Addiction and Dopamine — Comprehensive Study Notes

Instructor and Course Context

• Professor BSc (Hon) and PhD from UNSW; has worked in USA and Australia; Head of Behavioural Neuroscience Laboratory at UNSW.

• Teaches in PSYC2081, PSYC3051, Honours, and PhD program.

• Office: 512 Mathews (Level 5). Always happy to chat about the brain and behaviour; hosts interns.

What are we covering in these lectures?

• Motivation:

  • General Concepts (Lecture 1: watch first or last)

• Addiction (Lectures 2 and 3)

• Attachment and Love (Lectures 4 and 5)

Exam strategy

• Look out for “What should I know by now?” as a cue for key learnings.

Addiction: Lecture outline

• 1. Assessing drug reward in animals

• 2. How do drugs of abuse affect the brain?

  • Dopamine and neurotransmission

• 3. Why do people persist in taking drugs?

  • Pavlovian incentive learning

  • Opponent process and Pavlovian conditioning

  • Instrumental incentive learning

• 4. Treatment

  • How do we treat addiction and are we effective?

• 5. Conclusions

What is addiction? (Definitions and scope)

• Addiction is not recreational drug use; a proportion of recreational users become ‘addicted’.

• DSM-IV: substance dependence diagnosis criteria (3 or more in the past 12 months):

  • Tolerance

  • Withdrawal symptoms

  • Increasing doses

  • Unsuccessful efforts to reduce intake

  • A considerable amount of time obtaining/using the substance

  • Interference with important social, occupational, or recreational activities

  • Continuation of use despite recognition of physical/psychological problems

• Addiction affects both licit (e.g., nicotine, alcohol) and illicit (e.g., opiates, cocaine) substances; a leading cause of death and disability worldwide.

How do drugs of abuse work? Four big questions

• 1. How do drugs of abuse work?

• 2. Why do people start taking drugs?

• 3. Why do people persist in taking drugs?

• 4. Can it lead to effective treatment?

• These require an adequate explanatory framework for addiction.

Assessing drug reward and drug taking in animals (Learning systems)

• Pavlovian learning: conditioned stimuli (CS) paired with unconditioned stimuli (US, e.g., drug) -> conditioned response (CR)

  • Conditioned place preference: context–drug association (CS–US)

• Instrumental learning: action (lever press) – outcome (drug) association

  • Stimulus (lever) – response association

The mesolimbic dopamine system and why drugs are rewarding

• Key pathway: mesolimbic dopamine system involving the ventral tegmental area (VTA)

• VTA = ventral tegmental area; part of the tegmentum (floor of the midbrain) that projects to limbic regions

• Summary: Dopamine in the mesolimbic pathway is central to reward processing and incentive motivation

• VTA →Nucleus Accumbens (NAc) →Limbic/Cortical targets

Imaging evidence for mesolimbic activation in humans

• Human studies show activation of mesolimbic dopamine system in response to drugs:

  • Heroin: pre/post drug/placebo comparisons with measures like cerebral blood flow (CBF) and Z-values in functional imaging

  • Cocaine: similar cues and drug administration paradigms reveal dopaminergic activation

• Notable sources cited: Sell et al. (1999); Fowler et al. (2001); Drevets et al. (2001); Oswald et al. (2005); Martinez et al. (2007); Wand et al. (2007); Schneier et al. (2009); Leyton et al. (2002); Boileau et al. (2007); Narendran et al. (2010); Shotbolt et al. (2011); Brody et al. (various years); plus many others; NB: competitive binding assay and 11C-raclopride binding changes are often used.

• Visual takeaway: drug exposure and drug cues modulate ventral striatal dopamine signaling as reflected in imaging metrics

Dopamine release dynamics: animal and human data

• Nicotine effects in rat nucleus accumbens: dopamine (DA) increases relative to baseline over minutes after exposure

• Cocaine and amphetamine effects in rats: self-administration increases DA concentration; time-course aligned with injections/behavior

• Key idea: DA release in the nucleus accumbens correlates with rewarding properties and drug-taking behaviors

Dopamine synthesis, storage, release, and clearance (the core biology)

• Synthesis pathway:

  • Tyrosine --(tyrosine hydroxylase)--> L-DOPA --(DOPA decarboxylase)--> Dopamine

• Storage and release:

  • DA is stored in vesicles in the presynaptic neuron

  • Arrival of action potential causes vesicles to fuse with the membrane and release DA into the synaptic cleft

• Receptors and signaling:

  • D1 receptor (postsynaptic): increases cAMP; associated with rewarding aspects

  • D2 receptor (presynaptic): reduces cAMP and reduces further DA release; can be aversive or punishing

• DA clearance and inactivation:

  • Reuptake by dopamine transporter (DAT) removes DA from the synaptic cleft

  • Monoamine oxidase (MAO) enzymes degrade DA inside the presynaptic terminal; remaining DA is deactivated in the cleft

• Formally:

  • $ext{Tyrosine} \xrightarrow{\text{tyrosine hydroxylase}} \text{L-DOPA} \xrightarrow{\text{DOPA decarboxylase}} \text{Dopamine}$

How do drugs of abuse increase dopamine?

• Cocaine: blocks dopamine reuptake (DAT), increasing extracellular DA levels

• Opiates: disinhibit dopamine neurons via endogenous opioid mechanisms (μ-opioid receptor effects on GABA interneurons), leading to increased DA release

• Simplified view: many drugs enhance DA transmission directly or indirectly, amplifying reward signaling

What should I know by now? Core takeaways

• Drugs of abuse have motivationally significant, rewarding properties.

• These properties can be studied in animal models via Pavlovian and instrumental paradigms.

• Drugs affect dopamine neurotransmission in characteristic ways.

• Understanding dopamine system function helps explain drug properties and informs treatment approaches.

• Key questions for further thought: what is dopamine doing? what does this mean for treatment? how do these properties relate to other neurotransmitters?

Theories of addiction: Why do people persist in taking drugs?

Pleasure/Reward theory (Olds & Milner, 1954)

• Animals will repeatedly perform actions to obtain electrical stimulation of brain reward regions (e.g., medial forebrain bundle)

• High reward-site stimulation is immensely reinforcing; humans show similar effects

• Concept: addiction may reflect engagement of a reward circuit

• The broad idea: stimulation-induced reward can sustain drug-seeking behavior

Theoretical framework: The brain’s reward pathway hijacked

• The brain contains circuits that generate pleasure; this pleasure is both “liked” (consummatory) and “wanted” (incentive drive)

• These circuits are normally activated by natural rewards (food, water, sex, money, etc.) and can be hijacked by drugs of abuse

Incentive sensitisation (Motivational ‘wanting’)

• Addictive drugs enhance transmission in the mesolimbic dopamine pathway

• Function of this pathway: attribute incentive salience to stimuli associated with activation (i.e., make them attractive or pulling toward them)

• Distinction: Wanting (incentive salience) vs. Liking (hedonic/affective response)

• Dopamine mediates incentive salience; repeated drug exposure sensitises the mesolimbic system

• This sensitisation is gated by associative learning, which assigns incentive value to drug-taking acts and associated cues

Advantages of incentive sensitisation

• Integrates psychological explanations with dopamine function

• Aligns with the prominent role of craving in addiction

• Compatible with neurobiological data; does not attribute withdrawal as the primary cause of addiction

Limitations of incentive sensitisation

• Limited clinical evidence for sensitisation of drug responding in humans with drugs of abuse

• Not much evidence for clear dissociations between wanting and liking in humans or animals for many drugs

Opponent process model

• Addiction arises from compensatory responses that drive drug withdrawal

• A-process = reward; B-process = aversive state counteracting the reward

• Overall experience is A + B; B strengthens with use and weakens with disuse

• Over time, B-process dominates; drugs alleviate withdrawal rather than create a pure A-state

• Early use: use drugs for the rewarding A-state; later use to alleviate withdrawal (B-state)

Advantages and limitations

• Advantages: explains many features of addiction; could meet DSM substance dependence criteria; reconcilable with neurobiology; relevant to overdose causes

• Disadvantages: fails to explain persistent drug-taking in the absence of withdrawal (e.g., cannabis, psychostimulants); tolerance is not inevitable with all drugs

Withdrawal and behavior: motivational state effects

• To study reward relevance to current motivation, one must consider withdrawal states

• For opiates, withdrawal can enhance the value of the drug, enabling withdrawal-triggered taking if the subject has prior relief experiences

• Key study reference: Hutcheson et al. (2001)

What should I know by now? Review prompts

• Main theories of addiction

• The role of reward in each theory

• The role of withdrawal in each theory

• Which theories predict increased drug-taking during withdrawal?

• How might these theories inform treatment?

• Are these theories specific to drug addiction or applicable to other motivated behaviours?

Treating addiction: Overview and history

Historical context and advertising around addictive substances

• 1898: Bayer introduced diacetylmorphine (heroin) as a cough suppressant and for addiction treatment contexts

• 1995: Purdue Pharma introduced MS Contin (morphine) and OxyContin (oxycodone) as treatments for pain, contributing to the opioid landscape

The opioid epidemic by the numbers (as presented)

• 130+ deaths per day from opioid-related overdoses (estimated)

• 11.4 million people misused prescription opioids

• 47,600 deaths from overdosing on opioids

• 2.1 million people had an opioid use disorder

• 81,000 people used heroin for the first time

• 886,000 people used heroin

• 2 million people misused prescription opioids for the first time

• 15,482 deaths attributed to heroin overdoses

• 28,466 deaths attributed to synthetic opioids other than methadone

Pharmacotherapies for addiction

• Opioid addiction: available pharmacotherapies include agonists and antagonists

  • Agonist-based pharmacotherapies counter withdrawal and reduce craving by mimicking opioid effects

  • Antagonist-based pharmacotherapies blunt rewarding effects of drugs

• Key agents and targets (examples):

  • Methadone: full opioid receptor agonist (slow acting)

  • Buprenorphine: partial opioid agonist

  • Naltrexone: opioid receptor antagonist

  • Acamprosate: mixed effects on GABA receptors (alcohol use disorders)

  • Disulfiram: increases sensitivity to acute aversive effects of alcohol

• Applicability: opioid addiction and alcohol use disorders

Pharmacotherapy efficacy: what the data suggest

• Acamprosate: Number Needed to Treat (NNT) to prevent return to any drinking ≈ 12

• Naltrexone/Naloxone: NNT ≈ 20 (note: source text uses “Naloxone”; typical clinical reference is naltrexone for relapse prevention)

• Overall: some pharmacotherapies work for some people some of the time (Jonas et al., 2014; large N studies cited)

Psychology and pharmacotherapy: cue exposure and extinction

• Cue exposure therapy aims to reduce power of drug-associated stimuli via extinction

• Evidence is mixed: some studies show limited or no benefit, and some show potential relapse worsening in certain designs

• Key meta-findings (Conklin & Tiffany, 2001): often no robust, consistent improvement; results vary by paradigm and substance

Contingency management: behavioural reward systems

• Concept: reward abstinence with tangible incentives (e.g., vouchers) for negative drug tests

• Structure: frequent urine testing and reinforcement for each negative test; can extend reward over time

• Evidence across substances shows reductions in drug-taking and increased abstinence

• Meta-analytic trend: contingency management increases abstinence; magnitude can vary by substance and setting

Social connectedness and addiction treatment

• Non-human primate data show social status affects response to cocaine; social rewards can be leveraged in treatment strategies

• Contingency management can incorporate social rewards to bolster effectiveness

• Monkeys in subordinate vs. dominant positions show differential reactivity to drug cues and rewards

Are we getting better at treating addiction?

• Longitudinal comparisons (1973 vs 2011) show shifts in abstinence curves across drugs (heroin, opiates, nicotine, cocaine, alcohol)

• General trend: some improvements in abstinence days over time, but results vary by substance and context

• Graphs indicate changes in the trajectory of abstinence across decades, suggesting partial progress but ongoing challenges

Final synthesis: what should you know for exams?

• What are the main theories of addiction and how do they conceptualize reward and withdrawal?

• How does the dopamine system contribute to drug reward and incentive motivation?

• How do drugs of abuse modulate dopamine signaling (direct vs indirect mechanisms)?

• What are the major animal models used to study drug reward and drug-taking behavior?

• What are the key pharmacotherapies for addiction, their mechanisms, and what does the clinical evidence say about their efficacy (including NNT in relevant cases)?

• How do behavioral therapies (cue exposure, contingency management) fit within neurobiological theories and what does the evidence suggest about their effectiveness?

• What are the broader social and historical contexts of addiction treatment (e.g., opioid epidemic, pharmaceutical history)?

• How can understanding withdrawal states inform predictions about relapse and treatment planning?