Drug Addiction and the Brain's Reward Circuits - Comprehensive Notes

Week 11: Drug Addiction and the Brain's Reward Circuits

Learning Objectives

• Part A:

  • Summarize key features (mechanisms, effects, health hazards) of popular psychoactive substances of abuse.

  • Describe the principles of pharmacokinetics and pharmacodynamics and implications for dose responses across individuals.

• Part B:

  • Describe the development of different types of drug tolerance and subsequent processes of withdrawal.

  • Describe the criteria for physical dependence and addiction.

• Part C:

  • Describe the role of the nucleus accumbens (and related brain regions) that underpin transitions from initial drug taking to addiction.

  • Describe key developments in the biopsychological models of addiction.

Part A: Psychoactive Substances and Principles of Pharmacokinetics/Dynamics

Drug Use Rates in Australia

• Most common principal drugs of concern:

  • Alcohol: 36.0%

  • Amphetamines: 28.0%

  • Cannabis: 19.8%

  • Heroin: 2.7%

  • Other: 5.2%

Psychoactive Drugs

• Definition: Drugs which influence experience and behavior by acting on the nervous system.

Popular Psychoactive Drugs

• Drug Classes:

  • Depressants (e.g., alcohol, benzodiazepines, GHB, Kava)

  • Stimulants (e.g., cocaine, methamphetamine, nicotine, caffeine, synthetic cathinones)

  • Opioids (e.g., heroin, morphine, fentanyl, codeine, oxycodone, methadone, buprenorphine, opium)

  • Cannabinoids (e.g., cannabis, medicinal cannabis, butane hash oil, synthetic cannabis)

  • Empathogens (e.g. MDMA, Ethylone, Mephedrone, PMA/PMMA)

  • Dissociatives (e.g., ketamine, methoxetamine (MXE), nitrous oxide)

  • Psychedelics (e.g., LSD, psilocybin, ayahuasca, NBOMes)

Alcohol (Ethanol)

• Effects:

  • Increases extracellular dopamine levels in mesocorticolimbic circuitry indirectly (via GABA, glutamate).

  • Euphoria, feeling relaxed, increased confidence, feeling happier/sadder, difficulty concentrating, motor impairing, sedating.

  • Chronic use promotes compensatory neuroadaptations that suppresses monoamine activity.

• Withdrawal Symptoms:

  • Sweating, tremors, rapid heartbeat, nausea, anxiety, difficulty sleeping, irritability, seizures, delusions.

• Treatment Approach:

  • Detoxification, counselling, group therapy, pharmacotherapy.

  • Disulfiram (deterrent), acamprosate (withdrawal), naltrexone (cravings).

• CNS depressant.

Nicotine

• Effects:

  • Increased alertness, relaxation alongside stimulation, reduced appetite, some cognitive benefits.

• Withdrawal Symptoms:

  • Irritability, anxiety, difficulty concentrating, increased appetite, cravings, depressed mood, restlessness, and sleep disturbances.

  • Many users continue using nicotine to avoid these uncomfortable symptoms.

• Treatment Approach:

  • Success varies by individual, often requiring multiple attempts to quit.

  • Nicotine replacement therapy (patches, gum, lozenges), pharmacotherapy (bupropion/varenicline), psychotherapy (e.g., CBT), behavioral support (counselling or support groups).

• CNS stimulant.

Cocaine

• Effects:

  • Short-acting, direct effects on dopamine signaling at mesolimbic structures.

  • Binds to dopamine transporter to block re-uptake of extracellular dopamine.

  • Feeling physically strong and mentally sharp, energetic, alert, happy & confident, reduced appetite, higher blood pressure & faster heartbeat, increased sex drive, insomnia.

• Withdrawal Symptoms:

  • Depression, anxiety, lack of energy, inability to feel pleasure, irritability and paranoia, mood swings, exhaustion.

• Treatment Approach:

  • Detoxification, counselling and group therapy

  • Anti-epileptic medication being trialled to reduce craving/consumption.

• CNS stimulant.

Opioids (Heroin, Morphine)

• Effects:

  • Highly Addictive

  • Opioids bind to opioid receptors which depress the CNS and stimulate the release of dopamine (very simplistic overview).

  • Euphoria (high), drowsiness, slowed breathing, and reduced pain signaling.

• Withdrawal Symptoms:

  • Profound negative emotions

  • Physical symptoms including restlessness, bodily discomfort, chills, pain, sweating, and intestinal distress, seizures (extreme cases).

  • Further opioid must be taken to avoid the severe withdrawal symptoms.

• Treatment Approach:

  • Treatment success is low.

  • Example: Methadone program — also opioids but less pleasurable.

• CNS depressants.

(Psycho)pharmacology

• Pharmacology = effects of drug consumption.

• Pharmacokinetics: How the body processes the drug.

  • Absorption: process by which drugs reach the bloodstream.

  • Distribution: where the drugs are carried throughout the body.

  • Elimination: metabolism.

• Pharmacodynamics: Drug's effect on the body.

  • Different receptors/targets.

  • Pharmacological effect (biochemical/physiological).

  • Clinical response.

Pharmacokinetics: Routes of Administration

• Oral (gastrointestinal tract):

  • Slow (minutes/hours).

  • Natural defenses (gag/vomit).

  • Inefficient (<100% absorbed) - selective absorption.

  • Good absorption for lipid-soluble drugs (e.g., alcohol) and acidic drugs (e.g., aspirin).

  • Poor absorption for alkaline drugs (e.g., heroin/cocaine).

• Inhalation (via lungs):

  • Fast (seconds).

  • Efficient.

  • Natural defenses (coughing).

Pharmacokinetics: Absorption (Nasal/Oral/Rectal)

• Sniffing:

  • Especially rapid.

  • Absorption via nasal membranes.

  • Efficient (almost immediately present in blood).

• Dipping:

  • Absorption via tissues in mouth.

• Enema:

  • Absorption via rectal membranes.

Pharmacokinetics: Injection

• (Directly into bloodstream):

  • Very fast and efficient (almost immediate).

  • Drug spreads throughout the body.

  • Bioavailability varies (high for lipid-soluble drugs).

• Blood-Brain Barrier:

  • System of membranes separating circulatory system outside vs inside the brain.

  • Regulates which molecules can enter (e.g., lipid-soluble are more robust/efficient).

Elimination

• Body breaks down the drug into other molecules.

  • Biotransformation.

  • Metabolism.

  • Metabolites (some of these may have their own drug effects).

• Different rates of elimination:

  • Usually depends on concentration.

  • First-order (elimination rate ~ drug concentration).

    • elimination \ rate \propto drug \ concentration

  • Zero-order (e.g., alcohol) – fixed rate of elimination (alcohol dehydrogenase become saturated at low concentrations, maintaining a steady rate of elimination).

Elimination: Drug Half-Life

• Drug half-life (T_{\frac{1}{2}}) represents rate of excretion for most drugs.

  • T_{\frac{1}{2}} = Time taken for body to eliminate half of circulating drug level in blood.

  • T_{\frac{1}{2}} duration (mins/hrs) varies by drug.

Psychopharmacology: Dose Response

• Drug’s effect on the body

  • Different receptors/targets

  • Pharmacological effect (biochemical/physiological)

  • Clinical response

Metabolism: Genetic Variation

• Normal metabolizer:

  • Genes produce typical amount of enzyme.

  • Alleviates depression, few side effects.

  • Recommended dosage.

• Slow metabolizer:

  • Genes produce too little enzyme.

  • Medication not processed quickly enough (builds up); side effects arise.

  • Reduce dosage (or switch antidepressant).

• Fast metabolizer:

  • Genes produce too much enzyme.

  • Medication eliminated too quickly; little/no symptom improvements.

  • Increase dosage (or switch antidepressant).

Metabolism: Types of Tests

• Urine (most common method)

• Blood

• Sweat, saliva, hair (newer methods)

• Testing for drug presence (in blood):

  • Typically shorter detection window

  • Confirms drug presence

• Testing for metabolites:

  • Typically longer detection window

  • Drug may have been used

  • Timeline not always clear

• False positives vs false negatives

  • High rates of FPs (25% or more) -> requires follow-up testing

  • FNs due to various factors (substitution, dilution, contamination)

• Urine testing - elimination vs detection

Factors Influencing Alcohol Intoxication

• Dosing

  • Circulating drug dose (mg/kg body weight).

• Same dose, different effects

  • Depends on body weight/concentration of drug in the body.

• Administration/absorption

  • Different methods/routes of administration (RoA)

  • Bioavailability of drug

• Interference/interactions

  • Food, polysubstances

  • Surface area of membranes

  • Metabolism

Part B: Drug Tolerance, Withdrawal, Physical Dependence, and Addiction

Comparison of Drug Classes: Health Hazards & Addiction

• Tobacco & alcohol have greatest negative impacts.

• Global death rates: Tobacco + alcohol > all other drugs combined

Addiction vs. Habitual Drug Taking

• DSM-IV Criteria (Abuse):

  • Hazardous use.

  • Social/interpersonal problems related to use.

  • Neglected major roles to use.

  • Legal problems.

• DSM-IV Criteria (Dependence):

  • Tolerance.

  • Withdrawal.

  • Used larger amounts/longer.

  • Repeated attempts to quit/control use.

  • Much time spent using.

  • Physical/psychological problems related to use.

  • Activities given up to use.

• DSM-5 (Substance Use Disorders):

  • Craving is included as a criterion.

  • Advancements in neurobiological understanding of dependence models.

Drug Tolerance

• Definition: Decreased sensitivity to drug effects from increasing exposure.

• Tolerance can apply to some (but not all) effects of the drug (e.g., inebriation vs. liver burden).

• Multiple mechanisms and features of tolerance.

Metabolic Tolerance

• Drug is broken down/eliminated before reaching site of action.

• E.g., lower resulting spike in BAC

Functional Tolerance

• Reduced reactivity at the site of action.

• E..g., neuroadaptations at the synaptic cleft

• Chronic drinkers may not present as intoxicated despite high blood alcohol levels

Principles of Drug Tolerance

• Maintain homeostasis/allostasis.

• Occurs via opponent processes.

• Body seeks to restore balance when disrupted by drugs.

• ‘Equal and opposite reaction’ principle.

• Such changes promote opposite withdrawal effects.

Mechanisms of Tolerance

• Functional tolerance: Cell adaptation/neuroadaptation

  • Changes in receptor number, sensitivity.

  • Changes in neurotransmitter production and/or receptor number/density/sensitivity.

  • Decreased activity of the nervous system in response to drug.

  • Compensatory reaction & learning.

  • E.g., coffee drinkers: caffeine speeds up heart / body slows down heart

  • MDMA: massive monoamine release → subsequent high

  • Neurons downregulate, disrupts acute monoamine production

  • Acute depression & negative reinforcement

Functional Tolerance (Pharmacodynamic Tolerance)

• Acute tolerance (occurs within one session).

  • E.g. alcohol impairment of STM (greater impairment when BAC is rising than when falling).

  • Cocaine - diminishing returns across a session; greatest for the first use of a session); continue consuming until supply finishes.

Contingent Drug Tolerance

• Anticonvulsant effect of alcohol.

• Rats received alcohol either before or after a convulsant shock.

• Duration of convulsion measured and compared across groups.

• Tolerance to convulsive shocks observed only in the ‘before’ group.

Dispositional Tolerance

• Pharmacokinetic tolerance (increase in metabolism - drug is removed faster).

• Emphasis: getting the drug to the NS.

• Liver enzyme test (to index liver activity).

Cross-Tolerance

• Regular use of one drug affects the dose of another drug.

• Common biochemical mechanisms between drugs.

• Becoming tolerant to one means tolerant to another.

• E.g., LSD & psilocybin; alcohol & benzodiazepines.

Behavioral Tolerance

• User learns (sub/consciously) to compensate for drug effects.

• Drug dose produces a smaller effect.

• E.g., alcohol impairment of coordination

  • Learn to walk with lower center of gravity

• Anticipatory mechanisms (e.g., smell of coffee -> increased heart rate)

• Classical conditioning principles (repeated priming: one stimulus gets associated with another)

Conditioned Drug Tolerance

• Compensatory response theory.

• Hypothermic effects of alcohol tolerance.

• Potential drug overdose.

• Conditioned sensitization.

• Conditioned-withdrawal effects

• Situational specificity of tolerance to the hypothermic effects of alcohol in rats

• Opposing effects of tolerance vs. withdrawal

Drug Withdrawal

• Relationship between tolerance & dependence

• Chronic consumption → physical dependence

• Neuroadaptations

• Sudden cessation (detox) can promote adverse effects (i.e., withdrawal)

  • Physical

  • Emotional

  • Cognitive

  • Sexual

Part C: Nucleus Accumbens, Brain Regions, and Biopsychological Models of Addiction

Human Biopsychological Models of Addiction

• Development of addiction:

  • Initial drug exposure -> repeated drug taking -> habitual drug taking -> craving & relapse

Model of Interacting Circuits Underlying Addiction

1. Binge/Intoxication: Reinforcing effects of drugs — reward neurotransmitters and engage the NaCC (via dopamine).

   • Positive-incentive model

   • Incentive-Sensitization.

2. Withdrawal stage: Extended amygdala — varies across drugs.

3. Preoccupation/Craving: Relies on the conditioned reinforcement and regulatory control. Difficulty inhibiting drug use related to the prefrontal cortex.

   • Incentive-Sensitization.

   • PFC: Regulatory control

• Three stages of the addiction cycle

Brain Networks Involved in Addiction

• Mesolimbic Pathway

  • Arises from the ventral tegmental area (VTA) projecting to the Nucleus Accumbens (NAc)

  • Direct goal-oriented behaviors

  • Responsible for increasing stimuli's salience or importance, effectively making them desired incentives

• Nigrostriatal Pathway

  • Arises from dopamine neurons in the substantia nigra projecting to the dorsal striatum

  • Critical for translating recurring reward signals into habits

• Mesocortical Pathway

  • Connects different PFC areas with various striatum subregions

  • Implicated in cognitive aspects, impulsivity, compulsivity, and reward processing in addiction.

Developments in Biopsychological Models of Addiction

• Physical dependence model

• Positive-incentive model

• Dopamine models

• Incentive-sensitization theory

• Prefrontal cortex: regulatory control

Physical Dependence Model

• Vicious cycle of drug-taking and physical dependence (including withdrawal symptoms)

• Maintain use to offset withdrawal

• However - some caveats/challenges….

  • High relapse rates even after withdrawal/detoxification

  • Many addictive drugs (i.e., amphetamines) ≠ severe withdrawal

• New proposition: focuses on positive effects (hedonic features) rather than avoiding withdrawal ….

• Positive-incentive theories of addiction

Positive Incentive Models

• Reward system activation: Exposure to rewarding stimuli increases dopamine release.

• Key pathway: The mesolimbic pathway, originating in the VTA and linked to the nucleus accumbens, drives reward-related behavior.

• Drug effects: Addictive substances stimulate VTA dopamine neurons, boosting dopamine in the nucleus accumbens.

• Additional pathway: The mesocortical pathway extends from the VTA to the cerebral cortex, influencing frontal lobe functions.

• Importance: The mesocorticolimbic pathway is essential for the brain's reward system.

Dopamine Model of Addiction

• Defining study by Olds & Milner (1954)

• Rats willingly & repeatedly self-stimulate particular areas of the brain with electricity.

• These ‘reward sites’ were described as those which mediate pleasurable effects of natural rewards.

• Further studies noted intracranial self-stimulation is associated with increased dopamine release in mesocorticolimbic pathway.

• Dopamine agonists increase self-stimulation, dopamine antagonists & lesions of mesocorticolimbic pathway decrease it.

Later Evidence from Animal Models

• Researchers further explored specific sites within the mesocorticolimbic dopamine pathway (Nestler, 2005).

• Focused on nucleus accumbens: Dopaminergic pathways from the VTA to the nucleus accumbens identified as reward/pleasure pathway.

• Lesions to VTA or nucleus accumbens blocked self-administration of drugs (drug-associated cue preferences).

• Self-administration of addictive drugs associated with elevated levels of extracellular dopamine in the nucleus accumbens.

Research Shortcomings (Positive Incentive & Dopamine Models)

• Do Lab conditions reflect human conditions?

  • If rats were given non-drug reinforcers, what would happen?

  • Would it reduce drug taking?

  • Effect of environmental cues?

• Focused mainly on stimulants

  • Majority of drug self-administration studies conducted with stimulants. However drugs such as opioids and cannabinoids have different effects on the dopamine pathways.

• Why do humans continue drug use even when it is not pleasurable?

• Recent animal studies demonstrated that cue-exposure led to rats overcoming aversive situations (electricity) to obtain cocaine and not sucrose (Barnea-Ygael et al., 2011)

Incentive Sensitization Theory (Robinson & Berridge, 1993)

• Positive-incentive value of addictive drugs increases from repeated drug use (especially in vulnerable individuals)

  • Increases the pathological incentive motivation ('wanting') to seek/consume the drug beyond just pleasure.

• Therefore, habitual use is not just from hedonic values (liking) but also the anticipated pleasure (i.e. wanting/craving).

• Neurobiology: different circuitry for wanting vs liking drug.

  • Dopamine release in NaCC more closely related to ‘wanting’ the drug.

• Urge intensity depends both on the cue’s reward association and on the current state of dopamine-related brain systems in an individual.

• State of 'wanting' amplified by brain states (such as stress, emotional excitement or intoxication) that increase dopamine reactivity.

Incentive Sensitization Theory: Example

• Amphetamine microinjection into the NAcc enabled Pavlovian reward cues in incentive paradigm to trigger use.

• Sensitization due to previous amphetamine administration promotes associated rewards even when drug free

• How?

  • Rats learned to lever press for sucrose pellets.

  • Amphetamine sensitization = six daily injections of amphetamine.

  • Rats were tested for lever pressing 10 days later

  • Cue-triggered pursuit of sucrose reward was assessed by increases in pressing sucrose-associated lever during presentation of sucrose cue.

  • Reference: Wyvell, C. L., & Berridge, K. C. (2001). Incentive sensitization by previous amphetamine exposure: increased cue-triggered "wanting" for sucrose reward. The Journal of Neuroscience, 21(19), 7831–7840. https://doi.org/10.1523/JNEUROSCI.21-19-07831.2001

Prefrontal Cortex: Impaired Regulatory Control (Goldstein and Volkow, 2011)

• Basic Premise:

  • Impaired control (top-down inhibition) over compulsive drug use despite risks.

• Circuitry Involvement:

  • Mesolimbic reward system includes interconnected limbic and prefrontal circuits.

  • Limbic system linked to drug incentive-sensitization (Robinson & Berridge, 2001)

  • Prefrontal circuitry linked to compulsive drug-seeking behaviors (Goldstein & Volkow, 2002; Jentsch & Taylor, 1999; Lubman et al., 2004).

• Neuropsychological Impact:

  • Chronic exposure to addictive drugs linked to abnormalities in frontostriatal circuitry

  • Associated impairments in executive functions, inhibition, and decision-making (Feil et al., 2010).

Neuroimaging Evidence

• Orbitofrontal Cortical Activation: Increased orbitofrontal cortical activation in active cocaine abusers during a cocaine theme interview compared to a neutral theme interview (Volkow et al., 1999).

• Reduced Glucose Metabolism: Lower relative glucose metabolism in the prefrontal cortex (PFC) and anterior cingulate gyrus of a cocaine abuser compared to controls (Volkow et al., 1992).

• Lower Striatal Dopamine D2 Receptor Binding: Lower striatal dopamine D2 receptor binding in drug users during withdrawal across a range of drugs (cocaine, methamphetamine, alcohol) compared to controls (Goldstein, R. Z., & Volkow, N. D. (2002).)

Take Home Message

• Developing neurobiological models of addiction is complex process and constantly evolving.

• Biopsychological Models of Addiction recruit a number of interconnected brain circuits with a range of functions.

• Neurobiological models are being advanced by both animal and human studies.

• Very exciting field of research with real-life implications.