Lecture 1: Drug craving & Neural basis Flashcards
hoeveel nederlandse volwassenen drinken alcohol
80%
4 redenen dat mensen alcohol en verslavende middelen gebruiken
- to feel good
- to feel better (anxiety/stress)
- to do better
- to explore
from use to abuse =
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.
% substance abuse
17% of people in the Netherlands suffer from substance abuse at some point in their life.
(alcohol 12.2%, drugs 6.6%)
sociodemographics of SUD
- younger age
- men
- living alone
- being unemployed
- high degree of urbanization
waar is SUD niet aan gerelateerd
- inkomen
- afkomst (country of origin)
individuele risico & protective factors
(-) early aggressive behaviour in childhood
(-) early drug use (importance of prevention!)
+ self efficacy
+ academic performance
family risico en protective factors
(-) lack of parental supervision
(-) substance abuse of caregivers
(+) parental monitoring and support
peers risico & protective factors
- low refusal skills
- poor social skills
+ positive relationships
school protective & risico factoren
- drug availability
+ school anti-drug policies
community protective & risico factors
- community poverty
+ neighbourood resources
welke drug routes zijn het meest verslavend
- smoking
- injecting
- snorting
- ingestion (slow)
personality traits that are risk factors
- sensation seeking
- impulsivity
- difficulty with self-regulation
mental health issues, comorbidity =
- depression
- early childhood trauma
- anxiety
- adhd
belangrijk als we het hebben over risicofactoren
- 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
wat is de vicieuze cirkel in SUD
the negative consequences of alcohol/drug abuse maintain or worsen the abuse.
wat is een barriere bij mensen met SUD behandelen
deze mensen maken het minst vaak gebruik van mental health services, vergeleken met andere mentale stoornissen
barriers to seeking treatment for alcohol use disorder
- attitudinal (ik dacht dat ik het zelf wel kon)
- readiness for change (ik dacht dat het niet echt een probleem was)
- stigma (te beschamend om over te praten)
- financieel (bv als geen verzekering)
- structural (ik wist niet waar ik heen moest)
relapse rates SUD
40-60%
3 most common triggers into relapse
- returning to a place or seeing a person associated with drug use
- stressful circumstances that trigger drug or alcohol use
- pre-existing emotional or mental health challenges
societal impacts of drug abuse
- healthcare resources
- lost productivity
- the spread of diseases
- crime
- homelessness
NIDA=
national institution of drug abuse
wat zegt het brain disease model over drug abuse
addiction is a chronic, relapsing brain disease. it is similar to other chronic diseases such as diabetes, cancer, and cardiovascular diseases.
centrale factoren in brain disease
- hyperactive reward system, sensitized to drug rewards (craving & habits)
- cognitive dysfunction
genetic contribution of addiction
- CYP2A6 (nicotine metabolism)
- FAAH (cannabinoid regulator)
- Mu-opioid receptor (heroin)
environmental contributions to addiction
- early abuse
- violence witness
- stress
- peers who use drugs
- drug availability
critics of the brain disease model (quotes)
- 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)
hoe kan je cravings meten
questionnaire on smoking urges and the obsessive compulsive drinking scale
waar speelt dopamine een grote rol in
craving and reward
studies in dieren over natural rewards en substances of abuse:
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)
hoe krijg je dan craving
exposure to drugs and drug-associated cues -> dopamine release in nucleus accumbens -> cravings
striatum =
is a small group of subcortical structures in the basal ganglia:
- caudate
- putamen
- nucleus accumbens (= ventral striatum)
mesolimbic dopamine pathway=
dopamine neurons in ventral tegmental area (VTA) project to the nucleus accumbens
structural differences in DA system between addicted individuals and controls
PET studies lower density of dopamine D2 receptors in addicted individuals relative to controls.
maar is dit een cause of een consequentie?
Homeostatic account =
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.
waar is d2 receptor down-regulation nog meer een verklaring voor
- decreased (natural) reward sensitivity in addiction (anhedonia, dysphoria, natural rewards too weak)
- tolerance to the reinforcing effects of the drug
wat liet PET scanning bij monkeys using cocaine zien
dat chronic cocaine use can cause D2 receptor downregulation
argumenten voor cause en argumenten voor consequence D2 receptors decrease in drug addicts
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
reward deficiency syndrome theory=
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)
via welk paradigma kan je de rol van drug associated cues laten zien in relapse
pavlovian learning: the neutral conditioned stimulus (CS) zijn de mensen/andere cues die je doen herinneren aan de motivationally relevant unconditioned stimulus (US)
hoe kan je pavlovian learning laten zien in studies
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
pavlovian learning paradigm in detail
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).
Resultaten studie monkeys fruit juice
- 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
dus conclusie van pavlovian learning in drug use =
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.
temporal difference account =
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.
dus mesolimbic dopmaine pathway in addiction=
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).
wat is het achterliggende mechanisme voor de vicieuze cirkel (the negative consequences of the abuse seem to worsen the abuse)
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
- 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
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
opzoeken in schrift ahhaha, ik denk B
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
wat zei Berridge als kritiek op de mesolimbic suppressions
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
wie hebben de Incentive-sensitization theory bedacht
Berridge & Robinson
incentive-sensitization theory=
- Repeated substance abuse leads to a
decrease in liking (the hedonic experience
during consumption of the substance). - At the same time, however, according to I-S
theory, (cue-triggered) “wanting” of the
substance increases. - “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
incentive-sensitization at the neurobiological level
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.
Neural sensitization=
“Increase in the ability of drugs to elevate dopamine transmission in brain regions that receive dopamine inputs, such as the nucleus
accumbens”
incentive sensitization theory at the behavioural level
the incentive salience of drug-associated stimuli increases in substance abuse:
- Drug-associated stimuli elicit attention and approach towards them (they become ‘wanted’), acting as ‘motivational magnets’.
- Drug-associated stimuli become reinforcers in their own right.
- Drug-associated stimuli (and drugs) can induce relapse
Furthermore, incentive sensitization is expressed behaviourally in an increasing willingness to work for the drug.
drug-associated cues become motivational magnets =
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.
paradigm for studying “drug associated cues become motivational magnets”
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
paradigm for studying “drug-associated cues become (conditioned) reinforcers in their own right”
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.
paradigm for “drugs reinstate drug seeking (relapse)”
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.
wat is er naast conditioned reinstatement by drug-associated cues nog meer
- drug reinstatement (having just 1 drink leads to a full blown relapse)
- stress reainstatement (a stressful episode at work leads to a relapse)
dus 3 verschillende vormen van reinstatement
- 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.
hoe kun je die reinstatement tegengaan
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
human translations of the reinstatement paradigms
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
paradigm for “motivation to work for the drug increases as a result of chronic use”
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.
Verschil wanting en liking
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.
