in which it is affected by acute and chronic drug use (e.g., as reflected in receptor density,
extracellular DA levels NAcc, DA neuron activity midbrain, fMRI BOLD signal
NAcc).
* Some of these have been linked to genetic vulnerabilities toaddiction.
* In any case, there appears to be a vicious cycle, with chronic drug
use increasing dopamine levels, leading to dopamine D2 receptor
downregulation, which in turn leads to anhedonia and tolerance,
thereby contributing to the escalation of drug use.
79
John always snacks on crisps when he watches Netflix. Now, whenever
he turns on Netflix he crave crisps (he even salivates), and then he grabs
some crisps from the kitchen. Which description is correct?
A. CS = crisps, CR = salivating
B. CS = television, CR = salivating
C. US = crisps, CR = grabbing crisps from the kitchen
D. US = television, CR = grabbing crisps from the kitchen
B.
80
Schultz and colleagues trained monkeys on a Pavlovian conditioning paradigm and measured the activity of midbrain dopamine neurons. An icon
on a computer screen predicted that they would receive fruit juice. At the start
of the training, the monkeys did not know yet that the icon predicted fruit
juice, but by the end of training they had learned this relationship well. When did the dopamine neurons fire upon delivery of the fruit juice?
A. At the start of Pavlovian training
B. At the end of Pavlovian training
C. Never upon delivery of fruit juice
D. Throughout Pavlovian training
A. Dopamine release is strongest at the beginning of training as a response to unexpected rewards but at the end of training, the monkeys will fully expect the delivery of fruit juice by seeing the icon. Therefore dopamine neurons fire upon delivery of fruit juice only in the beginning of training when it is unexpected
81
Incentive-sensitization theory
by Kent Berridge and Terry Robinson
A pathological motivation for drugs (together with impaired cognitive control) is the core problem in addiction
82
According to I-S theory, the incentive salience of drug-associated stimuli
increases in substance abuse.
* This is expressed behaviorally most prominently in the following 3 ways:
1. Drug-associated stimuli elicit attention and approach towards them (they
become ‘wanted’), acting as ‘motivational magnets’.
2. Drug-associated stimuli become reinforcers in their own right.
3. Drug-associated stimuli (and drugs) can induce relapse.
Furthermore, an increasing willingness to work for the drug
83
pathological motivation
due to effect of repeated substance use on the mesolimbic dopamine system (including the Nacc) that plays a role in motivational processes and craving
This system becomes sensitized (hyperreactive) to the incentive effects of drugs and drug-associated cues, a process called "neural sensitization"
84
Neural sensitization
explains that
repeated drug use leads to increased
“wanting”: extreme craving that does not have to be experienced consciously, and
that is triggered especially by drug-associated cues.
At the same time, repeated substance
abuse also leads to a decrease in liking (the hedonic experience during
consumption of the substance; which is not dopamine-dependent).
Addiction is driven by “wanting”, not
liking.
85
Research on incentive sensitization according to 4 central features of incentive sensitization at the behavioral level
1. CSs become motivational magnets
2. CSs become reinforcers in their own right
3. CS (and drug) exposure lead to relapse
(reinstatement)
4. Willingness/motivation to work for the drug
increases
86
1. Drug-associated cues become motivational magnets: animal experimental model + results
Conditioned place preference:
1. Animal placed in one of 2 chambers
- in one chamber it receives no substance and in the other it receives a substance (usually ethanol)
2. Then animal gets access to both chambers
Result:
Animals that were given ethanol became conditioned to the chamber they were in
CS = chamber
US = substance / ethanol
--> substanced animals will choose to stay more in the chamber where they got the substance in (the chamber has become a drug-associated cue that motivates animals)
the same has been done in humans with similar results
87
2. Drug-associated cues become (conditioned) reinforcers in their own right: experimental model + results
Conditioned reinforcement paradigm: occurs when a stimulus (CS) has
acquired the capacity to reinforce behaviors due to its learned
association with a (drug) US
Phase 1 (Pavlovian):
Light (CS) -> drug (US)
Phase 2 (instrumental):
Response 1 = Press lever associated with light (CS)
Response 2 = Press lever associated with nothing
Results:
Rats will perform R1 more vigorously than R2
88
3. Drug-associated stimuli reinstate drug seeking (relapse): experimental model + results
Conditioned reinstatement: ability of drug-associated cues (CS) to powerfully reinstate a previously extinguished instrumental response
- e.g., when context changed (from rehab center to an environment where drug was previously taken)
1. Acquisition / initial learning phase
Animals learns that when it presses a lever, it receives a drug AND a light comes on
2. Extinction
Learns that lever press results in nothing
3. Reinstatement test (in extinction)
Drug associated cue, the light is presented out of nowhere
Results:
in extinction the animal learns that pressing the lever doesn't lead to a drug reward anymore --> they stop pressing the lever eventually
BUT
a single presentation of the CS during extinction out of nowhere immediately reinstates the drug seeking response to a high level
89
Next to conditioned reinstatement by drug-associated cues there is also:
* Drug reinstatement
– For example, just having one drink (or hit) leads to a full-blown relapse.
- Reinstatement when you are exposed to a little bit of the drug
* Stress reinstatement
– For example, a stressful episode at work leads to relapse
90
3. Drugs reinstating drug seeking responses: human studies
For example in the form of a computer task where participants work for a cigarette:
Instrumental training
R1 -> cigarette
R2 -> chocolate
then extinction
Choice reinstatement test: R1 vs. R2
Results: smokers preferentially perform response 1
91
Incubation of craving
even increases in craving doesn't go away during extinction, some studies even indicate that these cravings get stronger during periods of abstinence / extinction
92
4. Motivation to work for the drug increases as a result of chronic use: experimental model
Progressive ratio experiment: the instrumental response requirement to obtain a substance gradually increases. The maximum number of responses that the subject makes in order to receive the substance is referred to as the break point
Break point is the primary outcome variable = the point at which an animal is no longer willing to press harder for the drug
* The effort exerted and vigor to initiate lever
presses are signaled by dopamine
transmission in the Nucleus Accumbens
--> a useful paradigm to see how motivated individuals are to obtain a drug
93
Results of the progressive ratio experiments
Rats will work harder to self administer a drug (i.e, reach the breakpoint
later) when they have been pre-exposed tothis drug (e.g., Lorrain et al., 2000).
94
4. Which statement is FALSE according to the incentive-sensitization account
of addiction?
A. Drug-associated cues trigger “wanting” in addicts
B. Incentive sensitization can explain why addicts relapse even in the absence
of withdrawal symptoms.
C. When people repeatedly take drugs, this leads to an increasingly strong
hedonic experience, thereby decreasing motivation for other rewards (e.g.,
food or social interaction).
C. is false
95
5. Which task can NOT be used to study the incentive salience of drug associated cues?
A. Conditioned approach paradigm
B. Progressive ratio paradigm
C. Conditioned reinstatement paradigm
B.
96
Summary and conclusions
* According to the incentive-sensitization account, chronic drug use leads to
neural sensitization of the mesolimbic dopamine pathway and to incentive
sensitization.
* Drug CSs evoke a strong dopamine signal these stimuli become hyper-salient
and trigger aberrantly strong “wanting“ (even though liking decreases).
* Incentive sensitization can persist for years after drug use has been quitted
(and withdrawal symptoms are gone), and can thus play a role in relapse,
sometimes even after many years of abstinence.
* In fact, some research even suggests that cue-induced recovery of responding
continues to increase for weeks-months after abstinence, i.e. ‘incubation of
craving’ (e.g., Grimm, Hope, Wise, & Shaham, 2001).
* Different measurement methods can be used to study incentive
sensitization: – Pavlovian conditioned approach
– Conditioned reinforcement – Reinstatement (by CSs, drugs, and stress) – Progressive ratio experiments
* These have all been related to dopamine transmission in the mesolimbic
dopamine pathway. * At the same time, this is also a criticism of the incentive-sensitization
theory: the concept is very broad and therefore lacks specificity.
Nevertheless, it remains one of the most influential theories of addiction
97
NOTE on dopamine receptors from Berridge
Mesolimbic suppressions (low D2 receptor density) are more a consequence than a cause of drug taking, and not the essence of addiction
98
According to Leshner, the reason for a delay in gaining control over the drug abuse problem is
a gap between scientific facts and public perception
99
Additionally one major barrier to the transfer of information from scientific facts and to public perception is
Tremendous stigma attached to a drug user or an addict
- e.g., there are people who think that addicted individuals do not deserve treatment
100
According to Leshner, addiction is
a chronic, relapsing illness characterized by compulsive drug seeking and use
101
Another barrier is
Attitudes of those working in the fields of drug abuse
- most of them are previous drug addicts and they may defend a single approach extensively
102
Drug abuse and addictions as public health problems
Research indicates addiction to be a deal-edged health issue as well as social issue
Social burdens: major vector for many serious infectious diseases
- HIV, AIDS, hepatitis and tuberculosis
- violence
103
Well-delineated outreach strategies are able to
modify behavior of addicted individuals that put themselves at risk (for HIV) even if they continue to use drugs and do not want to enter treatment
-> this shows that addicted individuals are not so incapacitated by drugs to the point where they can't modify
any of their behaviors
-> it also provides the ground for public health approaches that would take into account the social nature of drug abuse
104
What matters in addiction; Our focus is on the wrong aspects of addiction like whether a drug is addicting and therefore whether its withdrawal symptoms are high
It is largely thought that the more dramatic the physical withdrawal symptoms, the more serious or dangerous a drug must be
105
What has been shown as counter evidence to this common thought
1. even intense withdrawal symptoms from heroin addiction can be managed with appropriate medicine
2. many of the most addicting and dangerous drugs do not produce severe physical symptoms upon withdrawal
- e.g., crack cocaine and methamphetamine
106
What then DOES matter in addiction
whether or not a drug causes compulsive drug seeking and use, even in the face of negative health and social consequences
- essence of addiction
--> these are characteristics that matter most to the patient and where treatment should be directed
107
Addiction is a brain disease
The addicted brain is distinctly different from the nonaddicted brain, as manifested by changes in brain metabolic activity, receptor availability, gene expression and responsiveness to environmental cues
-> addiction being tied to certain brain structure changes and functions is what makes it a brain disease
108
If we understand addiction to be a brain disease, what implications does that have for treatment
the goal must be to reverse or to compensate for the brain changes
--> either through medication (particularly antiaddiction medications) or behavioral treatments
109
Leshner also realize that addiction is not JUST a brain disease, what other factors are important
social contexts in which the addiction develops and is expressed
this is important because it was shown that soldiers addicted to heroin in Vietnam were successfully treated back in the US solely due to the lack of environmental cues that originally were associated with drug usage in Vietnam
--> the presence of conditioned drug-associated cues are a major reason for relapse and persistent drug cravings
--> not only should the underlying brain disease be treated but the behavioral and social cue components must also be addressed
110
A chronic relapsing disorder
Total abstinence is rarely easily accomplished and relapses are the norm
--> addiction must be approached as a chronic illness instead of an acute one
--> treatment outcome and most reasonable expectation is a significant decrease in drug use and long periods of abstinence with only occasional relapses
111
Substance abuse poses a burden on (5)
* quality of life
* physical health
* mental health
* social relationships
* professional functioning
112
Substance abuse and its cost to society (4)
* increased health care spending
* drug-related crime
* lost productivity
* social welfare
+ other social consequences
113
NIDA definition of addiction
a chronic, relapsing disorder, characterised by compulsive drug seeking, continued use despite harmful consequences, and long-lasting changes in the brain
114
What is an important factor that contributes to individual differences in relapse rates?
comorbidity: those with an alcohol use disorder and an anxiety disorder are at greater risk for relapse
! recently there has been evidence showing that many do recover without treatment -> high relapse rates observed in scientific literature might be due to usage of clinical samples
115
Moral model + suggested intervention
addiction is a sign of moral weakness
intervention:
- lock up ppl in prisons
- put them in re-education
! nowadays the model can be seen in societies in the form of care farms and criminal relief facilities for addicts
116
Pharmacological model + suggested interventions
the highly addictive substance is the cause of addiction, instead of the individual
intervention:
- prevent contact with these substances
117
one criticism of the pharmacological model
the model is one-sided as the availability of and use of potentially addictive substances are in themselves insufficient for the development of an addiction
118
Symptomatic model + suggested interventions
addiction is not a condition in itself but a symptom of underlying character-neurosis or personality disorder
interventions:
- long term, insight oriented psycho-therapeutic treatment of chatacter-neurosis
! still used in some psycho-therapeutic communities for addicts
119
The disease model + suggested interventions
fundamental (premorbid) biological and psychological differences exist between addicts and non-addicts, as a result of which the former are unable to use alcohol and other drugs in moderation
- main features are uncontrolled use and physical dependence (tolerance & withdrawal symptoms)
interventions:
- moderate use by addicts is impossible so complete abstinence is the only option
120
Learning theory model + suggested interventions
Addiction viewed as a form of maladaptive learned behavior that can be un-learned again (with the help of behavioral therapeutic interventions)
interventions:
- aversion therapy
- cue exposure
--> little success
121
Bio-psycho-social development model
both the onset and termination of the addiction are seen as the result of a continuous interaction between innate vulnerability (biological), personal development (psychological) and circumstances (social)
- development of "dependence syndrome"
interventions:
- multimodal interventions; interventions in which biological (psychopharmacology), psychological (psychotherapy) as well as social (including e.g. housing) aspects.
122
Brain disease model + suggested interventions
an innate vulnerability forms the indispensable basis for repeated use of psychoactive substances, while the repeated use of these substances in turn leads to important, difficult to reverse, changes in the brain
interventions:
- pharmacological and behavioral therapeutic interventions
123
one risk regarding the brain disease model
whether such a neurobiological perspective comes at the expense of analyses on the environmental, social and societal factors in addiction
124
the complex systems model: a new promising approach
biological/psychological/social factors play a role in addiction in a dynamic fashion, with the resistance to change depending upon the relationship between different relevant factors, that will be unique for each individual
125
types of substances (3) +what do they all have in common
* sedatives
- make you calm and relaxed
- opium, heroine, morphine
* stimulants
- make you feel energized
- caffeine, nicotine, cocaine
* psychedelics
- alter your state of consciousness and perception of the world around you
- cannabis, extasy, LSD
all have in common: directly or indirectly result in a release of dopamine in the NAcc (important role in their addictive effect)
126
People with addiction have been shown to be less sensitive to __. What implication does this have?
rewards
According to the reward deficiency syndrome (RDS) account, these people may look for stronger stimuli to compensate this, such as through the use of drugs (or perhaps also gambling or eating extra sweet/fatty food) --> it is therefore a vulnerability factor
--> they have a lower D2 receptor density --> are less sensitive to natural rewards --> need more to feel rewarded
127
Drug abuse can create a risk for a (fatal) overdose, how
due to tolerance that may develop with repeated drug use --> you keep taking more and more of the drug to feel the same effects
128
withdrawal symptoms also occur, they consist of
* anxiety
* irritability
* malaise
* dysphoria
* hyperkatifeia (hypersensitivity to emotional distress)
* alexithymia (inability to express one's feelings)
* a feeling that everything is gray
