Addiction

Question 1

What is the general definition of addiction?

Answer 1

From Latin meaning “bound to” or “enslaved by”; historically not substance-specific.

Question 2

What is the DSM-5 definition of addiction?

Answer 2

‘Substance use disorder’ with severity based on symptom count (2+ mild, 4+ moderate, 6+ severe).

Question 3

What are the shared features of addiction across definitions?

Answer 3

Continued behaviour despite harm, diminished control, and appetitive urge or craving.

Question 4

How does neuroscience define addiction?

Answer 4

A condition of motivated behaviour gone awry.

Question 5

What is the Incentive Salience Theory of addiction?

Answer 5

Drugs increase midbrain dopamine, making cues ‘wanted’ via incentive salience. ‘Wanting’ becomes hypersensitive, not ‘liking’. Related to Rescorla-Wagner learning and overshadowing.

Question 6

What is Reward Deficiency Syndrome?

Answer 6

Suggests individuals can’t gain pleasure from natural rewards, seek intense/pure rewards like drugs. Linked to D2 receptor mutations.

Question 7

What is the Allostasis Theory of addiction?

Answer 7

Drug use changes reward set point (normally a homeostatic set point) via synaptic plasticity, leading to persistent altered reward processing and reduced D2 striatal receptors.

Question 8

What is the Habit Theory of addiction?

Answer 8

Behaviour transitions from voluntary/goal-directed to compulsive/habitual. Neural control shifts from dorsomedial to dorsolateral striatum. Decision making moves from RPE to APE.

Question 9

How do historical addiction theories synthesize?

Answer 9

Overvaluation of the drug (Incentive Salience) leads to persistent neuroadaptation (Allostasis), followed by habitual APE-driven behaviour (Habit Theory), collectively describing motivated behaviour gone awry.

Question 10

What role does dopamine play in addiction?

Answer 10

Drives learning and acquisition (RW and TD learning), and salience (‘wanting’). Dopamine increase is a common endpoint of drugs, though mechanisms differ. Shifts from goal-directed (DMS) to habitual (DLS/TS) behaviour.

Question 11

What are the different primary pharmacological mechanisms by which drugs achieve dopamine increase?

Answer 11

Cocaine/amphetamine: Dopamine reuptake inhibitors.
Nicotine: Directly depolarises and activates dopamine neurons (via excitatory nAchRs).
Alcohol: Influences GABA signalling, causing dopamine release in the NAc (removes GABAergic inhibition).
Opioids: Inhibit VTA GABA interneurons and indirectly activate dopamine neurons (disinhibition).

Question 12

What are the two key dopamine pathways in addiction?

Answer 12

Mesocorticolimbic (VTA to NAc, limbic, cortex) for encoding rewards. Nigrostriatal (SN to dorsal striatum) for habit and movement.

Question 13

What is the function of the nucleus accumbens (NAc)?

Answer 13

Ventral striatum region involved in reward/reinforcement; early drug control; integrates model-free and model-based RL.

Question 14

How does the striatum contribute to addiction?

Answer 14

Ventral striatum handles early reward; Dorsomedial supports goal-directed actions; Dorsolateral supports habitual responses; TS important for sensory learning and action initiation.

Question 15

What is the prefrontal cortex’s role in addiction?

Answer 15

Involved in ‘higher cognitive areas’ like state inference, regulating behaviour, thought, and emotion; impaired by stress. PFC/OFC balance affects goal-directed vs habitual control. Involved in compulsive behaviour/craving in later addiction phases.

Question 16

How does the amygdala contribute to addiction?

Answer 16

Generates emotional responses and habits; stress enhances amygdala function, impairs PFC control and strengthens fear conditioning. Biases towards habitual motor response.

Question 17

What learning models are relevant in addiction?

Answer 17

Rescorla-Wagner (prediction errors), Temporal Difference (delayed outcomes), Q-learning (action values), goal-directed (RPE) and habitual behaviour (APE) models.

Question 18

What is the difference between RPE and APE?

Answer 18

RPE: Difference between expected and received rewards (dopamine-driven); drives goal-directed behaviour (DMS). APE: Difference between expected and taken actions; drives habits (DLS, TS).

Question 19

What is state inference and its role in addiction?

Answer 19

Inferring context to guide behaviour; affects prediction errors. Impairments contribute to relapse; involves ACh signalling.

Question 20

What are the three pharmacological treatment phases for addiction?

Answer 20

(1) Acute Acquisition: Prevent initial use. (2) Initial Detox: Safe, sustained abstinence. (3) Recovery: Prevent relapse, resisting craving; most difficult to treat.

Question 21

What is the major challenge in drug treatment right now?

Answer 21

Lacking effective pharmacology for phase 3. The compulsive behaviour, relapse, and craving in Phase 3 are likely not solely under dopaminergic control and are likely regulated by higher-order cortical circuits.

Question 22

Why are psychedelics of interest in addiction treatment?

Answer 22

May target cortical circuits, promote synaptic plasticity, and enhance top-down control. Often used with behavioural therapy.

Question 23

What are common animal models of addiction?

Answer 23

Non-contingent exposure, self-administration (FR, PR), incubation of craving, DSM-compatible 0/3 model.

Question 24

What is the Non-contingent exposure model?

Answer 24

Experimenter administers the drug (e.g., IP injection). Measures things like locomotion increase (sensitisation) or conditioned place preference.

Question 25

What are the benefits and caveats of the Non-Contingent Exposure model?

Answer 25

Benefits: High throughput, feasible for complex investigations. Caveats: Skips key behaviours like seeking, motivation, working for reward. Unlikely to model compulsive behaviour.

Question 26

What is the Self-Administration/Contigent exposure model?

Answer 26

Rodent works (e.g., lever press, nose poke) to receive the drug (usually I.V. via catheter). Models the acquisition of drug taking.

Question 27

What are the FR and PR measures in the Self-Administration model?

Answer 27

Fixed Ratio (FR): Drug given after a fixed number of actions. Measures motivation to get drug. Progressive Ratio (PR): Required actions per drug delivery increase progressively. Used to measure breakpoint (maximum drive).

Question 28

What are the benefits and caveats of the Non-Contingent model?

Answer 28

Benefits: Models aspects like working, approaching, goal-directed behaviour. Allows identifying causal risk factors (stress, impulsivity, sweet preference, exercise, D2R mutations). Caveats: Can be supported by non-addictive substances. May just be reward learning, not addiction. Doesn't reflect the ~20% transition rate to addiction in humans. Initial acquisition doesn't predict transition to addiction in more complex models.

Question 29

What is the 'incubation of craving and relapse' model?

Answer 29

Models the chronic, relapsing nature of addiction. Defined as resuming a previously reinforced response after extinction training, triggered by non-contingent reward/cues/stress.

Question 30

How does state inference relate to relapse?

Answer 30

Cues can reinstate behaviour learned in a different state. Triggers identified include the drug itself, drug cues (lever, lighter/needle), and stress (foot shock, food deprivation, social isolation).

Question 31

What are the benefits and caveats of the 'incubation of craving and relapse' model?

Answer 31

Benefits: Captures a key aspect of addiction, helps identify triggers for relapse. Anthropomorphically mimics the human problem. Caveats: All cocaine-exposed animals relapse in this model, unlike humans, suggesting missing mechanisms. Could be just reward learning with extinction/reinstatement.

Question 32

What is the purpose of the DSM-compatible 0/3 animal model?

Answer 32

Models multiple DSM criteria (seeking, motivation, use despite consequences). Classifies rats by addiction severity. Used to study vulnerability and mechanisms.

Question 33

What are the benefits and caveats of the DSM-compatible 0/3 animal model?

Answer 33

Benefits: Closely mimics DSM criteria. Allows causal relation of risks (stress, impulsivity). Allows investigating prone vs. resistant subjects. Provides a framework to look for mechanisms underlying the transition. Caveats: Very hard, time-consuming (weeks/months), high attrition (~40% usable), low throughput for neurobiological investigation.

Question 34

Why do some animal models fail to translate to humans?

Answer 34

Phase 3 behaviours (relapse, compulsion) involve complex cortical circuits less conserved across species. Rodent findings often fail in human trials.

Question 35

What are some newer ideas in animal models & mechanisms of addiction?

Answer 35

A different mechanism likely mediates Phase 3; higher order circuits and top-down control; investigate addiction-prone vs resistant animals; perseverers vs. renouncers; PFC excitability; striatial shift; optogenic sufficiency.

Question 36

What is a DSM-compatible model of addiction?

Answer 36

3 criteria rats show very high scores for each of the three addiction-like criteria and are therefore considered as ‘addicted’, whereas 0 criteria rats are considered ‘resistant’ to addiction.

Question 37

What are the 3 main DSM criteria looked at in this model?

Answer 37

(i) Inability to refrain from drug seeking (ii) High motivation for the drug (iii) Maintained drug use despite negative consequences

Question 38

What are the findings from the DSM-compatible model?

Answer 38

3 criteria rats show more ‘binge’-like self-administration of drug at early stages even though the total infusions are the same. Shows quite clearly that overall acquisition of self-administration is not a marker for transition to ‘addiction’ (all the rats have same initial acquisition of drug/drug history).

Question 39

What is the idea behind optogenetic sufficiency in addiction models?

Answer 39

Artificial dopamine stimulation via optogenetics can cause addiction-like behaviors, increasing perseveration in the face of punishment.

Question 40

Why might optogenetic stimulation lead to increased 'persevering' behaviour in rats?

Answer 40

It may create tighter stimulus-outcome coupling, mimicking compulsive drug-seeking behaviour.

Question 41

What did the Chen et al. study reveal about addiction behaviors in rats?

Answer 41

Rats underwent drug self-administration and then faced foot shocks; some persevered in drug seeking while others stopped, despite similar baseline behavior.

Question 42

What brain regions are implicated in later stages of addiction?

Answer 42

Cortical regions and top-down regulation mechanisms are implicated, contrasting with the dopaminergic, bottom-up control seen in acquisition.

Question 43

What has electrophysiology shown about the prefrontal cortex in addiction-prone rats?

Answer 43

Addiction-prone rats show reduced PFC excitability; persevering rats require more current to fire an AP, suggesting altered excitatory connectivity.

Question 44

How might excitatory synaptic strength from cortex influence addiction?

Answer 44

Stronger or altered cortical excitatory connectivity may influence the transition to compulsive behavior.

Question 45

What striatal shift is thought to occur during addiction progression?

Answer 45

A shift from goal-directed ventromedial striatal activity to habit-related dorsal posterior striatal activity.

Question 46

How can outcome devaluation experiments confirm the striatal shift in addiction?

Answer 46

By testing whether behavior becomes insensitive to changes in outcome value, indicating habitual control.

Question 47

What brain area is hypothesized to contribute to 'state inference' in this model?

Answer 47

The orbital frontal cortex (OFC).

Question 48

What role does the prefrontal cortex (PFC) play in contrast to the OFC?

Answer 48

The PFC is thought to support temporal difference reinforcement learning, associated with value and goal-directed behavior.

Question 49

What does calcium imaging of OFC axon terminals in the striatum show before and after punishment?

Answer 49

Both groups show decreased activity at baseline, but after foot shock, perseverers show increased OFC activity, while renouncers show decreased activity.

Question 50

What effect does inactivating the OFC have on previously persevering mice?

Answer 50

It reduces their persevering behavior, making them behave more like renouncers.

Question 51

What neural mechanisms may underlie differences in OFC activity between perseverers and renouncers?

Answer 51

Differences in OFC→dorsomedial striatum connectivity, especially in NMDA:AMPA receptor ratios.

Question 52

What receptor change is observed in persevering mice?

Answer 52

A lower NMDA:AMPA ratio due to increased AMPA receptors, leading to increased excitatory drive.

Question 53

How does inducing LTP (long-term potentiation) affect non-perseverers?

Answer 53

It increases their perseverance permanently, mimicking addicted behavior.

Question 54

What is the effect of inducing LTD (long-term depression) in perseverers?

Answer 54

It reduces perseverance permanently, even after initial stimulation.

Question 55

What overall conclusion can be drawn about OFC input to the striatum?

Answer 55

Increasing OFC drive promotes perseverance, while reducing it diminishes perseverance despite negative consequences.

Question 56

What does the study suggest about cortical control over striatal regions in addiction?

Answer 56

Different cortical regions project to different parts of the striatum, influencing goal-directed vs habitual behavior.

Question 57

How does the OFC compare to the PFC in terms of behavioral control?

Answer 57

OFC contributes to state inference, while PFC is involved in value-based, goal-directed decisions.

Question 58

What shift in striatal activity is hypothesized to occur in addiction?

Answer 58

A transition from goal-directed (ventromedial striatum) to habitual (dorsal posterior striatum) control.

Question 59

What experiment is needed to confirm a shift from goal-directed to habitual behavior in addiction?

Answer 59

An outcome devaluation test to see if perseverers still seek the drug despite reduced value, while renouncers extinguish the behavior.

Question 60

What would be expected from perseverers and renouncers in a devaluation test?

Answer 60

Perseverers would continue to seek the drug, showing habitual, value-insensitive behavior. While renouncers would likely stop seeking the drug, showing they remain goal-directed.