Drug Use and Addiction Flashcards

Basic Principles of Drug Action

• Routes of administration:
  • Ingestion/oral
  • Injection: SC (subcutaneous), IM (intramuscular), IV (intravenous)
  • Inhalation: gases, smoke
  • Intranasal
  • Transdermal

Cell Membranes and Drug Absorption

• Cell membranes:
  • All cells are surrounded by a double layer of fat molecules (lipid bilayer).
  • Each lipid molecule has a negatively charged head and an uncharged tail region.
  • Large protein molecules are embedded in the lipid bilayer, integral to information flow along neurons.
• Drug absorption:
  • For a drug to be absorbed, it must pass through cell membranes.
  • It must be lipid-soluble to dissolve in the lipid molecules and pass via diffusion, or
  • Be carried through by a specialized transporter molecule.

Absorption Rates by Administration Route

• The graph illustrates the concentration of drug in blood over time for different administration routes.
  • i.v./inhalation: intravenous/inhalation
  • i.p.: intraperitoneal
  • S.C.: subcutaneous
  • i.m.: intramuscular
  • p.o.: per os / oral

Drug Action, Metabolism, and Elimination

• Drug penetration of CNS: Blood-brain barrier (BBB)
• Mechanisms of drug actions:
  • Agonist and antagonist effects on neurotransmitters (NTs)
• Drug metabolism and elimination

Mechanisms of Drug Actions

• Most drugs interfere with the chemical process at a synapse.
• Drugs alter the synaptic process by:
  • Mimicking NTs and occupying their receptor sites.
  • Decreasing the activity of enzymes that create or destroy NTs.
  • Altering NT reuptake.
  • Altering the activity of a second messenger.
  • Interfering with ion channels.
  • Changing the amount of NT released.

Agonistic and Antagonistic Drug Effects

• Agonistic Drug Effects:
  • Increase the synthesis of neurotransmitter molecules (e.g., by increasing the amount of precursor).
  • Increase the number of neurotransmitter molecules by destroying degrading enzymes.
  • Increase the release of neurotransmitter molecules from terminal buttons.
  • Bind to autoreceptors and block their inhibitory effect on neurotransmitter release.
  • Bind to postsynaptic receptors and either activate them or increase the effect of neurotransmitter.
  • Block the deactivation of neurotransmitter molecules by blocking degradation or reuptake.
• Antagonistic Drug Effects:
  • Block the synthesis of neurotransmitter molecules (e.g., by destroying synthesizing enzymes).
  • Cause the neurotransmitter molecules to leak from the vesicles and be destroyed by degrading enzymes.
  • Block the release of the neurotransmitter molecules from terminal buttons.
  • Activate autoreceptors and inhibit neurotransmitter release.
  • Act as a receptor blocker; binds to the postsynaptic receptors and blocks the effect of the neurotransmitter.

Plasticity of Physiology & Neurophysiology

• The CNS is not static; changes take place in response to drug taking (e.g., increase in receptor sites, increase in sensitivity of receptors, etc.).
• Such plasticity may account for drug tolerance.

Drug Tolerance, Withdrawal Effects, & Physical Dependence

• Drug tolerance
  • Measured via dose-response curves.
  • Types:
    • Metabolic: decrease in the amount of the drug reaching the target cells.
    • Functional: decrease in the ability of the drug to influence the target cells.
• Drug withdrawal effects
• Physical dependence

Tolerance

• Tolerance: decreased sensitivity to a drug’s effects, usually resulting from prior exposure (repeated administrations), necessitating an increased dose to maintain its effect.
• Related concepts:
  • Cross-tolerance: tolerance to one drug diminishes the effect of another drug.
  • Acute tolerance & tachyphylaxis: tolerance after one drug administration.
  • Sensitization (reverse tolerance): less common than tolerance; refers to increased effects of a drug usually following repeat administrations.

Drug Tolerance Dose-Response Curve

• Drug tolerance is a shift in the dose-response curve to the right as a result of exposure to the drug.

Tolerance and Withdrawal

• The same adaptive neurophysiological changes that develop in response to drug exposure and produce drug tolerance manifest themselves as withdrawal effects once the drug is removed.
• As the neurophysiological changes develop, tolerance increases; as they subside, the severity of the withdrawal effects decreases.

Drug Addiction

• Use drugs despite adverse effects, and despite attempts to stop using it.
• Addiction is not the same as physical dependence.
• Addiction is not restricted to drugs.

Contingent Drug Tolerance

• Contingent drug tolerance: tolerance that develops only to drug effects that are actually experienced.
• Tested in before-and-after experiments (drug-before-test vs drug-after-test conditions).
• Pinel research on ethanol and convulsions.

Contingent Tolerance

• Rats that received alcohol before each convulsive stimulation became tolerant to its anticonvulsant effect; those that received alcohol after each convulsive stimulation did not become tolerant.

Conditioned Drug Tolerance

• Conditioned drug tolerance: drug predictive stimuli
• Research:
  • Potential drug overdose
  • Siegal conditioned compensatory response theory
  • Pavlovian conditioning
  • Conditioned sensitization
    • Occurs for both interoceptive and exteroceptive stimuli
  • Conditioned-withdrawal effects

Conditioned Tolerance

• The situational specificity of tolerance to the hypothermic effects of alcohol in rats is demonstrated.

Specific Drugs

• Nicotine
  • Psychoactive ingredient (acts on nicotinic receptors)
  • Highly addictive
  • Leading cause of preventable death
  • Drug craving
  • Buerger’s disease/smoker’s syndrome
  • Effects/teratogenic effects
• Alcohol
  • Both fat and water-soluble
  • Depressant
  • Effects
  • Tolerance and physical dependence
  • Withdrawal syndrome
  • Fetal alcohol syndrome
• Cannabis
  • Cannabis plant
  • THC and other psychoactive compounds
  • Administration
  • Effects
  • Addiction/tolerance/withdrawal
  • Binds anandamide
  • Clinical benefits
• Cocaine and Other Stimulants
  • Stimulants/potency
  • Cocaine
    • Administration of cocaine
    • Addiction/tolerance/withdrawal
    • Mechanism of action
    • Effects
  • Amphetamines and methamphetamines
    • Administration varies
    • Highly addictive
    • Mechanisms of action
    • Effects
• Opioids: Heroin and Morphine
  • Opiate examples
  • Analgesics
  • Highly addictive/tolerance/withdrawal
  • Effects
  • Side effects
  • Bind to opioid receptors
  • Treatments (methadone/buprenorphine)

Interpreting Studies of the Health Hazards of Drugs

• Most are correlational.
• Most use the most addicted populations.

Prevalence of Drug Use in US

• Figure illustrates the global prevalence of addiction to each of six commonly used psychoactive drugs (used in past month).

Australian Smoking Prevalence and Tobacco Control Measures

Australian smoking prevalence (daily) and key tobacco control measures in Australia from 1990 to 2023:

• 1990: Advertising ban in print media
• 1993: Tobacco Advertising Prohibition Act
• Increase in tobacco excise
• 1995: Health warnings on packs
• 1997: First National Tobacco Campaign
• 1998-2006: Point-of-sale advertising bans
• 2003: Smoke-free dining
• 2006: Graphic health warnings on packs
• 2007-2014: Smoking ban in the home and cars with minors
• 2008: Tackling Indigenous Smoking Initiative
• 2010: 25% excise rise
• 2011: Point-of-sale display bans
• 2012: Plain packaging and new larger health warnings
• 2013: First 12.5% excise rise
• 2014-2020: 12.5% excise rises on 1 Sep. each year
• 2023: First of 3 5% excise rises
• 2024: New tobacco legislation

Australian Alcohol Consumption Frequency

• Figure shows Australian alcohol consumption frequency from 2001 to 2023.
• Drinking status includes daily, weekly, monthly, less often than monthly, ex-drinker, and never a full glass of alcohol.

Australian Illicit Drug Use

• Figure illustrates Australian illicit drug use (past 12 months) from 2001 to 2023.
• Drug types include any illicit drug, cannabis, cocaine, ecstasy, inhalants, hallucinogens, pain-killers/pain-relievers and opioids, and methamphetamine and amphetamine.

Physical-Dependence and Positive-Incentive Perspectives

• Physical-Dependence:
  • Withdrawal avoidance
  • Withdrawal in observed setting leads addicted individuals to return to use
• Positive-Incentive:
  • Take drugs for pleasurable effects

Intracranial Self-Stimulation & the Mesotelencephalic DA System

• 1950s Olds and Milner activate reward circuits
• Mesocorticolimbic pathway:
  • Substantia nigra
  • Ventral tegmental area
  • Nucleus accumbens
• Evidence:
  • Brain sites at which self-stimulation occurs are part of mesocorticolimbic pathway
  • Intracranial self-stimulation often associated with increase DA release in the mesocorticolimbic pathway
  • DA agonists tend to increase intracranial self-stimulation, & DA antagonists tend to decrease it
  • Lesions of the mesocorticolimbic pathway tend to disrupt intracranial self-stimulation.

Intracranial Self-Stimulation

• A rat pressing a lever to obtain rewarding brain stimulation.
• Stimulator delivers electrical stimulation.
• Lever press activates stimulator.

The Mesotelencephalic Dopamine System

• The mesotelencephalic dopamine system in the human brain, consisting of the nigrostriatal pathway (green) and the mesocorticolimbic pathway (red).

Early Evidence of the Involvement of DA in Drug Addiction

• Drug self-administration paradigm
• Conditioned place-preference paradigm

Drug Self-Administration & Conditioned Place Preference

• Two behavioral paradigms used extensively in the study of the neural mechanisms of addiction:
  • Drug self-administration paradigm
  • Conditioned place-preference paradigm

Nucleus Accumbens and Drug Addiction

• Dopamine in the nucleus accumbens
  • Critical to experience of reward and pleasure
  • Self-administer addictive drugs to nucleus accumbens
  • Lead to conditioned place-preferences
  • Reinforcers release dopamine in nucleus accumbens

Timeline of Addiction Theory

• Evolution of theories about the brain mechanisms of addiction over time.
• 1950s: Original Theories of Drug Tolerance and Physical Dependence
• 1960s:
  • Dopamine and Intracranial Self-Stimulation
• 1970s:
  • Role of Conditioned Responses in Drug Tolerance
  • Mesocorticolimbic Pathway: Mechanisms of Reward
  • Physical-Dependence Theories of Addiction
• 1980s and 1990s:
  • Role of Conditioned Responses in Drug Craving and Relapse
  • Positive-Incentive Theories of Addiction
• 21st Century: Current Theories of the Brain Mechanisms of Addiction

Stages in the Development of an Addiction

• Initial drug taking
• Habitual drug taking
  • Positive incentive value (vs hedonic value)
  • Incentive-sensitization
  • Dopamine in the nucleus accumbens
• Drug craving and addiction relapse
  • Stress
  • Drug priming
  • Conditioned environmental cues

Three Stages In Addiction

• Drug Craving
• Initial Drug Taking
• Habitual Drug Taking and Repeated Relapse

Incubation of Cocaine Craving

• Increase in cocaine craving in rats that were previously self-administering cocaine after cocaine withdrawal

Current Concerns about the Drug Self-Administration Paradigm

• Enriched environments
• Excessive focus on stimulants

A Noteworthy Case of Addiction

• Sigmund Freud
  • Cocaine
  • Oral cancer