Week 10-Addiction

Question 1

What is addiction?

Answer 1

-Not been used as an ‘official’ diagnosis for decades

Official diagnostic labels are currently:
-‘(substance) use disorder’ (e.g., ‘alcohol use disorder’) (DSM-V)
-‘Harmful use’ and ‘dependence syndrome’ (ICD-10)

‘Addiction’ fell out of favour because it is pejorative (implies a character weakness or a moral failure) and because (at one time) it was thought to be tied to heroin addiction rather than other types.

‘Dependence’ was dropped for DSM 5 because it is associated with physical adaptations (tolerance and withdrawal), and these may not actually be that important!

Question 2

What are SUDs?

Answer 2

Often described as a chronically relapsing disorder characterised by:
-Compulsion to seek and take substance

-Loss of control limiting intake

-Emergence of a negative emotion state when access to substance is prevented (e.g., withdrawal)

Question 3

What are the 3 main characteristics of compulsion in AUD?

Answer 3

1. A great deal of time is spent in activities necessary to obtain alcohol, use alcohol or recover from its effects
2. Craving, or a strong desire or urge to use alcohol
3. Continued alcohol use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of alcohol

Question 4

What are the 3 main characteristics of loss of control in AUD?

Answer 4

1. There is a persistent desire or unsuccessful efforts to cut down or control alcohol use
2. Recurrent alcohol use in situations in which it is physically hazardous
3. Alcohol use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been cause or exacerbated by alcohol

Question 5

What is the main characteristic of a negative emotional state in AUD?

Answer 5

Withdrawal as manifested by either of the following: a) The characteristic withdrawal syndrome for alcohol; b) Alcohol (or a closely related substance, such as a benzodiazepine) is taken to relieve or avoid withdrawal symptoms

Question 6

What pattern does the development of an AUD/SUD typically follow?

Answer 6

1. Experimental drug use
2. Casual drug use
3. Heavy drug use (abuse/misuse)
4. Compulsive drug use (dependence)

=AUD/SUD

Question 7

What is the Prevalence and impact of AUDs/SUDs?

Answer 7

-AUD/SUDs are one of the largest contributers to the global burden of mortality and premature death

-Also a high economic burden

-Importantly, they are preventable (i.e., non-communicable disease)

-Disability Adjusted Life Years (DALYs): The sum of years of potential life lost due to premature mortality and the years of productive life lost due to disability

Question 8

What’s the Global Prevalence of alcohol use?

Answer 8

-Approx. 18.4% of the population (39.6% of the drinking population) report heavy drinking (bingeing)

-DALYS: 85m

-Cirrhosis, traffic accidents, cancers

-Peacock et al. (2018)

Question 9

What’s the Global Prevalence of illicit substance use? (Peacock et al., 2018)

Answer 9

-Cannabis 3.8%

-Amphetamine 0.77%

-Opioids 0.37%

-Cocaine 0.35%

-Injecting drugs 0.25%

-DALYS: 27.8m

-Cirrhosis, HIV, liver cancer

-Harms and prevalence etc., are much more difficult to keep track of when drug use is unsanctioned

Question 10

What’s the Global Prevalence of Tobacco use? (Peacock et al., 2018)

Answer 10

-15.2% of the adult population smoke daily (approx. 933.1 million people)

-DALYS: 170.9m

-Cancers, chronic respiratory disease, chronic obstructive pulmonary disease

Question 11

How is Prevalence use different in countries?

Answer 11

-Countries with predominantly Muslim populations: lower rates of alcohol problems, higher rates of tobacco smoking

-Tobacco smoking is declining in Western countries but increasing in developing countries

-Other regional trends e.g., methamphetamine in some states of the USA

Question 12

What are the Prevalence use trends over time in the UK?

Answer 12

-Rates of smoking are declining (taxation and the smoking ban have helped)

-The number of people who drink alcohol has declined, but among drinkers the number of people who drink too much has increased (pricing and availability probably played a role again)

-New drugs become fashionable (e.g., mephedrone), others fall out of favour (e.g., ectasy)

-E-cigarettes seemed to come out of nowhere and have divided opinion

Question 13

How is drug use a cost-benefit analysis? (West, 2006)

Answer 13

Historical account: Moral failure, lack of willpower or a weakness of self

Benefits:
-Pleasurable high
-Increased alertness
-Social aspects

Costs:
-Hangover
-Illness
-Death

Question 14

What are the consequences of a ‘free’ choice model?

Answer 14

-Addicts are stigmatised (but there’s also negatives of the BDM view!)

-Funding and research is unnecessary - a punitive response to the problem is required (but there’s also negatives to the BDM view!)

-Doesn’t really account for the preference shift in addiction (but the BDM also doesn’t account for incentives!) incentives=motivation

Question 15

The opposing view: What are the key claims that addiction is a disease? (Leshner)

Answer 15

-All drugs of abuse affect (directly or indirectly) a pathway deep within the brain

-Both acute and prolonged drug use causes pervasive changes in brain structure and function that persist long after the individual stops taking the drug. The ‘addicted’ brain is different than the non-addicted brain in terms of structure and function (True, but with caveats)

-‘A metaphorical switch in the brain seems to be thrown as a result of prolonged use’ (Leshner, 1997) That addiction is tied to changes in brain structure and function is what makes it, fundamentally, a disease.’ (Murky at best - everything changes the brain!)

Implications: We shouldn’t marginalise those with an A/SUD, but rather we should be trying to treat them. Similarly, incarcerating individuals won’t work

Question 16

What is the “Reward” systems in the brain?

Answer 16

-Mesolimbic dopamine systems: the ventral tegmental area and areas that project to and from it

-All drugs of abuse stimulate dopamine release in the mesolimbic system (directly or indirectly) (Nestler et al., 2005)

-Also stimulated by food, sex, warmth, and other “natural” rewards

Question 17

What are the key steps in synaptic transmission?

Answer 17

Background
-The key steps in fast synaptic transmission. An action potential, initiated at the axon hillock of the presynaptic cell, propagates to, and depolarizes the presynaptic terminal.

-Voltage-gated calcium channels in the presynaptic terminal are activated by this depolarizing wave, allowing a rapid and localized increase in calcium at the active zone.

-This increase in calcium results in the rapid fusion of neurotransmitter-filled vesicles to the presynaptic membrane which then release their contents via exocytosis.

-The neurotransmitter molecules diffuse across the synaptic cleft where they bind to ligand-gated ion channels which gate the influx of ions into the postsynaptic dendritic bouton.

-This influx of ions generates an excitatory or inhibitory postsynaptic potential depending on whether the channels are excitatory (glutamatergic) or inhibitory (GABAergic).

-The neurotransmitter molecules are then taken back up into the presynaptic terminal by active mechanisms.

-This entire process, from the initiation of the action potential in the presynaptic terminal to the generation of a postsynaptic potential, takes only a couple of milliseconds.

References:
-Kandel et al (2000)

-Squire et al (2003).

-Lisman et al (2007).

Question 18

What did Ikemoto, McBride, Murphy, Lumeng & Li (1997) find with 6-OHDA lesions in the Nucleus Accumbens for the brain disease model?

Answer 18

-Rats will self-administer most directly into Nucleus accumbens (NAcc) and have it drip fed or electrically stimulated (area of incentive salience)

-Rat self-administration model is a valuable tool for assessing abuse potential/liability (can grade substances on a curve to see what they prefer and what they’ll do to achieve it (O’Connor, 2011)

-If the NAcc is destroyed, rats will reduce self-administration

Question 19

How did Lepore et al. (1995) find when testing conditioned place preferences in rats?

Answer 19

A rat experiences a drug in environment A and nothing in B. In a drug-free state the rat will choose to spend time in environment A.

-Administered a lesion in NAcc

-External cues may play a role in craving and rats seemed to prefer the hue environment where they had the drug

-Can be seen in humans with external cues such as advertising and environment e.g., shops and pubs (treatment involves avoiding these areas to avoid engagement of drinking/drug use)

-Rats take a while to like drugs (like humans)

Question 20

Is dopamine linked to reward?

Answer 20

-It’s an oversimplistic view

-This is because has a multitude of functions in the body e.g., in the retina, kidney, gut, heart etc., (Klein, Battagello, Cardoso, Hauser, Bittencourt & Correa, (2019)

-Does a lot of stuff related to addiction and reward-related behaviours that aren’t just reward in itself

-fMRI study found activation in orbitofrontal cortex related to motivation and drive in response to high value rewards (abstract monetary rewards they wouldn’t actually get) (Duckworth, Wright, Christiansen, Rose, & Fallon, (2022).

-Dopamine activity is high

Basal ganglia dopamine is controlling:
-Pavlovian conditioning
-Eye movements
-Habit formation
-Reward learning

Essentially, dopamine does not equal reward

It has many functions

Other neurotransmitters are also important (glutamate, GABA, etc).

Question 21

What’s the Incentive Sensitisation Theory? (Robinson & Berridge, 2008)

Answer 21

-Repeated drug administration = sensitisation

-Brain mesolimbic dopamine system becomes ‘hyper-responsive’ to the drug (Not hyperactive, hyper(RE)active)

-Sensitisation = drug effects increase over repeated use (opposite of tolerance)

HOWEVER, not everything is sensitised just:
1. Psychomotor effects (e.g., blinking, vigour)
2. Incentive motivational effects (incentive salience)

-Robinson & Berridge argue that the most important psychological change is ‘sensitisation’ (i.e., hypersensitivity) to the incentive motivational effects of drugs and drug-associated stimuli

Question 22

What is incentive salience? (Robinson & Berridge 1993, 2003)

Answer 22

-Repeated drug use leads to a sensitised (increasing) spike in DA activity in the mesolimbic pathway

-Importantly, this is not only seen when the drug is ingested but ALSO when they are exposed to drug related cues (Pavlovian conditioning)

-Exaggerated dopamine manifests as incentive salience. Drug cues have strong motivational properties

-Exposure to drug-related cues increase wanting

Question 23

What’s the paradox with the incentive sensitisation theory?

Answer 23

-As incentive sensitisation develops, drugs are wanted more but liked less

-Although to begin with most drugs produce positive effects (e.g., euphoria) which can maintain drug use, over time these effects seem to decrease (as addiction develops - tolerance)

-The incentive sensitisation theory: repeated drug use sensitises the neural systems that mediate the motivational process of incentive salience (wanting), but NOT the neural systems that mediate the pleasurable effects of drugs (liking)

-Therefore, drugs will be wanted more but liked less over time (This is difficult for the free choice model to explain!)

Question 24

State the paradox

Answer 24

-Individuals who are dependent on drugs often report that they ‘want’ drugs but no longer ‘like’ them

-Think back to the DSM 5 criteria - Craving, strong urges, despite wanting to cut down, no longer finding the drug appealing (helped inform criteria)

-The incentive salience model therefore has considerable intuitive appeal

Question 25

What experiments did Hobbs et al (2005) do to find the difference between ‘wanting’ and ‘liking’?

Answer 25

Experiment 1: Separated individuals into heavy and light drinkers and examined liking ratings of a variety of drinks (alcoholic and non-alcoholic)

-No interaction between drinking status and type of drink on liking

Experiment 2: Manipulated ‘wanting’ by a small priming dose of alcohol

-Again, no changes in liking for the alcohol but an increase in wanting

Question 26

How can withdrawal and relapse occur in the incentive sensitisation theory?

Answer 26

-The sensitisation process lasts a long time (longer than tolerance or physical withdrawal)

-Even after the negative effects of withdrawal have diminished, the brain’s neural system underlying ‘wanting’ is sensitised

-This long-term sensitisation results in enhance, long-term risk of relapse

-For example, if the circumstances are right, relapse may be likely even after years of abstinence

-Sensitisation is a long-term adaptation. Remember addiction is a ‘chronic relapsing disorder’ IS can help to explain this

Question 27

What is Robinson & Berridge’s theory based on?

Answer 27

-Based on incentive sensitisation (core principle)

-However, the theory acknowledges that drugs do have other effects (e.g., cognitive impairments)

(Why you should read their later papers/reviews especially 2008, 2016)

Question 28

What is the interaction between IST & Learning?

Answer 28

-We focus on drugs because of an interaction between incentive salience and associative learning mechanisms which usually directs our motivation to appropriate targets e.g., food/sex

-Although learning processes identify the stimulus of interest, it is sensitisation of brain circuits that mediate classical conditioned incentive motivational processes i.e., incentive sensitisation) that results in pathological drug-related motivation

Question 29

IST & Learning: Why are Associative learning processes important?

Answer 29

-They can determine where, when and how sensitised behaviour is expressed

-This helps explain why pathological drug behaviour can be restricted to certain environments (i.e., those that have been previously associated with drug taking)

-So there is contextual control over the expression of sensitisation and this stems from associative learning

-Null research findings may be due to absence of CSs (Vezini & Leyton, 2009)

Question 30

What is the interaction between IST & Cognitive dysfunction?

Answer 30

-Drug addicts show significant cognitive impairment; executive function, decision making, inhibitory control etc., are all affected (via adaptations to prefrontal cortex)

-Incentive sensitisation theory: impairment of executive function has an important role in addiction, esp. the bad choices about drugs. Combine this with the pathological incentive motivation for drugs (via incentive sensitisation) and the result is addictive behaviour.

Question 31

How is chronic drug use is associated with volumetric loss of frontal lobes?

Answer 31

-Neurotoxicity: Structural loss/DA loss

-Cocaine

-Alcohol

-Heroin

-Methamphetamine

Question 32

What’s the Summary for IST?

Answer 32

-Naturally, the brain directs animals to stimuli that holds incentive salience that is can help survival (e.g., food, water, sex) Drugs hijack this system so that the brain system attends to substance cues rather than natural reward cues rather than natural reward cues

-The activation of neural structures which supports wanting (incentive salience) persists, increasing the risk of relapse

-Wanting and liking are served by different neural systems. Drug wanting increases while drug liking can decrease

-Other cognitive mechanisms such as associative learning and cognitive dysfunction, interact with sensitisation to produce addiction

-First model to account for the disassociation between wanting and liking

Question 33

What is a drug addiction characterised by? Koob & Volkow (2010)

Answer 33

Chronically relapsing disorder characterised by:
-Compulsion to seek and take the drug
-Loss of control in limiting intake
-A negative emotional state reflecting a motivational withdrawal syndrome access to the drug is prevented

Question 34

What are the 3 stages of an Addiction Pathway?

Answer 34

1. Binge/intoxication
2. Withdrawal/negative affect
3. Preoccupation/anticipation

Question 35

What is the development from recreational to dependent use due to?

Answer 35

-Due to brain adaptations as with most brain models, lots of research from animal models. For example, animal models can be used to represent the withdrawal/negative affect stage of Koob et al’s (2009) addiction cycle

-Conditioned place aversion (animals avoid environments paired with withdrawal)

-Increased motivation for self-administration in dependent animals (animals are motivated to take drugs to remove withdrawal state)

-Anxiety-like responses (e.g., freezing, burying)

Question 36

When are impulsivity and compulsivity important?

Answer 36

-Impulsivity tend to be more important in early stages

-Both impulsivity and compulsivity are important in later stages

Question 37

What’s Impulsivity? (Koob & Volkow, 2010

Answer 37

-Behavioural disposition for fast, unplanned actions triggered by ext/int stimuli with no regard to potential negative consequences, impulsivity is a core deficit in SUD

Measured: 1) choice of small immediate over large delayed reward 2) Inability to inhibit behaviour by changing or stopping a behaviour once initiated (i.e., response inhibition)

Question 38

What’s Compulsivity? (Koob & Volkow, 2010)

Answer 38

Persevere in responding despite adverse consequences and incorrect responding in choice situations. Persistent reinstatement of habit-like acts, DSM-V: persistent use despite knowledge of negative physical/psychological problems; lots of time spent in activities trying to obtain this substance.

Question 39

Define Addicition

Answer 39

A cycle of spiralling dysregulation of brain reward/anti-reward mechanisms that progressively increases, resulting in the compulsive use of drugs

Question 40

What does counter adaptations/opponent processes do?

Answer 40

Increases activation thresholds and allostatic processes attempt to adapt to the new ‘brain environment’ (i.e., a brain with drugs in) - change in set-points

When drugs are stopped, the counter adaptations are perceived as withdrawal (-rein)

Question 41

What does sensitisation do to the reward threshold?

Answer 41

Reduces it making it easier to activate. Drugs will become highly rewarding and the drug and cues will be strong incentives (+rein). But this has disrupted homeostasis, so the brain triggers counter adaptation.

Question 42

What does brain adaptation fuel?

Answer 42

Fuels addiction. Adaptations in different brain regions occur at different times. Hence shifts from +rein (impulsivity) to -rein (compulsivity)

Question 43

What does repeated drug use lead to?

Answer 43

Leads to repeated spikes in dopamine activity which eventually leads to long-term suppression of dopamine function. Key point of this theory is that dopamine is involved in mood regulation, not just salience attribution

Question 44

What are the states of the opponent processes?

Answer 44

State A: the emotional or affective state caused by the drug

State B: an opponent process opposite to A. ‘After addiction’ – if you take the same amount of the drug, you get none of the high (or at least very little of it), but still experience the opponent process (withdrawal)

Question 45

What’s Hedonic Homeostatic Dysregulation? (Koob & Le Moal, 1997)

Answer 45

-Both sensitisation and opponent-processes contribute to ‘hedonic homeostatic dysregulation’: dysregulation of brain reward (DA) that gets progressively out of control

-Sensitisation occurs in the early stages of addiction and causes increased liking for drugs (results in binging). Represents a break from homeostasis.

-Counteradaptation (e.g., opponent-processes) occur in the latter stages to produce withdrawal and negative effect

Question 46

What did Koob find with allostasis?

Answer 46

-The brain works to maintain homeostasis. Counter adaptation is one mechanism of maintaining homeostatic regulation

-Over prolonged drug use, the brain tries to adapt and counter adaptations / opponent processes alter set-points

-Deviation from normal brain-reward threshold regulation is described as an allostatic state

-Allostasis: stability through change

-Allostasis is more complex than homeostasis and it results in changes to reward mechanisms in an attempt to achieve stability

Question 47

What occurs after the brain tries to respond to the continued presence and effects of drugs altering the set-points (so drugged brain is ‘normal’)?

Answer 47

-Sensitisation and counteradaptation processes cause further attempts to maintain mood at this new set point (allostasis) > but with increasing drug use, it becomes more difficult to maintain this set point

-At some point, allostasis breaks down and the individual cannot maintain a set-point > ‘spiralling distress’, or mood disturbance

Hedonic homeostatic dysregulation drives dependent drug use

IST = incentive salience drives addiction

HHD = Opponent processes (withdrawal) drives addiction

Question 48

What are 4 key points about Hedonic homeostatic dysregulation?

Answer 48

1. Hedonic homeostatic dysregulation drives dependent drug use
2. HHD is a negative emotional state which is apparent when drug use is prevented (which creates craving etc.,)
3. HHD is a result of a combination of decreased reward system function and increased brain stress response, system function
4. HHD lasts a long time (into protracted withdrawal), therefore there is a residual negative state which is an ongoing relapse risk

Question 49

Brain adaptations: What 5 circuits did Koob identify which change as addiction progresses? Koob & Volkow (2010); Everitt & Wolf (2002)

Answer 49

1. Mesolimbic dopamine system (incentive salience and reward)
2. Ventral striatum (increase in DA activates the VS)
3. Ventral striatum / dorsal striatum / thalamus circuits (activitu shifts from ventral to dorsal striatum (fMRI). Corresponds with drug use going from acute/goal-directed to chronic/habitual)
4. Prefrontal cortex / hippocampus circuits (impaired executive function, poor decision making e.g., choose reward now [drug] rather than longer term reward)
5. Extended amygdala (stress system activated, leads to a negative states which drives use of natural reinforcers)

Question 50

What evidence is there for Brain model and treatments?

Answer 50

-Pharmacological strategies that target specific clinical components of addiction are developing. These may target alcohol/substance-induced euphoria (e.g. naltrexone), hedonic dysregulation, cue- or stress-induced craving (e.g. acamprosate??) etc.

-For instance, naltrexone may work by reducing opiate and alcohol-induced reward, modafinil may reduce cocaine-induced euphoria (e.g. Anton (2008) Naltrexone for the Management of Alcohol Dependence)

-Research suggests vaccines may be possible which blocks the drug entering the brain (e.g. Kosten (2005) Future of anti-addiction vaccines)

-Disulfiram disrupts the metabolism of alcohol to induce sickness, so people avoid drinking (serious side effects, including death can occur if a person persists in drinking heavily/regularly on disulfiram) (e.g. Skinner (2014) Disulfiram Efficacy in the Treatment of Alcohol Dependence: A Meta-Analysis)

-Naltrexone = opiate receptor antagonists; alcohol releases opioids, and naltrexone blocks the receptors which opioids want to attach to. This reduces the please produced by alcohol (by blocking endogenous opioid transmission).

-Acamprosate is less well understood

-There have been fatalities from disulfiram

Question 51

What are the consequences of a disease model?

Answer 51

-Led to over investment: 41% of addiction funding is for basic neuroscience; additional 17% developing ‘biological cures’.

-But are we any closer to really understanding and treating addiction?

-A good theory of alcohol/substance use should be able to inform development of treatments.

-The disease model has supported development of new pharmacotherapies BUT few new drugs have been developed based on neurobiology.

The most widely used drugs in addiction:
-Methadone Replacement Therapy
-Nicotine Replacement Therapy

What about spontaneous remission / unassisted recovery?
Recovery is a social process – we change our identity, we become empowered.

-It’s argued to have helped reduce stigmatization of ‘addicts’(but see Buchman et al (2010) The Paradox of Addiction. Neuroethics DOI 10.1007/s12152-010-9079-z)