Addiction

Question 1

Define substance dependence/addiction

Answer 1

Compulsive substance taking, lives centred around a substance, possibly building a tolerance to it or experiencing withdrawal symptoms when they stop taking it

Question 2

Why may people ‘enjoy’ taking addictive drugs?

Answer 2

When administered systemically, they enhance dopamine release in nucleus accumbens

• Amphetamine, cocaine
• Nicotine, ethanol, opiates, barbiturates
• Dopamine release is relatively specific to nucleus accumbens
• These are the same drugs which:
• – Enhance self-stimulation
• – Support self-administration
• – Show conditioned place preference
• – Enhance reinforced behaviours

Question 3

Describe the opponent-process model of addiction

Answer 3

Stein, 1964:

• A-process: leads to the ‘high’ (drug = positive reinforcer, high = positive hedonic process)
• B-process: restores homeostasis and leads to aversion from not taking the drug, negative mood state = negative hedonic process
• The driving force for addiction is to avoid withdrawal symptoms
• Dopamine has been implicated in the reinforcing effects of cocaine and amphetamine (Koob et al., 1997)
• Doesn’t explain the initiation of compulsive drug use

Question 4

Describe the aberrant learning model of addiction

Answer 4

• Strong explicit or implicit learning associated with drug taking
• Leads to association between action (drug-taking) and outcome (high)
• Driving force is expectation of ‘high’
  Torregrossa, Corlett and Taylor (2011):
• It has been hypothesized that drugs of abuse enhance positive learning and memory about the drug while inhibiting learning about the negative consequences of drug use
• So the addict’s behavior becomes increasingly directed towards obtaining and using drugs of abuse, while at the same time developing a poorer ability to stop using, even when the drug is less rewarding or interferes with functioning in other facets of life
• Drugs of abuse enhance learning about environmental cues associated with reinforcing events and may cause the rapid formation of habitual and ultimately compulsive behavior related to obtaining and using drug
• Addictive drugs also cause neuroplasticity in circuits involved in cue learning and habit formation
  Wallenstein (2008)
• Aberrant learning theory suggests that modern addictive drugs have much greater potency in activating endogenous receptors than their natural counterparts and hence act like an abnormally powerful stimulus
  — A neural system that is designed to learn stimulus-response pairings will be hyper-activated by such a powerful stimulus
  — This learning might be very quick and enduring
• Does not explain why an unusually strong stimulus-response association would immutably lead to compulsive behaviors

Question 5

Describe the incentive salience model of addiction

Answer 5

• Incentive salience is a distinct component of motivation and reward, and is distinguishable from hedonic impact and reward learning
• Incentive salience is a cognitive process which confers a “desire” or “want” attribute, which includes a motivational component, to a rewarding stimulus
• Dopamine provides the driving force to perform a behaviour
• Dopamine systems drive ‘wanting’ incentives, but not for ‘liking’ them, nor for learning new ‘likes’ and ‘dislikes’
• Drugs which increase dopamine ‘tap into’ this innate mechanism and thus reinforce the drug taking behaviour
• The behaviour is not necessarily pleasurable
• May also lead to physiological changes in neurotransmitter systems, leading to a state where ‘normal’ function requires the presence of the drug

Question 6

Describe the incentive-sensitisation model of addiction

Answer 6

• Originally described by Robinson and Berridge (1993)
• Makes the distinction between ‘wanting’ and ‘liking’ in the context of dopamine systems
  — Links this to addictive processes
• Suggests that drug addiction occurs due to a sensitisation of the mesolimbic dopamine system, with the dopamine acting to attribute incentive salience to stimuli associated with rewards
• Repeated exposure to potentially addictive drugs can, in susceptible individuals and under particular circumstances, persistently change brain cells and circuits that normally regulate the attribution of incentive salience to stimuli
• If rendered hypersensitive, these systems cause pathological incentive motivation (‘wanting’) for drugs
• Develop a bias of attentional processing towards drug-associated stimuli and pathological motivation for drugs
  Robinson and Berridge, 2008
• Persistence of incentive sensitization makes pathological incentive motivation (wanting) for drugs last for years, even after the discontinuation of drug use.
• Sensitized incentive salience can be manifest in behaviour via either implicit (as unconscious wanting) or explicit (as conscious craving) processes, depending on circumstances
• Associative learning processes can modulate the expression of neural sensitization in behaviour at particular places or times (and not others), as well as guide the direction of incentive attributions
• S-R habits play a role in addiction but they require a motivational component (e.g. people brush their teeth every day but they do not perform this task compulsively)
• Evidence for incentive sensitisation: from studies showing that past drug treatment, which produces psychomotor sensitization, facilitates all three features of incentive stimuli:
  — Pavlovian conditioned approach behaviour = act as motivational magnets, become ‘wanted’ (Harmer & Phillips 1998)
  — Pavlovian instrumental transfer = elicit cue-triggered wanting for their associated unconditioned rewards (Wyvell & Berridge 2001)
  — Conditioned reinforcement = act as reinforcers in their own right (Taylor & Horger 1999; Di Ciano 2007)
• But in most studies on incentive sensitisation they used pairing with natural rewards (food/water) rather than a drug reward to confer CS with incentive motivational properties
  — It is difficult to determine whether prior sensitization directly facilitates the incentive properties of drug-associated stimuli in animal experiments because the pairing of a stimulus with drug administration may itself produce sensitisation
  — Di Ciano (2007) found that cocaine sensitisation did facilitate the conditioned reinforcing effects of a cocaine-associated stimulus, consistent with incentive sensitisation
• Criticism: little evidence that humans showed behavioural or neural sensitisation
  — Review by Leyton (2007): the acute administration of drugs of abuse across pharmacological classes increases extracellular dopamine levels within the human ventral striatum (Boileau et al., 2007)
  — Individual differences in the magnitude of this response correlate with rewarding effects of the drugs and the personality trait of novelty seeking (Leyton et al, 2002)
  — Transiently diminishing dopamine transmission in humans decreases drug craving, the inclination to preferentially respond to reward-paired stimuli and the ability to sustain responding for future drug reward (Leyton et al., 2004)
  — But in individuals with a long history of substance abuse, drug-induced dopamine release is decreased

Question 7

How do learning processes play a role in addiction?

Answer 7

Berridge and Robinson, 2003

• Learned responses require knowledge
• – Knowledge is required for reward prediction, for making anticipatory responses, for guidance by cues, and for goal-directed action
• Learning processes can be associative or cognitive
• – Associative learning usually refers to either pavlovian conditioning (stimulus-stimulus and stimulus-response associations) or instrumental conditioning (response=contingent reinforcement)
• – Cognitive forms are more elaborate: they encode multiple relationships among stimuli and actions, including declarative representations of temporal, spatial, predictive and causal relationships that guide goal-directed plans of actions
• The products of learning can be declarative (conscious memories) or procedural (habits)
• Neural manipulations could influence rewarded behaviour because they alter any one of many forms of learning
• Neural manipulations could alternatively alter an affective (emotional) or motivational process
• – Emotional and motivational components of reward can occur implicitly (without conscious awareness)
• – Implicit affective reactions can exist objectively without necessarily being experienced subjectively

Question 8

Discuss “liking” in relation to addiction

Answer 8

• Berridge and Robinson, 2003:
  — An objective affective reaction
  — “Liking” for tastes involves activity in a distributed neural network that also has been implicated in drug reward
  — One neural component of “liking” involved opioid neurotransmission onto GABAergic spiny neurons in the nucleus accumbens
  — Dopamine is neither necessary nor sufficient for generating “liking”, but it may have other roles in reward, such as incentive salience, reward learning, etc.
• Berridge (2003): evidence suggests activity in a subcortical network involving portions of the nucleus accumbens shell, ventral pallidum and brainstem causes ‘liking’ and positive affective reactions to sweet tastes
  — These are all parts of the mesolimbic reward system
  — Lesions of ventral pallidum also impair normal sensory pleasure
  — The same subcortical ‘liking’ network, via connection to brain systems involved in explicit cognitive representations, may also in turn cause conscious experiences of sensory pleasure
  — Many studies have also indicated that mesolimbic dopamine projection to this system to be a shared substrate at least for ‘wanting’ for multiple types of reward
  • Including food, sex, heroin, cocaine and related drugs
  • Rewards electrical brain stimulation, maternal interaction with infants, and even social and culturally based rewards

Question 9

Discuss “motivation” in relation to addiction

Answer 9

• Berridge and Robinson, 2003
  — Manipulation of dopamine systems powerfully changes motivated behaviour, but not taste “liking”
  — Incentive salience is a motivational, rather than an affective, component of reward
  — Its attribution transforms mere sensory information about rewards and their cues into attractive, desired, riveting incentives
  — Incentive salience is particularly influenced by dopamine neurotransmission, but it is also dependent on other brain substrates
  — Conditioned stimuli (which are attributed with incentive salience) can act as motivational magnets, eliciting appetitive approach and even consumatory behaviour
  • This form of incentive salience depends heavily on mesolimbic dopamine systems, and its associative guidance seems to depend on the basolateral amygdala and nucleus accumbens core
  — Conditioned stimuli also trigger motivation for their unconditioned rewards
  • E.g. when drug cues elicit craving or reinstate drug-taking behaviour
  • This may occur because CSs cause mesolimbic systems additionally to attribute incentive salience to associated neural representations of their reward UCS, spurring cue-triggered ‘wanting’ for that reward
  — People often have an explicit cognitive expectation that they will like the things they want
  • In those cases, a cognitive incentive is known or imagined, expected to be pleasant, subjectively desired and intended to be gained, and may be known to be obtainable by actions that cause it to occur

Question 10

What is the attentional bias model?

Answer 10

Franken, 2003

• Attentional bias = the presence of biases in selective attention to threat-relevant information in anxiety
• – The attentional processing of salient stimuli is mainly automatic in nature and is poorly controlled by the subject
• Cognitive processes mediate between drug stimulus and the subject’s response to this stimulus and subsequent behavioural response (e.g. drug use, relapse)
• A conditioned drug stimulus produces an increase in dopamine levels in the corticostriatal circuit, in particular the anterior cingulate gyrus, amygdala and nucleus accumbens, which in turn serves to draw the subject’s attention towards a perceived drug stimulus
• This process results in motor preparation and a hyperattentive state towards drug related stimuli that, ultimately, promotes further craving and relapse
• Preoccupation with drugs and drug-related cues in addiction

Question 11

What is the role of dopaminergic system in drug addiction?

Answer 11

Woolverton and Johnson, 1992

• The midbrain dopamine system is composed of 2 major projections: the nigrostriatal system, which projects from the substantia nigra to the corpus striatum, and the mesocorticolimbic dopamine system
• – It is the mesocorticolimbic system that has been primarily implicated in the reinforcing actions of drugs of abuse
• Psychostimulants such as cocaine and d-amphetamine elevate extracellular dopamine by inhibiting reuptake of dopamine by the dopamine transporter and, in the case of d-amphetamine, also by promoting reverse transport of dopamine
• During IV cocaine self-administration, increased extracellular dopamine can be detected in the nucleus accumbens using in vivo microdialysis
• – Pettit and Justice, 1989
• Selective destruction of mesocorticolimbic dopamine neurons with the neurotoxin 6-hydroxydopamine (6-OHDA) eliminates cocaine self-administration
• – Roberts et al, 1980
• Antagonists for the dopamine D1, D2 and D3 receptor subtypes all decrease the reinforcing properties of cocaine
• – Woolverton, Johnson, 1992 and Caone, heinrichs, coffin, koob, 1995

Question 12

How can neuronal responses influence drug addiction?

Answer 12

Carelli and deadwyler, 1996 = electrophysiological recordings in animals receiving IV cocaine by self-administration have identified several patterns of neuronal responses in the nucleus accumbens, all time-locked to the self-administered drug infusion

• 1 group of neurons fires just before the lever press
• – This anticipatory response may be an initiation or trigger mechanism
• A second group of neurons appears to change firing rate only after the cocaine infusion
• – These neurons may represent the direct effects of reinforcement
• Other neurons fire in proportion to the interinfusion interval between consecutive self-administration responses
• – Peoples and west, 1996
• A fourth type of neuronal firing pattern is unique to cocaine self-administration: these “cocaine specific cells” fire both before and after the cocaine-reinforced response
• – This subset of neurons also fires to sensory stimuli that have been experimentally paired with cocaine delivery
• Nucleus accumbens neurons may therefore mediate conditioned drug responses
• Conditioned sensory stimuli are strong elicitors of “craving” in cocaine-taking humans

Question 13

Why are drug addicts vulnerable to relapse?

Answer 13

Koob and le moal, 1997
- Vulnerability to reinstatement of drug-taking behaviour and ultimately a continuation of compulsive drug use presumably reflects some underlying prolonged perturbation that emerges long after the withdrawal reactions have subsided
- A residual deficit state in the reward system, or sensitization of the reward system to stimuli that predict drug effects, or both, could be responsible for this vulnerability
Koob, 1995
- Animal models of drug craving and relapse are largely based on conditioned reinforcement where previously neutral stimuli have become paired with the drug state of the drug withdrawal state
Everitt et al., 1991
- The neural substrates for such conditioned positive reinforcement may involve elements of the extended amygdala and its afferent circuits from the basolateral amygdala and the mesolimbic dopamine system
- The neural substrates for any hypothetical conditioned negative reinforcement are largely unknown

Question 14

How is negative reinforcement associated with addiction?

Answer 14

Koob, Sanna and Bloom, 1998

• The transition from occasional drug use to drug addiction has been thought to require an additional source of reinforcement, the reduction of the aversive emotional state arising from repeated use
• A possible molecular mechanism for such learned, long-term neuroadaptation may involve alterations to gene expression
• Acute cocaine induces the transcription factor complex AP-1 in the striatum and nucleus accumbens (Nestler, 1994)
• – `With continued exposure to drugs, the composition of AP-1 gradually changes from one in which the immediate early-gene product, c-fos, is present, to one in which a longer-lived, Fos-related antigen (chronic FRA) substitutes for c-fos (Hope et al., 1994)
• – Because of the longer half-life of chronic FRA, repeated exposure to cocaine leads to its progressive accumulation (Hope et al., 1994)
• – Shifts of AP-1 composition in relevant CNS regions may represent a general neuroadaptive process that contributes to long-term functional changes (Rossetti and caroni, 1995)
• Nicotine or cocaine self-administration has also been shown to elicit overlapping patterns of c-fos induction followed by induction of FRA immunoreactivity in the nucleus accumbens and other regions, but not in the amygdala (Merlo-Pich et al, 1997)