Addiction

Addiction

A chronic condition characterised by compulsive engagement in rewarding stimuli despite adverse consequences; involves loss of control and continued behaviour even when it causes harm.

Official diagnostic labels of addiction 

• DSM= substance use disorder

• ICD-10= harmful use and dependence syndrome 

Substance use disorders

• 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 (withdrawal)

DSM criteria for SUD/AUD

• A problematic pattern of alcohol use leading to clinically significant impairment or distress, as manifested by ay least two of the following, occurring within a 12month period 

• compulsion

  • great deal of time spent in activities necessary to obtain alcohol, use alcohol 

  • craving/strong desire to use alcohol 

  • continued alcohol use despite problems 

• loss of control 

  • persistent desire/ unsuccessful efforts to cut down 

  • recurrent use when in hazardous situations

  • continue despite knowledge of problem

• negative emotional state

  • Alcohol/benzodiazepine is taken to relieve or avoid withdrawal symptoms 

Cost of substance use 

• largest contributor to global burden of mortality and premature death

• high economic cost

• DAILYS (sum of potential life lost) of alcohol= 85m

• most used illicit substance is cannabis then amphetamine

• DAILYS of illicit drugs= 27.8m

UK alcohol figures

• 2022= 10,048 alcohol specific deaths (4.2% higher than 2021)

Typical patterns of AUD/SUD development

• experimental

• casual (social)

• Heavy (abuse/misuse)

• compulsive (dependence)

= AUD/SUD

Uses of animal models 

• see what factors affect the extent to which animals self-administer drugs 

• assess abuse potential of new drugs and classify them 

Drug self-admin model

• begin with continued reinforcement- each response leads to the outcome

• short timeout period

• investigates

  • initial drug use

  • acquisition of drug behaviours

  • rates and patterns of drug use

interval schedules

require a minimum amount of time that must pass between successive reinforced responses 

fixed interval schedule

• Fixed time-period between reinforcers.

• Produce accelerate rate of response as the rime of the reinforcement approaches

• (scalloped response pattern)

variable interval schedule 

variable time period between reinforcers: produce a steady rate of response 

Ratio schedule

• require a certain number of operant responses to produce the next reinforcer

fixed ratio schedule

The required number of responses is fixed from one reinforcer to the next

Variable ratio schedule

The required number of responses may vary from one reinforcer to the next

Progressive ratio schedule 

• reward presented after a fixed number of responses but number of responses needed increases progressively (1,2,4,8,16)

Breakpoint

• used progressive ratio schedule

• For cocain average is 330 times in which animals stop responding

• max was 490 times

• different for different drugs (the higher means the drug is more prone to abuse)

Substitute procedure 

• substitute current drug animal is using for another 

• then assess whether this new drug becomes sought after 

• allows assessment of abuse potential of new drugs 

Conditioned place- preference paradigm

• used to study the rewarding and aversive effects of drugs

• animal is injected with one drug then placed in a particular environment

• on alternate days animal is injected with a vehicle (control drug) and placed in a different environment

• sometimes third environment with no drug

• animal (drug-free) is then placed in the chambers and free to move among the different environments

• drugs often result in a conditioned place preference

Advantages of conditioned place-preference method

• high sensitivity to low drug doses

• test positive and negative reinforcement and aversion

• reinforcement is tested in a drug-free state

• can study the interaction between environmental cues and drugs

Disadvantages of conditioned place-preference method

• costly

• effortful

• takes time

• need to test different doses

• must conduct lots of conditions due to confounds (familiarity)

Intracranial self-stimulation model

• Electrical stimulation administered directly into specific areas of the brain.

• No substances used.

• Allows the investigation of which specific brain processes may be involved in substance seeking behaviour.

• Supports notion of so-called ‘pleasure centres’ in the brain- Often implicated is the Nucleus Accumbens (Nacc). 

• Robert Heath- 1970’s used in an attempt at ‘conversion therapy’ on a homosexual male known as B-19

Nucleus accumbens and addiction

• Lesions to the nucleus accumbens or the ventral tegmental area blocks self- administration of drugs and development of conditioned place preference.

• Both self-administration of addictive drugs and experience of natural reinforcers found to be associated with elevated levels of extra-cellular dopamine in nucelus accumbens

• A study found 6-hydroxydopamine (6-OHDA) lesions (damage dopamine neurons in the nucleus accumbens) impair acquisition of alcohol consumption but not maintenance

The reward circuit

• Ventral Tegmental Area (VTA) → origin of dopaminergic neurons.

• Nucleus Accumbens (NAc) → a major reward center receiving dopamine from the VTA.

• Prefrontal Cortex → involved in decision-making and impulse control.

• Amygdala → processes emotional significance of stimuli.

• Hippocampus → encodes contextual and associative aspects of reward.

• Ventral Pallidum → involved in translating motivation into action

Reward “systems” in the brain 

• Mesolimbic dopamine system- The ventral tegmental area (VTA) and its projections, especially to the nucleus accumbens, are central to reward processing.

• Mesolimbic Pathway- VTA → nucleus accumbens (core and shell), amygdala, hippocampus, and bed nucleus of the stria terminalis (BNST)

  • This pathway drives reward-seeking behavior and reinforcement learning.

• Mesocortical Pathway VTA → prefrontal cortex.

  • Important for cognitive control, motivation, and evaluation of rewards.

• Virtually all addictive drugs increase dopamine release in the mesolimbic system, either directly or indirectly. (Nestler et al., 2005)

evaluation of the reward (dopamine) theory of addiction

• Over-simplistic view.

• Originally believed that DA release meant experience of pleasure, or the rewarding aspects of a stimulus.

• Natural rewards (food, sex, water) also stimulate the mesolimbic pathway (good for survival).

• DA is also triggered when drug-related cues are present (before the drug is taken).

Incentive salience theory

• Robinson & Berridge

• Repeated drug use sensitises dopamine release in the mesolimbic pathway

• This happens both during drug use and when exposed to drug-related cues (via Pavlovian learning)

• These exaggerated dopamine responses cause strong wanting for drug cues

• Evidence: Hobbs et al: found no changes in liking for the alcoholic drink. But an increase in wanting from priming dose of alcohol #

• Sensitisation lasts longer than tolerance or withdrawal. This explains why addiction is a chronic relapsing disorder

• Chronic drug use may lead to structural and functional changes in the prefrontal cortex= executive dysfunction, decision making & inhibition

• Combined with sensitised wanting this can lead to poor self-control and compulsive use.

Impulsive use

• fast, unplanned actions triggered by ext/int stimuli with no regard to potential negative consequences

• 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).

• characterises early stages of addiction which is driven by reward

Compulsive use

• persevere in responding despite adverse consequences, and incorrect responding in choice situations

• characterises later stage addiction which is driven by relief from withdrawal

Addiction pathway: Koob & Volkow

1.Binge/Intoxication – the drug activates dopamine and reward systems

2.Withdrawal/negative affect- reduced reward, increased stress

3.Preoccupation/Anticipation- craving and relapse risk

Repeated cycles of these phases lead to neuroadaptations that shift behaviour from positive to negative reinforcement

Evidence:

• conditioned place aversion (animals avoid environments paired with withdrawal)

• Increased motivation for self-administration in dependent animals (motivation to remove withdrawal state)

Brain regions associated with addiction cycle 

1.Binge/Intoxication= basal ganglia specifically, the ventral striatum, including the nucleus accumbens, which is central to the brain's reward system

2.Withdrawal/negative affect= The Extended Amygdala (a brain area involved in stress, emotion, and the fear response).

3.Preoccupation/Anticipation= The Prefrontal Cortex (the brain's center for executive function, decision-making, and impulse control).

opponent processes

• The brain reduced dopamine activity and activates stress systems

• Results from repeated drug use which leads to sensitisation

• leads to reward function decreasing and worse mood regulation

• Motivation shifts from positive reinforcement (seeking pleasure) to negative reinforcement (relieving distress)

Allostasis

• usually brain aims to maintain homeostasis

• with repeated drug use brain has to adapt to constant stimulation

• Therefore there is a new set point (allostasis)

Hedonic dysregulation

• Sensitisation (early stage): increased liking and bingeing

• Counteradaptation (later stage): negative affect during withdrawal

• Together these create an imbalance in brain’s reward and stress systems that drives compulsive use.

  • Over time the brain can no longer return to baseline

George & Knobb, 2017 summary 

• Addiction involves hedonic dysregulation which is a breakdown in brain reward balance (homeostasis)

• There is a shift from impulsivity to compulsivity which reflects a change in brain reward systems

• Allostasis explains how brain’s set-points adapt to chronic use

• The result= Persistent negative emotional state, craving and relapse.

Evaluation of animal & brain disease models

Field & Kersbergen (2020):

• Animal models have failed to deliver effective pharmacotherapies for addiction ase some lack of transferability

• Animal models have generated a misleading picture of the nature of addictive behaviour in humans e.g., drug users will perform complex tasks to use a substance and can reduce drug use if paid to do so.

• Addiction may be uniquely human- role of language

• Rat park suggest if put rats in more an engaging/enriching environment then perhaps they wouldn’t become as addicted

• Excessive focus on stimulants in rat studies (cocaine) when may be differences

• Led to over investment: 41% of addiction funding

• Few new drugs have been developed based on neurobiology.

• What about spontaneous remission / unassisted recovery?

• Recovery is a social process – we change our identity, we become empowered.

• BUT has helped stigmatisation