Neurobiology of Substance Abuse

The Neurobiology of Substance Abuse

Key Learning Outcomes

  • Understanding the scale of substance use in Australia.
  • Definitions and conceptualization of substance use, including factors underlying vulnerability.
  • How neurobiologists use animal models to investigate the biological basis of substance use and addiction.
  • Neuronal circuits involved in the rewarding, affective, and anticipatory components of addiction.
  • Pharmacology of commonly abused drugs like opioids and alcohol.

Neurobiology of Addiction

  • Drug addiction (or substance dependence) is a chronically relapsing disorder characterized by:
    • Compulsion to seek and take the drug.
    • Loss of control in limiting intake.
    • Emergence of a negative emotional state (dysphoria, anxiety, irritability) when access to the drug is prevented.

Modern Views on Drug Use

  • Three types of drug use:
    1. Occasional, controlled, or social use.
    2. Drug abuse or harmful use.
    3. Drug addiction.
  • Progression: Occasional use → Abuse → Addiction

Substance Use Statistics in Australia (2022-2023)

  • E-cigarettes:
    • More people are using e-cigarettes than ever before.
    • Approximately 1.5 million people in Australia were using e-cigarettes.
    • People aged 18-24 were most likely to use e-cigarettes.
    • About 54% of e-cigarettes used contained nicotine.

Changes in Illicit Drug Use (2019 to 2022-2023)

  • Increases in use:
    • Hallucinogens: 1.6% to 2.4%
    • Cannabis: 11.5% to 11.6%
    • Cocaine: 2.1% to 2.7%

Recent Illicit Drug Use by Gender (18-24 years)

  • Data on the percentage of males and females using various illicit drugs.
  • Includes marijuana/cannabis, cocaine, pain-relievers and opioids.

Links Between Risky Behaviors

  • Links between daily smoking, risky drinking and recent illicit drug use.
  • Risky drinking is defined as having more than two standard drinks per day on average or more than four standard drinks on one occasion at least once a month
  • Recent illicit drug use: use of at least 1 of 16 drugs in the past 12 months

Prevalence of Dependence Among Users (1990-1992)

  • Estimated prevalence among 15-54 year olds of non-medical use and dependence among users from The National Comorbidity Survey:
    • Tobacco > heroin > cocaine > alcohol > cannabis

Social Costs of Drug Use (Australia)

  • Tobacco: 136.9 billion

Terminology

  • Substance use.
  • Substance intoxication.
  • Substance abuse.
  • Dependence.

Substance Use

  • Substance: chemical compounds ingested to alter mood or behaviour.
  • Does not interfere with social, educational, or occupational functioning.

Substance Intoxication/Abuse

  • Intoxication:
    • Impaired judgement, mood changes, impaired motor ability.
    • Depends on the drug, amount ingested, and individual biological differences.
  • Substance abuse:
    • Significant interference with the user’s life.

Dependence

  • Physiological:
    • Physiological dependence on the drug.
    • Tolerance: increasingly greater amounts needed for the same effects.
    • Withdrawal: negative physical response when the substance is not ingested.
  • Behavioral:
    • Drug-seeking behaviors.

Withdrawal: Opiates

  • Early symptoms:
    • Agitation, anxiety, muscle aches, insomnia, runny nose, sweating, yawning.
  • Late symptoms:
    • Abdominal cramping, diarrhea, dilated pupils, goose bumps, nausea, vomiting.

Stages of Addiction

  • Genetic variables, environmental factors, stress, and conditioning effects contribute to the stages of addiction:
    1. Acute Reinforcement/Social Drug-Taking.
    2. Escalating/Compulsive Use.
    3. Binge Drinking.
    4. Dependence.
    5. Withdrawal.
    6. Protracted Withdrawal.
    7. Relapse.
    8. Recovery.

Psychiatric View of Addiction

  • Impulse Control Disorders:
    • Tension → arousal → pleasure/relief/self-gratification → regret/guilt/self-reproach.
  • Compulsive Disorders:
    • Anxiety/stress → obsessions → repetitive behaviors → relief of anxiety/relief of stress.
  • Addiction progresses from impulsivity to compulsivity.

Vulnerability to Addiction

  • Highly heterogeneous; patterns leading to dependence are diverse.
  • Individual differences in:
    • Temperament (disinhibition/behavioral activation, sensation seeking, negative affect).
    • Comorbidity.
    • Social development.
    • Genetics.
    • Protective factors.
  • Initiation: social/environmental factors.
  • Abuse → Addiction: neurobiological factors.

Vulnerability to Addiction: Comorbidity

  • 12-month prevalence of comorbid disorders among responders with nicotine dependence, alcohol dependence and any substance use disorder

Vulnerability to Addiction: Population Comorbidity

  • Males: Anxiety and substance abuse
  • Females: Anxiety and substance abuse

Social Development

  • Developmental factors are important components of vulnerability.
  • Adolescent exposure to alcohol, tobacco, or drugs of abuse leads to significant vulnerability to dependence.

Vulnerability to Alcohol/Nicotine/Illicit Drug Dependence

  • Age of first intoxication/nicotine use/drug use is correlated with increased risk of alcohol/nicotine/illicit drug dependence.

Genetic Vulnerability: Heritability Estimates

  • Heritability (h^2) describes how much of the variation in a given trait can be attributed to genetic variation.
    • Alcohol (AUD): h^2 = 0.50-0.64
    • Nicotine (NicUD): h^2 = 0.30-0.70
    • Cannabis (CanUD): h^2 = 0.40-0.80
    • Opioid (OUD): h^2 = 0.50
    • Cocaine (CocUD): h^2 = 0.40-0.80
  • Protective factors: Acetaldehyde dehydrogenase

Neuronal Circuits Involved in Substance Dependence

  • Animal laboratory models help understand the stages of the addiction cycle (intracranial self-stimulation).

Animal Laboratory Models for Stages of Addiction Cycle

  • Binge/Intoxication:
    • Intracranial self-stimulation, self-administration, conditioned place preference.
  • Withdrawal/Negative Affect:
    • Behavioral observations, conditioned place aversion, anxiety-like behavior.
  • Preoccupation/Anticipation (Craving):
    • Reinstatement (drug-induced, cue-induced, stress-induced).

Binge/Intoxication: Self Administration

  • Lever pressing leads to drug injection.

Binge/Intoxication: Self Administration Example Data

  • Unit dose of opioid

Binge/Intoxication: Conditioned Place Preference

  • Rats prefer the drug side after conditioning.

Withdrawal/Negative Affect: Behavioral Observation

  • Animals display signs and symptoms of withdrawal like people.
  • Examples: escape attempts, wet-dog shakes, facial fasciculations, diarrhea, vocalization, irritability on handling, abnormal posture, ptosis, eye-blinks, weight loss.

Withdrawal/Negative Affect: Conditioned Place Aversion

  • Rats prefer the non-withdrawal side after conditioning.

Clinical Focus: Precipitated Withdrawal

  • Occurs when a full agonist (e.g., heroin) is displaced from opioid receptors by an antagonist (e.g., naloxone).
  • Similar to regular withdrawal but more intense and faster onset.

Preoccupation/Anticipation (Craving): Reinstatement

  • The chronic relapsing nature of addiction.
  • Cues become associated with drug actions via classical conditioning.
  • Cues elicit subjective states that trigger use.
  • Human studies show that drug-associated stimuli increase relapse likelihood, craving, and motivation to seek drugs.

Extinction - Reinstatement

  • Extinction measures motivational properties of drugs.
  • Subjects trained to self-administer a drug until stable, then the drug is removed.
  • Extinction sessions occur without the drug.

Drug-Induced Reinstatement (Relapse)

  • Relapse induced by drug.

Cue-Induced Reinstatement (Relapse)

  • Relapse induced by cues associated with the drug.

Clinical Focus

  • Examples of drug-associated cues (alcohol bottles, paraphernalia).

Stress-Induced Reinstatement (Relapse)

  • Relapse more likely under stress.
  • Animal models show stressors elicit recovery of drug-seeking behavior in the absence of further drug availability.

Neurocircuitry of Addiction

  • From animal models, we understand neuronal circuits controlling addiction.
    • Binge intoxication: Reward circuits.
    • Withdrawal/Affect: Stress/Arousal circuits.
    • Preoccupation/Anticipation: Limbic forebrain.

Reward Circuits: Dopamine

  • Mesolimbocortical pathway:
    • Ventral tegmental area (VTA) projects to the nucleus accumbens, cortex, and hippocampus.
  • Mesostriatal pathway:
    • Substantia nigra projects to the striatum (caudate and putamen).
  • Acute rewarding properties associated with activation of mesolimbocortical dopamine system.

Reward Circuits: VTA - Nucleus Accumbens

  • Dopamine levels increase during self-administration of drugs like cocaine.

Circuits: Binge/Intoxication

  • Nucleus accumbens and dorsal striatum involved in reinforcement and habits.
  • Dopamine from VTA plays a key role.

Withdrawal/Affect: Stress/Arousal Circuits

  • The extended amygdala (CeA, BNST, NAc shell) plays a key role in fear conditioning and the emotional component of pain perception
  • May represent a common anatomical pathway to integrate stress/arousal systems with hedonic systems to produce negative reinforcement mechanisms associated with the development of addiction
  • Acute withdrawal from all drugs of abuse activate HPA-axis

Preoccupation/Anticipation: Limbic Forebrain

  • Key element in relapse (craving).
  • Drug-induced reinstatement:
    • Medial prefrontal cortex ↔ nucleus accumbens ↔ ventral pallidum.
  • Cue-induced reinstatement:
    • Basolateral amygdala ↔ medial prefrontal cortex.
  • Stress-induced reinstatement:
    • CRF and NE in the extended amygdala.

Summary Circuits

  • Multiple brain regions and circuits are disrupted in drug addiction and are likely to contribute differentially to the complex phenotype observed in addicted individuals.
  • Parallel to the neuroplasticity of the neurocircuitry are the molecular changes that occur in these same structures.
  • Therapeutic targets : Pharmacological and Behavioural.

Opioids

  • Originally derived from extracts of the opium poppy.
  • Endogenous opioid system: peptide neurotransmitters.
  • Major medical uses, high abuse potential.

Opioids: Abuse

  • Heroin: 1.4% lifetime prevalence among Australians.
  • Oxycodone (OxyContin):
    • US: 1.9 million used non-medically at least once.
    • Australia: 51% of injection drug users have used oxycodone; 27% via i.v.

Endogenous Opioids

  • Produced by proteolytic cleavage of large protein precursors (Enkephalin, Dynorphins, β-endorphin).
  • Bind to opioid receptors (Mu, Delta, Kappa).
  • Involved in nociception and analgesia, responses to stress, endocrine and immune function, mood, addictive behaviors.
  • Morphine binds predominantly with the μ-opioid receptor
  • Oxycodone binds predominantly with the κ-opioid receptor

Opioid Receptors

  • Opioid receptors are broadly expressed throughout the brain.

Pharmacokinetics (Heroin)

  • Heroin injected i.v. rapidly enters the blood, and smoking peaks at 1-5 min reaching limits of detection at 30 min.
  • Heroin doesn’t bind to opioid receptors.
  • Prodrug

Mechanism of Opioid Reward

  • Microinjection studies implicate the mesolimbic dopamine system.
  • Systemic or intra-VTA opiates increase the firing rate of dopamine neurons and increase dopamine release in the nucleus accumbens.
  • Blocked by μ-opioid receptor antagonists.

Mechanism of Opioid Tolerance

  • Acute administration disrupts homeostasis, chronic use leads to an adaptive mechanism that compensates for the acute effects to restore homeostasis.
  • Tolerance: same dose, different effects.
  • Cessation of the drug stops the drug effects, but the adaptive mechanism is still in place.
    • Withdrawal

Modes of Treatment for Opioid Dependence

  • Detoxification:
    • "Cold turkey" refers to termination of the drug without pharmacological intervention
    • With pharmacological intervention such as long acting opioid drugs (methadone, buprenorphine) or non-opioid drugs (clonodine, α2$$-adrenoceptor agonist).
  • Methadone maintenance:
    • Provides medically safe pharmacological relief for narcotic craving. Oral administration has mild euphoric actions (Cue-induced relapse).
  • Opioid antagonists:
    • Naltrexone (μ-opioid receptor antagonist)
    • Abrupt onset of withdrawal symptoms
    • Blocks rewarding effects of opioids

Alcohol

  • Earliest drug in common use.
  • Ethanol is the only one suitable for drinking.
  • Fermentation product of yeast.
  • Any carbohydrate that can be turned into sugar can be used to make alcohol.

Pharmacokinetics (Alcohol)

  • Rarely consumed in pure state - 5% beer; 10-12% wine; 40% liquor.
  • Reaction to alcohol intake varies.
    • Stomach absorbs only 10%.
    • Most rapid when ingested in 15-30% solution. Higher concentrations delay absorption by inhibiting gastric peristalsis and producing spasm of the pylorus.
    • Stomach contents: presence of food slows diffusion of alcohol.
    • Body size and gender

Alcohol: Behavioral Effects

  • Progression of subjective and physiological changes corresponding to increased blood alcohol levels. Includes normal behaviour, relief from anxiety, disinhibition, sedation, hypnosis, general anesthesia, coma, and death.

Metabolism (Alcohol)

  • Balance between absorption and metabolism determines the effects of alcohol consumption.
  • Liver - 90%; 10% lungs, urine, skin.
  • 0. 016% BAC/h
  • 6-8 g/h; maximal amount in 24 h, 170 g

Alcoholism and Alcohol Drinking Habits Predicted from Alcohol Dehydrogenase Genes

  • Genetic factors influence drinking habits and alcoholism.
  • ADH1B and ADH1C genetic variations affect alcohol degradation rate.

Alcohol & GABA

  • Alcohol activates GABAA receptors and increases inhibitory effects.
  • Major inhibitory neurotransmitter in the CNS.
  • GABAA – ligand gated Cl- channel

Alcohol interacts with the GABAA receptor

  • Benzodiazepines work by increasing the efficiency of GABA to decrease the excitability of neurons. Predominantly bind to the benzodiazepine site on GABAA receptors, but also GABAB receptors
  • Benzodiazepine receptors sites show widespread distribution throughout the brain

Modes of Treatment for Alcohol Dependence

  • Pharmacotherapy
    • Drugs for acute effects
    • Drugs for withdrawals
    • Disulfiram therapy (Antabuse):
      • Inhibitor of Aldehyde dehydrogenase
      • Results in toxic levels of acetaldehyde in bloodstream
    • Naltrexone:
      • Hypothesized that naltrexone diminishes the rewarding effects of alcohol
  • Non-drug approaches
    • Individual psychotherapy
    • Alcoholics Anonymous
    • Behavioural therapy

Summary

  • Drug addiction (or substance dependence) is a chronically relapsing disorder.
  • Drug addiction has been conceptualized as a disorder that progresses from impulsivity to compulsivity -Binge/intoxication → Withdrawal/Negative Affect → Preoccupation/Anticipation (craving).
  • Addiction is controlled by networks of brain systems - Mesolimbic dopamine systems in VTA and nucleus accumbens.
  • Drugs of abuse interact with neurotransmitter systems.