Lecture 1: Drug craving & Neural basis

Question 1

hoeveel nederlandse volwassenen drinken alcohol

Answer 1

80%

Question 2

4 redenen dat mensen alcohol en verslavende middelen gebruiken

Answer 2

• to feel good
• to feel better (anxiety/stress)
• to do better
• to explore

Question 3

from use to abuse =

Answer 3

at some point after continued repetition of voluntary drug-taking, the drug user loses the voluntary ability to control its use. at that point, the drug misuser becomes drug addicted and there is a compulsive, often overwhelming involuntary aspect to continuing drug use and to relapse after a period of abstinence.

Question 4

% substance abuse

Answer 4

17% of people in the Netherlands suffer from substance abuse at some point in their life.

(alcohol 12.2%, drugs 6.6%)

Question 5

sociodemographics of SUD

Answer 5

• younger age
• men
• living alone
• being unemployed
• high degree of urbanization

Question 6

waar is SUD niet aan gerelateerd

Answer 6

• inkomen
• afkomst (country of origin)

Question 7

individuele risico & protective factors

Answer 7

(-) early aggressive behaviour in childhood
(-) early drug use (importance of prevention!)
+ self efficacy
+ academic performance

Question 8

family risico en protective factors

Answer 8

(-) lack of parental supervision
(-) substance abuse of caregivers
(+) parental monitoring and support

Question 9

peers risico & protective factors

Answer 9

• low refusal skills
• poor social skills
  + positive relationships

Question 10

school protective & risico factoren

Answer 10

• drug availability
  + school anti-drug policies

Question 11

community protective & risico factors

Answer 11

• community poverty
  + neighbourood resources

Question 12

welke drug routes zijn het meest verslavend

Answer 12

• smoking
• injecting
• snorting
• ingestion (slow)

Question 13

personality traits that are risk factors

Answer 13

• sensation seeking
• impulsivity
• difficulty with self-regulation

Question 14

mental health issues, comorbidity =

Answer 14

• depression
• early childhood trauma
• anxiety
• adhd

Question 15

belangrijk als we het hebben over risicofactoren

Answer 15

• geen single factor kan het ontstaan van een verslaving voorspellen
• interplay tussen genetic/environment/development is belangrijk
• meer risicofactoren is meer kans dat het uit controle gaat
• hoe meer beschermende factoren hoe groter de resilience

Question 16

wat is de vicieuze cirkel in SUD

Answer 16

the negative consequences of alcohol/drug abuse maintain or worsen the abuse.

Question 17

wat is een barriere bij mensen met SUD behandelen

Answer 17

deze mensen maken het minst vaak gebruik van mental health services, vergeleken met andere mentale stoornissen

Question 18

barriers to seeking treatment for alcohol use disorder

Answer 18

1. attitudinal (ik dacht dat ik het zelf wel kon)
2. readiness for change (ik dacht dat het niet echt een probleem was)
3. stigma (te beschamend om over te praten)
4. financieel (bv als geen verzekering)
5. structural (ik wist niet waar ik heen moest)

Question 19

relapse rates SUD

Answer 19

40-60%

Question 20

3 most common triggers into relapse

Answer 20

1. returning to a 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

Question 21

societal impacts of drug abuse

Answer 21

• healthcare resources
• lost productivity
• the spread of diseases
• crime
• homelessness

Question 22

NIDA=

Answer 22

national institution of drug abuse

Question 23

wat zegt het brain disease model over drug abuse

Answer 23

addiction is a chronic, relapsing brain disease. it is similar to other chronic diseases such as diabetes, cancer, and cardiovascular diseases.

Question 24

centrale factoren in brain disease

Answer 24

• hyperactive reward system, sensitized to drug rewards (craving & habits)
• cognitive dysfunction

Question 25

genetic contribution of addiction

Answer 25

• CYP2A6 (nicotine metabolism)
• FAAH (cannabinoid regulator)
• Mu-opioid receptor (heroin)

Question 26

environmental contributions to addiction

Answer 26

• early abuse
• violence witness
• stress
• peers who use drugs
• drug availability

Question 27

critics of the brain disease model (quotes)

Answer 27

• In Addiction: a Disorder of Choice (2009), Gene Heyman describes addictive behavior as both voluntary and self-destructive. People take heroin out of choice, ultimately, and so can stop out of choice.
• Addicts are not blameless victims of some terrible illness they have no control over.
  (Theodore Dalrymple)
• Most people beat addiction by working really hard at it. If only we could say the same about medical diseases! (Marc Lewis)

Question 28

hoe kan je cravings meten

Answer 28

questionnaire on smoking urges and the obsessive compulsive drinking scale

Question 29

waar speelt dopamine een grote rol in

Answer 29

craving and reward

Question 30

studies in dieren over natural rewards en substances of abuse:

Answer 30

Microdialysis studies show that natural rewards lead to increased release of dopamine levels in the nucleus accumbens.

Substances of abuse also lead to increased dopamine release in the nucleus accumbens. But much more so than natural reinforcers!

While natural reinforcers lead to a modest increase in DA release, substances of abuse strongly increase it (above 100% baselevel). (drugs hijack the brains natural reward system)

Question 31

hoe krijg je dan craving

Answer 31

exposure to drugs and drug-associated cues -> dopamine release in nucleus accumbens -> cravings

Question 32

striatum =

Answer 32

is a small group of subcortical structures in the basal ganglia:
- caudate
- putamen
- nucleus accumbens (= ventral striatum)

Question 33

mesolimbic dopamine pathway=

Answer 33

dopamine neurons in ventral tegmental area (VTA) project to the nucleus accumbens

Question 34

structural differences in DA system between addicted individuals and controls

Answer 34

PET studies lower density of dopamine D2 receptors in addicted individuals relative to controls.

maar is dit een cause of een consequentie?

Question 35

Homeostatic account =

Answer 35

these patterns of dopamine receptors result from homeostatic compensatory brain changes after chronic drug use, in order to lower the dopamine transmission. therefore balance is established through down regulation of these d2 receptors.

dus increased dopamine activity due to the drugs leads to decrease of the dopamine receptors to establish balance again.

Question 36

waar is d2 receptor down-regulation nog meer een verklaring voor

Answer 36

• decreased (natural) reward sensitivity in addiction (anhedonia, dysphoria, natural rewards too weak)
• tolerance to the reinforcing effects of the drug

Question 37

wat liet PET scanning bij monkeys using cocaine zien

Answer 37

dat chronic cocaine use can cause D2 receptor downregulation

Question 38

argumenten voor cause en argumenten voor consequence D2 receptors decrease in drug addicts

Answer 38

cause:
- family members of drug addicts also show relatively low D2 density

consequence:
- monkeys using cocaine; chronic use lead to less receptors
- D2 receptor density can recover following a period of abstinence

Question 39

reward deficiency syndrome theory=

Answer 39

the number of D2 receptors relates to the individual differences in reward sensitivity: less receptors means lower reward sensitivity and higher vulnerability for addiction (natural rewards such as food are not sufficient)

Question 40

via welk paradigma kan je de rol van drug associated cues laten zien in relapse

Answer 40

pavlovian learning: the neutral conditioned stimulus (CS) zijn de mensen/andere cues die je doen herinneren aan de motivationally relevant unconditioned stimulus (US)

Question 41

hoe kan je pavlovian learning laten zien in studies

Answer 41

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). Gemeten met BOLD (blood-oxygenation-level-dependent) signals.

Studies have shown that this correlates with cue-induced self-reported craving.

dus drug-related cues -> nucleus accumbens activity -> craving

Question 42

pavlovian learning paradigm in detail

Answer 42

Single cell recordings in monkeys to
Pavlovian cues. Extremely thin electrodes were implanted in the animal’s midbrain (comprising the ventral tegmental area (VTA) and substantia nigra (SN)) nearby or inside DA neurons to detect action potentials (phasic dopamine activity). Pavlovian learning paradigm: Monkeys learned to predict the delivery of fruit juice (US) based on visual icons (CS).

Question 43

Resultaten studie monkeys fruit juice

Answer 43

• start of the CS-US training: burst to unexpected rewards (when the food is given)
• end of the CS-US training: burst response transfers to reward predictors (when the CS appears, which is not expected)

Neuronal firing shows bursts of heightened activity at motivationally significant events, when a reward is received unexpectedly (prediction error).
= unpredicted USs and unexpected CSs

Question 44

dus conclusie van pavlovian learning in drug use =

Answer 44

when the prediction of reward in that situation is not yet completely accurate, this leads to surprise and a reward prediction error occurs. this is encoded in the brain via the midbrain dopamine neurons. this signals to the cortico-striatal brain circuits that the current reward value does not match the expected value. therefore it functiones as a teaching signal. once the CS-US relationship has been learned, the predictve cue (VS) will evoke a dopamine response. therefore the DA neurons fire at the (unexpected) presentation of the CS, instead of the fully predicted US.

Question 45

temporal difference account =

Answer 45

the idea that because the dopamine response to the CS is stronger for drug rewards, drug-related cues and actions would continue to be reinforced to pathological levels.

Question 46

dus mesolimbic dopmaine pathway in addiction=

Answer 46

The mesolimbic dopamine pathway (Ventral Tegmental Area -> Nuceus 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).

Question 47

wat is het achterliggende mechanisme voor de vicieuze cirkel (the negative consequences of the abuse seem to worsen the abuse)

Answer 47

chronic drug use increases dopamine levels, leading to D2 receptor downregulation, which in turn leads to anhedonia and tolerance, thereby contributing to the escalation of drug use

Question 48

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

Answer 48

C

Question 49

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

Answer 49

opzoeken in schrift ahhaha, ik denk B

Question 50

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

Answer 50

A

Question 51

wat zei Berridge als kritiek op de mesolimbic suppressions

Answer 51

I believe the mesolimbic suppressions (including D2 receptor downregulation in response to excessive dopamine levels), while mechanisms of tolerance and withdrawal, are relatively temporary, more a consequence than cause of drug taking, and not the essence of addiction

Question 52

wie hebben de Incentive-sensitization theory bedacht

Answer 52

Berridge & Robinson

Question 53

incentive-sensitization theory=

Answer 53

1. Repeated substance abuse leads to a
   decrease in liking (the hedonic experience
   during consumption of the substance).
2. At the same time, however, according to I-S
   theory, (cue-triggered) “wanting” of the
   substance increases.
3. “Wanting” is defined as extreme craving
   that does not have to be experienced
   consciously, and that is triggered especially
   by drug-associated cues.

-> addiction is driven by wanting, not liking

Question 54

incentive-sensitization at the neurobiological level

Answer 54

Repeated drug use leads to changes in the mesolimbic dopamine (DA) system that plays a role in motivational and Pavlovian processes. Specifically, this system becomes sensitized (hyperreactive) to the incentive effects of drugs and drug-associated cues.

Question 55

Neural sensitization=

Answer 55

“Increase in the ability of drugs to elevate dopamine transmission in brain regions that receive dopamine inputs, such as the nucleus
accumbens”

Question 56

incentive sensitization theory at the behavioural level

Answer 56

the incentive salience of drug-associated stimuli increases in substance abuse:

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, incentive sensitization is expressed behaviourally in an increasing willingness to work for the drug.

Question 57

drug-associated cues become motivational magnets =

Answer 57

Through their association with past substance use, locations, situations, people and other stimuli may become “motivational magnets” that draw the user to them, thereby increasing the likelihood of more substance use.

Question 57

paradigm for studying “drug associated cues become motivational magnets”

Answer 57

conditioned place preference paradigm.

rats are given a drug in a distinctively designed chamber (drug-associated chamber), when later being able to choose between a neutral and the drug-associated chamber, the latter is preferred. Kan ook in humans (in real or virtual environments, met alcohol)

• Neuronal activation in the ventral tegmental area (VTA), a brain region where dopamine neurons are expressed, is necessary for the acquisition of drug CPP
• Increases in dopamine in the nucleus accumbens are correlated with drug CPP

Question 58

paradigm for studying “drug-associated cues become (conditioned) reinforcers in their own right”

Answer 58

Rats are conditioned to associate a light (CS) with getting drugs (US), as in Pavlovian conditioning. Then, the rats can choose between 2 different responses, of which one is followed by the CS light (R1) and the other is not followed by anything (R2) -> they will perform R1 more than R2.
Furthermore, conditioned reinforcement is potentiated by stimulating dopamine release in the nucleus accumbens.

Question 59

paradigm for “drugs reinstate drug seeking (relapse)”

Answer 59

conditioned reinstatement = is the ability of drug-associated cues (CS) to powerfully reinstate a previously extinguished instrumental response. For example, after a period of abstinence in a treatment center, return to the original drug-associated context may trigger relapse to the same level of drug seeking as before.
(Even increases in drug seeking have been observed in animals after a period of extinction…. Indeed, craving may increase during extinction. This is referred to as “incubation of “craving”.)

3 phases of reinstatement experiments:
1. Acquisition: the rat learns to press a lever to receive drugs and the delivery of the drug is also paired with a neutral stimulus (a light; now the CS).
2. Extinction: the rat can still press the lever but is not reinforced anymore (drugs do not follow) -> the amount of drug-seeking behavior reduces (less lever pressing).
3. Reinstatement test: during extinction (still no drugs), the CS (a light) is presented -> there is reinstatement of the drug-seeking response (pressing the lever) after this presentation.

Question 60

wat is er naast conditioned reinstatement by drug-associated cues nog meer

Answer 60

• drug reinstatement (having just 1 drink leads to a full blown relapse)
• stress reainstatement (a stressful episode at work leads to a relapse)

Question 61

dus 3 verschillende vormen van reinstatement

Answer 61

• Prime-induced reinstatement: reinstatement by the drug itself.
• Cue-induced reinstatement: reinstatement by a drug-associated CS.
• Stress-induced reinstatement: reinstatement by a stressful stimulus.

Question 62

hoe kun je die reinstatement tegengaan

Answer 62

Experimental studies into these different forms of reinstatement show that reinstatement can be prevented by systemic or local manipulation of the ventral tegmental area (VTA) and nucleus accumbens (i.e., mesolimbic pathway), thereby implicating the mesolimbic pathway in reinstatement

Question 63

human translations of the reinstatement paradigms

Answer 63

instrumental training: Response 1 is followed by a picture of a cigarette, Response 2 is followed by a picture of chocolate. smokers preferentially perform response 1

Question 64

paradigm for “motivation to work for the drug increases as a result of chronic use”

Answer 64

progressive ratio experiments

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 the break point.

Rats learn to press levers for a drug. Following each delivery of the drug, they need to press increasingly frequently to get more drugs. The primary outcome is the breakpoint à rats will work harder to get a drug when they have been pre-exposed to the drug (they reach the breakpoint later).
Breakpoint = the point at which the animal is no longer willing to press for the drug.

Question 65

Verschil wanting en liking

Answer 65

Incentive salience or ‘wanting’, a form of motivation, is generated by large and robust neural systems that include mesolimbic dopamine. By comparison, ‘liking’, or the actual pleasurable impact of reward consumption, is mediated by smaller and fragile neural systems, and is not dependent on dopamine.