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Neurotransmitters and Neuropharmacology

Neurotransmitters and Neuropharmacology

Page 1: Introduction to Neurotransmitters and Neuropharmacology

  • Context of Neuropharmacology: Discussion begins with the stark reality of US drug overdose deaths.
  • Statistics: In the 12 months leading up to the presented data, there were 77,584 drug overdose deaths.
  • Primary Culprits: The majority of these deaths involved opioids, particularly fentanyl and other synthetic opioids.
  • Visual Data: A graph illustrates the rising trend of drug overdose deaths from 2015 to 2024, with fentanyl/synthetic opioids showing a steep increase.

Page 2: Case Study: Sheila and Tetanus

  • Patient Scenario: Sheila has tetanus.
  • Mechanism of Tetanospasmin: The tetanus toxin (tetanospasmin) binds irreversibly to the membrane at the synapse.
  • Impact: This binding blocks the release of glycine from axon terminals.
  • Physiological Consequence: Glycine is an inhibitory neurotransmitter. Its blockage leads to generalized rigidity, a severe symptom known as opisthotonus (a severe hyperextension and spasticity in which an individual's head, neck, and spinal column enter a complete opisthotonic posture).

Page 3: Synaptic Transmission

  • Focus: Understanding the intricate process of communication between neurons at the synapse.
  • Steps of Synaptic Transmission:
    1. Action Potential Arrival: An electrical signal (action potential) arrives at the synaptic terminal of the sending neuron.
    2. Vesicle Fusion: This arrival triggers synaptic vesicles, which contain neurotransmitters, to fuse with the presynaptic plasma membrane.
    3. Neurotransmitter Release: Neurotransmitters are then released into the synaptic cleft, the space between the sending and receiving neurons.
    4. Neurotransmitter Binding: The released neurotransmitter molecules bind to specific receptors on the membrane of the receiving neuron, often leading to the opening of ion channels.

Page 4: Case Study: Don and Parkinson's Disease

  • Patient Scenario: Don, a retired accountant, developed tremor and slowed movements, diagnosed with Parkinson's disease.
  • Initial Treatment: Levodopa (L-DOPA) was prescribed to restore dopamine levels, as Parkinson's involves a deficiency of dopamine.
  • Symptom Fluctuation and Additional Treatment: A couple of years later, his motor symptoms began to fluctuate. Ropinirole, a dopamine receptor agonist, was added to his treatment.
  • Emergence of Side Effect: A few months after starting ropinirole, Don developed a strong interest in gambling, culminating in a 100,000 loss, which he concealed.
  • Intervention and Resolution: During a consultation, ropinirole was replaced with a monoamine oxidase inhibitor (MAOI) drug. Don subsequently reported that his interest in gambling disappeared.
  • Clinical Implication: This case highlights how dopaminergic medications, particularly agonists, can lead to impulse control disorders like pathological gambling due to their effects on reward pathways in the brain. It also demonstrates how pharmacotherapy adjustments can alleviate such adverse effects.

Page 5 and 6: Two Receptor Subtypes & Synapses

  • Receptor Diversity: A single neurotransmitter can interact with multiple, different receptor types in various brain regions.
  • Ionotropic Receptors (Direct Synapses):
    • Also known as ligand-gated ion channels.
    • Neurotransmitter binding directly causes the ion channel to open.
    • This is a rapid process, directly affecting the postsynaptic cell's membrane potential.
  • Metabotropic Receptors (Indirect Synapses):
    • Neurotransmitter binding activates a G-protein.
    • The G-protein then initiates a cascade of intracellular events which may, in turn, open other ion channels or cause other slower, longer-lasting changes within the cell.
    • These are slower and can lead to more diffuse and complex effects.

Page 7: Metabotropic Receptors in More Detail

  • Prevalence: A significant majority, 75 ext{%}, of all drugs exert their effects by acting on metabotropic receptors.
  • Mechanism:
    1. A neurotransmitter (ligand) binds to the ligand site on the metabotropic receptor, which is embedded in the postsynaptic cell membrane.
    2. This binding activates an associated G-protein (composed of \alpha, \beta, \gamma subunits).
    3. The activated \alpha subunit (often exchanged GDP for GTP) detaches from the \beta and \gamma subunits.
    4. The \alpha subunit (or the G_{\beta\gamma} complex) can then interact with effector proteins.
    5. Example: The \alpha subunit might activate adenylate cyclase.
    6. Adenylate cyclase converts ATP into cyclic AMP (cAMP), a second messenger.
    7. cAMP can then activate protein kinase A (PKA).
    8. PKA can phosphorylate ion channels, causing them to open (e.g., Na^+ influx), or trigger other cellular changes by phosphorylating various proteins.

Page 8: Agonists

  • Definition: An agonist is a substance that initiates the normal physiological effects of a receptor.
  • Examples: This can be a natural ligand (like a hormone or neurotransmitter) or an agonist drug.
  • Action: When an agonist binds, it "opens" the receptor (or initiates its normal signaling cascade), resulting in a biological signal.
  • Partial Agonist: A partial agonist can bind to a receptor and produce a signal, but its maximal effect is less than that of a full agonist (e.g., <100 ext{%} signal compared to a full agonist).
  • Dose-Response: Graphs illustrate how the response increases with increasing concentration of the ligand or agonist, reaching a maximal signal at saturation.

Page 9: Antagonists

  • Definition: An antagonist is a substance that prevents a receptor from being activated by other ligands (including natural ligands or agonists).
  • Action: Unlike agonists, antagonists do not initiate a biological signal themselves; they primarily block the action of other molecules.
  • Types of Antagonists:
    • Competitive Antagonist: Competes with the natural ligand for the same binding site on the receptor. If the antagonist binds, the natural ligand cannot, and no signal is produced. Increasing the concentration of the natural ligand can overcome the competitive antagonism.
    • Noncompetitive Antagonist: Binds to a different site on the receptor (allosteric site) than the natural ligand. This binding alters the receptor's conformation, preventing the natural ligand from binding effectively or from activating the receptor, even if the ligand is bound. Noncompetitive antagonism cannot be overcome by increasing the natural ligand's concentration.
    • Effect on Response: In the presence of an antagonist, the signal or response generated by the natural ligand is reduced or completely abolished.

Page 10: Drugs Can Affect Synaptic Transmission at Many Steps

  • Neuropharmacological Targets (AGO = agonist; ANT = antagonist; NT = neurotransmitter):
    1. Drug serves as precursor (AGO): Increases the amount of neurotransmitter available. Example: L-DOPA for dopamine synthesis.
    2. Drug inactivates synthetic enzyme; inhibits synthesis of NT (ANT): Reduces neurotransmitter production. Example: PCPA for serotonin.
    3. Drug prevents storage of NT in vesicles (ANT): Depletes neurotransmitter availability for release. Example: reserpine for monoamines.
    4. Drug stimulates release of NT (AGO): Increases the amount of neurotransmitter released per action potential. Example: black widow spider venom for ACh.
    5. Drug inhibits release of NT (ANT): Decreases neurotransmitter release. Example: botulinum toxin for ACh.
    6. Drug stimulates postsynaptic receptors (AGO): Directly activates receptors on the receiving neuron. Example: nicotine, muscarine for ACh.
    7. Drug blocks postsynaptic receptors (ANT): Prevents neurotransmitter from activating its receptors. Example: curare, atropine for ACh.
    8. Drug stimulates autoreceptors; inhibits synthesis/release of NT (ANT): Autoreceptors are typically inhibitory. Activating them reduces overall neurotransmission. Example: apomorphine for dopamine.
    9. Drug blocks autoreceptors; increases synthesis/release of NT (AGO): Blocking inhibitory autoreceptors leads to increased neurotransmitter synthesis and release. Example: idazoxan for norepinephrine.
    10. Drug blocks reuptake (AGO): Prevents the reabsorption of neurotransmitter from the synaptic cleft, prolonging its action. Example: cocaine for dopamine.
    11. Drug inactivates acetylcholinesterase (AGO): Prevents the enzymatic breakdown of acetylcholine, prolonging its action. Example: physostigmine for ACh.

Page 11: Classes of Neurotransmitters (Overview)

  • Amino Acids: Major building blocks for proteins and also act as neurotransmitters.
    • Glutamate (excitatory)
    • Aspartate (excitatory)
    • Glycine (inhibitory)
    • GABA (Gamma-aminobutyric acid, inhibitory)
  • Monoamines: Derived from single amino acids.
    • Catecholamines: Synthesized from tyrosine.
      • Dopamine
      • Epinephrine (Adrenaline)
      • Norepinephrine (Noradrenaline)
    • Indolamines: Synthesized from tryptophan.
      • Serotonin
  • Soluble Gases: Unique in their synthesis and action (not stored in vesicles).
    • Nitric oxide
    • Carbon monoxide
  • Acetylcholine (ACh): Unique class, involved in muscle contraction and cognitive functions.
  • Neuropeptides: Larger molecules, often acting as neuromodulators (See Appendix VI for more details).
    • Endorphins

Page 12 and 13: Glutamate: Ionotropic and Metabotropic Receptors, & Excitotoxicity

  • Primary Excitatory Neurotransmitter: Glutamate is the most prevalent excitatory neurotransmitter in the brain.
  • Ionotropic Receptors: Glutamate activates several ionotropic receptors, which are ligand-gated ion channels that directly allow ion flow.
    • Receptor Types & Agonists:
      • AMPA receptor (agonist: AMPA)
      • NMDA receptor (agonist: NMDA)
      • Kainate receptor (agonist: Kainate)
  • Metabotropic Receptors: Glutamate also acts on mGluRs (metabotropic Glutamate Receptors).
    • These receptors are slower in action compared to ionotropic receptors.
  • Excitotoxicity: A critical concept related to glutamate.
    • Neural injury, such as stroke or head trauma, can cause an excessive release of glutamate.
    • This overstimulation of glutamate receptors, particularly NMDA receptors allowing excessive Ca^{2+} influx, leads to a cascade of events that are toxic to neurons, ultimately causing neuronal death.

Page 14: Summary of Glutamate's Actions

  • Presynaptic Neuron: Releases glutamate into the synaptic cleft.
  • Postsynaptic Neuron & Glial Cells:
    • AMPAR (AMPA Receptor): Ionotropic, primarily allows Na^+ influx and K^+ efflux, leading to rapid depolarization and activation of the neuron.
    • NMDAR (NMDA Receptor): Ionotropic, unique for allowing Ca^{2+} influx in addition to Na^+ and K^+ flux. Requires both glutamate binding and depolarization to open (voltage-dependent Mg^{2+} block).
    • mGluR (Metabotropic Glutamate Receptor): Coupled to G-proteins, can either activate (e.g., via Protein Kinase C, PKC) or inhibit (e.g., via Adenylate Cyclase, AC) various intracellular pathways, leading to slower, longer-lasting effects.
    • Glia Cells: Play a crucial role in removing excess glutamate from the synaptic cleft via glutamate transporters, preventing excitotoxicity.
  • Overall Effect: Activation of the neuron and generation of new nerve signals. However, the slide emphasizes that "too much is bad," referring to the concept of excitotoxicity where excessive glutamate can be detrimental.

Page 15 and 16: GABA: Most Common Inhibitory Neurotransmitter

  • Function: GABA (Gamma-aminobutyric acid) is the most common inhibitory neurotransmitter in the brain.
  • GABA_A Receptors:
    • Type: These are ionotropic receptors.
    • Mechanism: When GABA binds to a GABA_A receptor, it causes chloride (Cl^-) channels to open.
    • Effect: The influx of Cl^- ions hyperpolarizes the postsynaptic neuron, making it less likely to fire an action potential, thus producing fast inhibitory effects.
  • GABA Agonists:
    • Drugs that enhance the effects of GABA at GABA_A receptors, such as Valium (diazepam) and barbiturates, are potent tranquilizers.
    • Summary of GABA's Actions (Diagram): The diagram illustrates GABA binding to the GABAA receptor, leading to Cl^- influx and inhibition of the neuron, making the generation of new nerve signals more difficult. Neuroactive steroids and extrasynaptic GABAA receptors are also indicated.

Page 17: Glycine: Major Inhibitory Neurotransmitter in Spinal Cord

  • Primary Location: Glycine is the major inhibitory neurotransmitter found in the spinal cord.
  • Clinical Relevance: Disruptions in glycine function can lead to severe symptoms.
  • Strychnine Action: Strychnine is an antagonist that blocks glycine receptors.
  • **Symptoms of Strychnine Poisoning (and therefore glycine receptor blockade):
    • Symptoms appear rapidly (within 20 minutes).
    • Initial signs include stiffness of the neck, muscle twitching, and a feeling of suffocation.
    • Progresses to violent convulsions where the body arches severely backward (opisthotonus, similar to tetanus).
    • Convulsions may temporarily relax but recur spontaneously or in response to external stimuli like touch or noise, often every few minutes.

Page 18: Classes of Neurotransmitters (Recap)

  • This slide serves as a reiteration of the main categories of neurotransmitters previously introduced:
    • Amino acids (Glutamate, Aspartate, Glycine, GABA)
    • Monoamines (Dopamine, Epinephrine, Norepinephrine - Catecholamines; Serotonin - Indolamines)
    • Soluble gases (Nitric oxide, Carbon monoxide)
    • Acetylcholine
    • Neuropeptides (Endorphins)

Page 19: Catecholamine Synthesis and Clinical Case

  • Synthesis Process: Catecholamines (dopamine, norepinephrine, epinephrine) are synthesized from the amino acid tyrosine.
  • Rate-Limiting Step: Tyrosine hydroxylase is the enzyme that catalyzes the first and rate-limiting step in catecholamine synthesis, converting tyrosine to DOPA.
  • Clinical Case:
    • Patients: Three-year-old identical twins from London.
    • Symptoms: Severely low muscle tone, mental retardation, and seizures.
    • Diagnosis: Biochemical analysis of cerebrospinal fluid (CSF) revealed low activity of tyrosine hydroxylase.
    • Treatment & Outcome: Dopamine infusions temporarily improved their symptoms. This improvement occurred because the dopamine infusion bypassed the dysfunctional tyrosine hydroxylase step, directly providing the downstream neurotransmitter that was deficient.

Page 20: Two Dopamine Pathways in the Brain

  • Mesolimbocortical Pathway:
    • Origin: Ventral Tegmental Area (VTA).
    • Projections: To the nucleus accumbens, cortex, and hippocampus.
    • Functions/Associations: Strongly implicated in addiction, learning, and the pathophysiology of schizophrenia.
  • Mesostriatal Pathway:
    • Origin: Substantia nigra.
    • Projections: To the striatum (comprising the caudate and putamen).
    • Functions/Associations: Crucial for motor control. Degeneration of this pathway is characteristic of Parkinson's disease.

Page 21: Norepinephrine Pathways in the Brain

  • Primary Nucleus: The Locus Coeruleus (often referred to as the "blue spot" due to its appearance).
    • Projections: Sends widespread projections to the hippocampus, basal ganglia, and cortex.
    • Additional projections extend to the spinal cord and cerebellum.
  • Functions/Associations: Involved in regulating mood, arousal (e.g., wakefulness, attention), and sexual behavior.
  • Lateral Tegmental Area: Another origin for norepinephrine pathways.

Page 22: Serotonin Pathways in the Brain

  • Primary Nuclei: Originate from the Raphe nuclei, which are located in the brainstem (mesencephalic serotonergic cells).
  • Projections: Project widely throughout the brain, including the thalamus, hypothalamus, basal ganglia, and cortex.
  • Functions/Associations: Critically involved in regulating sleep, sexual behavior, and anxiety.

Page 23: Classes of Neurotransmitters (Recap)

  • This slide again lists the main categories of neurotransmitters, reinforcing the classifications covered earlier:
    • Amino acids (Glutamate, Aspartate, Glycine, GABA)
    • Monoamines (Dopamine, Epinephrine, Norepinephrine - Catecholamines; Serotonin - Indolamines)
    • Soluble gases (Nitric oxide, Carbon monoxide)
    • Acetylcholine
    • Neuropeptides (Endorphins)

Page 24: Gas Neurotransmitters

  • Examples: Nitric oxide (NO) and Carbon monoxide (CO).
  • Unique Properties:
    • Unlike classical neurotransmitters, they are not stored in vesicles.
    • They are produced in dendrites (e.g., NO) on demand and diffuse instantly across cell membranes.
  • Retrograde Transmission: Gas neurotransmitters serve as retrograde transmitters, meaning they diffuse back into the presynaptic neuron from the postsynaptic neuron.
  • Function: This retrograde signaling helps synchronize the activity of neighboring neurons.

Page 25: Classes of Neurotransmitters (Recap)

  • Another review slide for the classification of neurotransmitters, emphasizing the categories:
    • Amino acids
    • Monoamines (Catecholamines, Indolamines)
    • Soluble gases
    • Acetylcholine
    • Neuropeptides

Page 26 and 27: Acetylcholine (ACh) Receptors

  • Neurotransmitter: Acetylcholine (ACh).
  • Agonists:
    • Nicotine (activates nicotinic receptors)
    • Muscarine (activates muscarinic receptors)
  • Antagonists:
    • Curare (blocks nicotinic receptors)
    • Atropine (blocks muscarinic receptors)
  • Two Types of ACh Receptors:
    1. Nicotinic Receptors:
      • Type: Mostly ionotropic (ligand-gated ion channels).
      • Effect: Primarily excitatory.
      • Location/Function: Prevalent in peripheral muscles; activation leads to muscle contraction. Blockade by an antagonist like curare results in paralysis.
    2. Muscarinic Receptors:
      • Type: Mostly metabotropic (G-protein coupled).
      • Effect: Can be either excitatory or inhibitory, depending on the specific receptor subtype and cell it's on.
      • Location/Function: Primarily found in the Central Nervous System (CNS) and parasympathetic nervous system. Blockade by drugs like scopolamine can significantly alter cognition and memory.

Page 28: Cholinergic Pathways in the Brain

  • Primary Origin: The Basal Forebrain is a key region for cholinergic (ACh-producing) neurons in the brain.
  • Projections: These pathways project widely, including to the hippocampal formation (via the Fornix) and the cortex.
  • Clinical Significance: Acetylcholine pathways, particularly those originating in the basal forebrain, are strongly linked to cognitive functions and are implicated in Alzheimer's disease, where there is a significant loss of cholinergic neurons.

Page 29: Classes of Neurotransmitters (Recap)

  • This slide serves as another review of the five major classes of neurotransmitters:
    • Amino acids
    • Monoamines (Catecholamines, Indolamines)
    • Soluble gases
    • Acetylcholine
    • Neuropeptides

Page 30: Endogenous Opiates

  • Definition: Endogenous opiates are peptides naturally produced by the body that bind to opioid receptors.
  • Function: They primarily act as analgesics (pain relievers).
  • Addictive Nature: These substances are known to be addictive.
  • Types: The main classes of endogenous opiates include:
    • Enkephalins
    • Endorphins
    • Dynorphins
  • Conditions for Endorphin Release: Endorphins are produced by the brain during various activities and states, such as exercise, excitement, pain, eating spicy food, experiencing love, and orgasm.
  • Overall Effects: They produce both analgesia (pain relief) and a general feeling of well-being.

Page 31: Neuromodulators: Adenosine and Caffeine

  • Neuromodulators: These substances do not directly transmit signals across synapses but indirectly modify or affect the release of neurotransmitters or the response of receptors.
  • Adenosine:
    • Function: Normally released alongside catecholamines (like dopamine and norepinephrine).
    • Mechanism: It acts as an inhibitory neuromodulator by binding to presynaptic autoreceptors, thereby inhibiting the further release of catecholamines.
    • Wakefulness Connection: During extended wakefulness, adenosine gradually builds up in the brain, contributing to feelings of sleepiness and promoting sleep.
  • Caffeine:
    • Mechanism: Caffeine acts as an antagonist to adenosine receptors.
    • Effect: By blocking adenosine's inhibitory effects, caffeine leads to increased catecholamine release, which in turn causes arousal and alertness.
  • Health Note (FYI): A Mayo Clinic study (August 2013) of 40,000 individuals found more than a 50 ext{%} increased mortality rate in young men and women who drank more than 4 cups of coffee a day. However, conversely, moderate coffee intake has been linked to lower all-cause mortality (BMJ 2017, 359, j5024).

Page 32: Barbiturate Drug Mechanism (Question)

  • Question Context: This slide poses a question about the mechanism of action of a barbiturate drug.
  • Correct Answer (Implied from previous content): Barbiturates are potent tranquilizers that act as agonists on GABA_A receptors. They enhance the inhibitory effects of GABA by increasing chloride (Cl^-) conductance across the neuronal membrane, leading to hyperpolarization and reduced neuronal excitability. Therefore, the likely answer is "A. Increase chloride conductance."

Page 33: Drug Classes and Addiction (Transition)

  • This slide serves as a transition to a new section focusing on specific drug classes and their relationship to addiction, humorously noting a "Dad joke alert."

Page 34: Antipsychotic (Neuroleptic) Drugs

  • Purpose: These drugs are primarily used to treat schizophrenia and aggressive behavior.
  • Mechanism of Typical Neuroleptics: Typical (first-generation) antipsychotic drugs function as dopamine (D_2) receptor antagonists.
  • Dopamine Receptor Dynamics (Diagram Explanation):
    • Dopamine Synthesis: Tyrosine is converted to DOPA, then to Dopamine.
    • Pre- and Postsynaptic Interaction: Dopamine is released from the presynaptic terminal, where it can bind to postsynaptic D1 and D2 receptors or presynaptic autoreceptors.
    • D_1-receptor: Coupled to G-proteins that typically increase cAMP production, leading to excitatory effects.
    • D_2-receptor: Coupled to G-proteins that typically decrease cAMP production, leading to inhibitory effects or modulation of protein phosphorylation via kinases and phosphatases.
    • Neuroleptic Action: By blocking D_2 receptors, typical neuroleptics reduce the excessive dopamine signaling implicated in conditions like schizophrenia.
    • Dopamine Metabolism: Dopamine can also be metabolized by enzymes like Monoamine Oxidase (MAO) and Catechol-O-methyltransferase (COMT).

Page 35: Antidepressants: Monoamine Oxidase Inhibitors (MAOIs)

  • Mechanism: MAOIs are a class of antidepressant drugs that work by preventing the enzymatic breakdown of monoamine neurotransmitters (dopamine, norepinephrine, and serotonin) at the synapse.
  • Effect: This inhibition leads to an accumulation of monoamines in the synaptic cleft, prolonging their action on postsynaptic receptors.
  • Antidepressant Action: The increased availability of monoamines is considered a primary mechanism by which MAOIs exert their antidepressant effects.

Page 36: Antidepressants: Two Modern Classes

  • Tricyclic Antidepressants (TCAs - older class):
    • Mechanism: Increase the levels of norepinephrine and serotonin at synapses.
    • Action: They achieve this by blocking the reuptake of these neurotransmitters back into the presynaptic axon terminals.
    • Side Effects: Generally have more side effects compared to newer classes.
  • Selective Serotonin Reuptake Inhibitors (SSRIs - newer class):
    • Examples: Prozac (fluoxetine) or Zoloft (sertraline).
    • Mechanism: Specifically block the reuptake of serotonin from the synaptic cleft.
    • Effect: This causes serotonin to accumulate in synapses, enhancing serotonergic neurotransmission.
    • Side Effects: Tend to have fewer and less severe side effects than tricyclics, making them a more commonly prescribed option.

Page 37: Anxiolytics (Tranquilizers)

  • Purpose: Anxiolytics are drugs designed to reduce nervous system activity, thereby alleviating anxiety.
  • Benzodiazepine Agonists:
    • Mechanism: These drugs act as agonists on GABA_A receptors.
    • Effect: They enhance the inhibitory effects of GABA by increasing the influx of chloride (Cl^-) ions into the neuron, leading to hyperpolarization and reduced neuronal excitability.
  • Endogenous Benzodiazepines ('Endozepines'):
    • The body naturally produces substances that can act on benzodiazepine binding sites.
    • Allopregnanolone: An example of an endogenous benzodiazepine.
    • Diazepam-binding inhibitor: Another example, released by astrocytes.

Page 38: GABA_A Complex and Barbiturates

  • Barbiturates: A class of drugs known for their depressing (sedative-hypnotic) effects.
  • Mechanisms of Action:
    1. Sodium Channel Blockade: Barbiturates can block sodium channels on neurons, which prevents the inflow of sodium ions. This reduces the excitability and firing of neurons.
    2. Chloride Ion Flow Enhancement: They also increase the flow of chloride ions across the neuronal membrane, specifically by enhancing the action of GABA at GABA_A receptors (similar to benzodiazepines, but with distinct binding sites and potentially greater chloride channel opening duration).
  • Medical Use: Their primary medical uses today are for anesthesia and in the treatment of epilepsy, due to their potent CNS depressant properties.

Page 39: Alcohol: Biphasic Effects (Behavioral)

  • Metabolic Impact: Alcohol significantly reduces brain metabolism.
  • Biphasic Behavioral Effects: Alcohol exhibits dose-dependent, biphasic effects on behavior:
    • Low Doses: Acts as a stimulant. This is achieved by turning off cortical inhibition, leading to reduced social constraints and decreased anxiety. Individuals may feel more outgoing and less inhibited.
    • Higher Doses: Becomes a sedative, leading to impaired judgment, motor skills, and eventually stupor or coma.
  • Quote: The slide includes a philosophical quote by Omar Khayyam titled "In Praise of Wine," from around 1100, highlighting the disinhibiting and thought-altering aspects of wine.

Page 40: Alcohol's Biphasic Effects (Molecular and Behavioral Curve)

  • Psychoactive Compounds: All three compounds related to alcohol metabolism—ethanol (mM), acetaldehyde (\mu M), and acetate (mM)—are psychoactive.
  • Biphasic Behavioral Response Curve: The curve (BrAC mg% log scale vs. behavior) illustrates:
    • Initial Stimulant Phase (Lower Doses): Characterized by disinhibition and relaxation.
    • Followed by Depressant Phase (Higher Doses): Leads to impaired motor function, stupor, coma, and eventually death.
  • Individual Variation: There are 3-4 fold variations in behavioral response to alcohol between individuals, with approximately one-half of this variation attributed to genetic factors.
  • Multiple Molecular Targets: Alcohol affects multiple molecular targets in the brain across various neurotransmitter systems, including receptors and transporters for:
    • Dopamine (DA)
    • GABA
    • NMDA (Glutamate receptor)
    • Nicotinic Acetylcholine (NAch)
    • Serotonin (5HT)
    • Cannabinoid (CB)
    • Corticotropin-releasing factor (CRF)
    • Opioid systems.

Page 41: Alcohol Affects Several Neurotransmitter Systems

  • Glutamate Inhibition: At low doses, alcohol inhibits glutamate, an excitatory neurotransmitter.
  • GABAA Receptor Action: Alcohol acts at the GABAA receptor, increasing the binding and enhancing the inhibitory effects of GABA.
  • Sedative/Anxiolytic Effects: The combined effects on glutamate and GABA_A receptors contribute to alcohol's sedative properties, anxiety reduction, muscle relaxation, and inhibited cognitive and motor skills.
  • Pleasurable Effects: Alcohol also stimulates pleasurable effects by influencing dopamine, opiate, serotonin, and cannabinoid systems.
  • Withdrawal Seizures: Seizures experienced during alcohol withdrawal are partly due to a compensatory increase in glutamate receptors over time. During chronic alcohol use, the brain upregulates excitatory glutamate receptors to counteract alcohol's depressant effects. When alcohol is suddenly removed, this upregulation results in excessive excitation.

Page 42: Case Study: Alcohol Withdrawal Seizure (OJ)

  • Patient Presentation: OJ, a 45-year-old man, presented to the Emergency Department after experiencing a seizure on his first day at a local alcohol/drug rehab center.
  • History: Ordered by the court to attend rehab after his second drunk driving violation in one year.
  • Timeline: It had been approximately 60 hours since his last alcoholic drink.
  • Clinical Relevance: This case highlights the dangerous physiological effects of acute alcohol withdrawal, particularly the risk of seizures, which are a severe manifestation of the brain's hyperexcitability following the cessation of chronic alcohol use.

Page 43: Alcohol Shrinks Your Brain

  • Neuroimaging Evidence (MRI & DTI): Comparative brain images (MRI and DTI scans) illustrate the structural changes induced by chronic alcohol consumption.
  • Visible Differences:
    • Control Man vs. Alcoholic Man (MRI): The brain of an alcoholic man shows enlarged ventricles (fluid-filled spaces) and a reduction in the volume of the corpus callosum compared to a control man.
    • Control Man vs. Alcoholic Man (DTI - Diffusion Tensor Imaging): DTI, which visualizes white matter tracts, reveals reduced integrity or volume of these tracts in the alcoholic brain, suggesting damage to the brain's connective pathways.
  • Conclusion: These images visually demonstrate that chronic alcohol abuse leads to significant brain shrinkage and damage to white matter.

Page 44: Alcohol Damages Cerebellum and Frontal Lobe, But Recovery is Possible

  • Affected Brain Regions: Chronic alcohol consumption typically damages the cerebellum (involved in motor control and coordination) and the frontal lobe (responsible for executive functions, decision-making, and impulse control).
  • Potential for Recovery: Crucially, neurons and glia (support cells) in these regions can recover with sustained abstinence.
  • Recovery Data (Graph): A graph showing "Average % change in volume" over time for different groups:
    • Light drinkers: Show stable brain volume.
    • Abstainers: Show an increase in brain volume (recovery) over time (+10 ext{%}, +15 ext{%}, +20 ext{%}).
    • Relapsers: Indicate a continued decrease in brain volume (-5 ext{%}, -10 ext{%}), demonstrating that cessation of abstinence leads to ongoing damage.
  • Source: Based on V.A. Cardenas et al. 2007, NeuroImage (34:879-887).

Page 45: Fetal Alcohol Syndrome (FAS)

  • Cause: Fetal Alcohol Spectrum Disorder (FASD), with Fetal Alcohol Syndrome (FAS) being the most severe form, results from alcohol exposure during pregnancy.
  • Discriminating Facial Features (Panel A): Infants with FAS often present with characteristic facial anomalies, including:
    • Short palpebral fissures (small eye openings)
    • Flat midface
    • Small head (microcephaly)
    • Short nose
    • Indistinct philtrum (the groove between the nose and upper lip)
    • Thin upper lip
  • Associated Features: Other potential features include epicanthal folds, a low nasal bridge, minor ear anomalies, and micrognathia (small jaw).
  • Brain Impact (Panel B): Images compare a healthy infant brain with an infant brain affected by FASD.
    • The FASD brain shows significant structural anomalies, for example, a less developed or malformed corpus callosum (the band of nerve fibers connecting the two brain hemispheres).
  • Significance: FASD can lead to a range of lifelong physical, behavioral, and cognitive challenges.

Page 46 and 47: Opiates: Mechanism and Source

  • Mechanism of Action - Three Main Areas: Opiates exert their effects by binding to opioid receptors throughout the body and brain.
    1. Brain Stem: Opiates can depress breathing by altering neurochemical activity in the brain stem, which controls automatic body functions like respiration. This is a primary cause of overdose death.
    2. Limbic System: They can change activity in the limbic system, the brain's emotional control center, leading to an increase in feelings of pleasure and euphoria.
    3. Spinal Cord: Opiates can block pain messages transmitted through the spinal cord from the body, thus producing their potent analgesic effects.
  • Specific Binding Sites: Opiates bind to opioid receptors concentrated in specific brain regions, notably the brainstem (especially the locus coeruleus) and the periaqueductal gray (PAG).
  • Sources: Opium is derived from the opium poppy and contains various alkaloids, including morphine, which is a potent analgesic.

Page 48: Heroin: Origin and Misconception

  • Origin: Heroin was named for its "heroic" properties by the Bayer pharmaceutical company.
  • Historical Context (1898): Bayer initially sought a new replacement for aspirin and codeine.
  • Marketing Strategy: Heroin was famously marketed as a non-addictive cure for codeine addiction.
  • Unforeseen Problem: It was quickly discovered that heroin metabolizes into morphine in the body, which is highly addictive itself. This highlights a historical pharmaceutical misstep.

Page 49: Fentanyl Overdose Case Study and Broader Impact

  • Patient Scenario: A 53-year-old man was found unconscious in a driveway. Upon EMS arrival, he was comatose, and his pupils were tiny (2mm) and barely reactive to light (miosis, a classic sign of opioid overdose).
  • Intervention and Outcome: He was given naloxone intravenously. Within a minute, he aroused and opened his eyes.
  • Diagnosis: Fentanyl overdose. Naloxone is an opioid receptor antagonist that rapidly reverses the effects of opioid overdose.
  • Broader Context: This case is pertinent to the rising rates of drug overdose deaths, especially those involving synthetic opioids like fentanyl, as indicated by the initial data discussed in page 1.
  • Data Reference: (Refers to drug overdose death rates by age, typically showing peaks in certain adult age groups).

Page 50 and 51: Marijuana: Active Ligand, Endocannabinoids, and Effects

  • Active Ligand: The primary psychoactive compound in marijuana is THC (tetrahydrocannabinol).
  • Endocannabinoid System: The brain naturally produces endogenous cannabinoids (endocannabinoids) that bind to cannabinoid (CB) receptors.
    • Examples: Anandamide and 2-AG (2-arachidonoyl glycerol).
    • Retrograde Signaling: Endocannabinoids are unique retrograde signaling molecules. They are synthesized post-synaptically and diffuse back to presynaptic neurons to regulate neurotransmitter release.
    • Properties: They are lipophilic (fat-soluble), meaning they cannot be stored in vesicles and instead exist as part of the cell membrane. They are synthesized "on-demand" rather than pre-packaged.
  • Historical Use: As early as 3000 BC, Indian medical practices used marijuana to treat appetite loss.
  • Effects of Marijuana (THC):
    • Cognitive Impairment: Impairs short-term memory, making it difficult to learn complex tasks.
    • Motor Impairment: Slows reaction time, significantly impairing driving skills.
    • Judgment/Decision Making: Alters judgment and decision-making abilities.
    • Mood Alteration: Can induce calmness but, in high doses, may cause anxiety and paranoia.
  • CB Receptor Locations & Functions: CB receptors are concentrated in brain areas that influence pleasure, memory, concentration, time perception, appetite, pain, and coordination.

Page 52 and 53: Nicotine and Smoking Risks

  • Primary Psychoactive/Addictive Drug: Nicotine is the main psychoactive and addictive component found in tobacco.
  • Mechanism of Action:
    • Central Effects: Nicotine activates nicotinic ACh receptors, particularly in the ventral tegmental area (VTA), a key region of the dopamine reward pathway, contributing to its addictive potential. Centrally, it increases alertness and cognitive performance.
    • Peripheral Effects: In the periphery, it activates muscles, which can cause twitching.
  • Smoking Risks vs. Nicotine: While nicotine is highly addictive, the vast majority of health risks associated with smoking (e.g., cancer, cardiovascular disease, respiratory disease) are due to other compounds present in tobacco and tobacco smoke, not nicotine itself.
  • Public Health Impact: Smoking remains the primary cause of preventable death globally.
    • It kills approximately 493,000 people annually in the US.
    • Worldwide, this number escalates to 4,000,000 deaths per year (for comparison, heroin kills about 4000 people/year in the US).
  • Withdrawal Symptoms: Nicotine withdrawal symptoms are generally considered mild compared to some other substances, though they can significantly contribute to relapse.
    • Even mild withdrawal can impact safety, e.g., a 7 ext{%} increase in workplace accidents on Britain's 'No Smoking Day' due to nicotine craving and irritability among smokers.
  • Quitting Success Rate: Despite awareness of risks, only about 5 ext{%} of attempts to quit smoking are successful, a success rate comparable to that for heroin addiction.
  • Positive Trend: There is good news as the U.S. smoking rate has fallen to a historic low.

Page 54: Good News: Teen Drug Use Down (Any Illicit Drug)

  • Overall Trend: Data indicates a positive trend with a decrease in the 12-month prevalence of any illicit drug use (including inhalants) among 8th, 10th, and 12th graders.
  • Visual Representation: A graph tracking these trends from 1975 to 2020 (with a data point for 2022) shows a general decline after peaks in earlier decades.
  • 2022 Statistics: In 2022, the 12-month prevalence of any illicit drug use for 12th graders was 34.3 ext{%}.

Page 55: More Good News: Teen Vaping Nicotine Down

  • Trend: This slide presents more positive news, showing a decrease in the 12-month prevalence of vaping nicotine (e-cigarettes) among 8th, 10th, and 12th graders.
  • Visual Representation: A graph illustrates a noticeable decline in vaping rates across all three age groups from previous highs, although specific numerical values are not provided for the most recent years.

Page 56 and 57: Cocaine: From Plant to Addiction Mechanism

  • Coca Shrub Leaves: Traditionally, chewing leaves from the coca shrub helps alleviate hunger, enhance endurance, and provide a general sense of well-being. This form of use is generally not considered particularly addictive.
  • Cocaine (Purified Extract): The refined, purified extract of cocaine differs significantly.
    • Rapid Brain Entry: It enters the brain much more rapidly than consuming leaves.
    • High Addictiveness: This rapid entry contributes to its highly addictive nature.
  • Cocaine-Amphetamine-Regulated Transcript (CART): This is a peptide involved in the pleasure sensations derived from cocaine and amphetamines, as well as in appetite suppression.
  • Mechanism of Action: Cocaine primarily exerts its effects by blocking monoamine transporters, especially the dopamine transporter.
    • Effect: By preventing the reuptake of dopamine (and to a lesser extent, norepinephrine and serotonin) from the synaptic cleft, cocaine significantly enhances and prolongs their effects on postsynaptic receptors, leading to the characteristic euphoric "high" and powerful reinforcing properties.

Page 58: Amphetamine and Methamphetamine

  • Chemical Class: Amphetamine and methamphetamine are synthetic stimulants.
  • Mechanism of Action: These drugs exert their effects on catecholamine neurotransmitters (dopamine, norepinephrine, and epinephrine) through a dual mechanism:
    1. Block Reuptake: They block the reuptake transporters, preventing the removal of catecholamines from the synaptic cleft.
    2. Increase Release: They also increase the direct release of catecholamines from presynaptic terminals into the synapse.
  • Short-Term Effects: Result in enhanced alertness, euphoria, and increased stamina.
  • Long-Term Abuse: Chronic abuse can lead to severe consequences, including sleeplessness, significant weight loss, and the development of schizophrenic-like symptoms (e.g., paranoia, hallucinations) due to excessive dopamine activity.

Page 59: Trending Methamphetamine from P2P

  • Emergence of P2P Meth: Methamphetamine made using phenyl-2-propanone (P2P) as a precursor began to be produced in large quantities ("by the ton") in Mexico starting around 2016.
  • Dominance in US Market: This method of production has led to P2P crystal meth accounting for over 95 ext{%} of the methamphetamine found in the US market.
  • Reference: The Atlantic article from November 2021 provides further details on this trend.

Page 60: Stimulants for ADHD

  • Medications: Common stimulant medications for Attention Deficit Hyperactivity Disorder (ADHD) include:
    • Adderall (dextroamphetamine)
    • Ritalin (methylphenidate)
  • Brain Activity Changes: Brain imaging studies (e.g., fMRI) show that these stimulants increase activity in specific brain regions:
    • Prefrontal cortex
    • Some subcortical regions
    • Cerebellum
  • Executive Function Centers: These areas are crucial for executive functions, including attention, planning, decision-making, and impulse control.
  • Mechanism in ADHD:
    • Cortico-thalamic networks are responsible for inhibitory attentional and impulse control systems, and they also process internal and external stimuli.
    • ADHD medications stimulate these specific inhibitory networks, helping them to function more effectively.
    • Behavioral Link: The explanation suggests that hyperactive behaviors (like fidgeting) in individuals with ADHD might be an unconscious way to stimulate these brain networks to work better. When medication provides this stimulation, the need for such compensatory behaviors diminishes, making them unnecessary.

Page 61: LSD (Lysergic Acid Diethylamide)

  • Chemical Similarity: LSD structurally resembles serotonin and acts as a serotonin receptor agonist, particularly on receptors in the visual cortex.
  • Effects (Highly Unpredictable): The effects of LSD are largely unpredictable and are highly dependent on:
    • The amount taken
    • The user's personality
    • Mood at the time of use
    • Expectations about the drug's effects
    • The surrounding environment
  • Physical Effects: Common physical symptoms include dilated pupils, increased heart rate and blood pressure, sweating, sleeplessness, and tremors.
  • Psychological Effects:
    • Users may experience a wide range of emotions simultaneously or rapid shifts between different emotional states.
    • LSD can induce delusions and vivid visual illusions (hallucinations).
    • Synesthesia: A characteristic effect is synesthesia, where sensory experiences cross over, leading to perceptions such as "hearing colors" or "seeing sounds."
  • Reference: Scientific Reports, 2017; 7: 46421 for research on LSD's effects.

Page 62: Phencyclidine (PCP) (Angel Dust)

  • Primary Effects: PCP produces profound feelings of depersonalization (feeling detached from oneself) and detachment from reality.
  • Side Effects: Its extensive side effects commonly include combativeness, aggression, and catatonia (a state of unresponsiveness and immobility).
  • Mechanism of Action: PCP acts as a glutamate NMDA (N-methyl-D-aspartate) receptor antagonist. By blocking these excitatory receptors, PCP disrupts normal glutamatergic neurotransmission, leading to its powerful dissociative and psychotic effects.

Page 63: Ecstasy (MDMA)

  • Chemical Class: MDMA (3,4-methylenedioxymethamphetamine), commonly known as Ecstasy or Molly, is an amphetamine analog.
  • Primary Mechanism (Serotonin): Its main effects in the brain are exerted on neurons that use serotonin.
    • Serotonin Reuptake Blockade: MDMA blocks the serotonin reuptake transporter (SERT), which is responsible for removing serotonin from the synapse.
    • Excessive Serotonin Release: This blockade prolongs the serotonin signal and also causes an excessive release of serotonin into the synaptic cleft.
    • Oxytocin Release: MDMA additionally causes the release of oxytocin, a hormone associated with social bonding and empathy.
  • Therapeutic Application: MDMA has shown promise in therapeutic settings and has been approved for the treatment of Post-Traumatic Stress Disorder (PTSD) in certain contexts, capitalizing on its effects on serotonin and oxytocin to facilitate emotional processing.

Page 64: What's Trending in 2025? (Emerging Drug Trends)

  • Synthetic Opiates:
    • Carfentanil: This extremely potent synthetic opioid is 10,000 times more potent than morphine. Its lethal dose is remarkably small, around 20 micrograms (equivalent to approximately one grain of salt), highlighting its extreme danger and role in overdose crises.
  • Psychedelics:
    • Resurgence in Research: There is a significant renewed interest in the therapeutic potential of psychedelic compounds.
    • Clinical Trials: Currently, there are 80 active Phase II clinical trials investigating psychedelics such as psilocybin, MDMA, ketamine, and ibogaine.
    • Target Conditions: These trials are exploring treatments for a range of mental health conditions, including depression, PTSD, addiction, and anxiety.

Page 65: Psilocybin Reboots Brain Networks

  • Neuroplastic Effect: Research suggests that psilocybin, the psychoactive compound in magic mushrooms, has the ability to "reboot" the brain's default functional networks (e.g., the default mode network).
  • Network Re-establishment: While the acute effects of the drug wear off, the brain's networks re-establish themselves.
  • Persistent Changes: Significantly, small, subtle differences in brain network function and connectivity have been observed to persist for months after a single psilocybin session, indicating potential long-term therapeutic effects and neuroplastic changes.

Page 66: Drugs, Addiction, and Reward: Defining Addiction

  • Addiction as a Brain Disorder (NIDA Definition): Addiction is recognized as a chronic, often relapsing brain disorder.
  • Characteristics: It is characterized by compulsive drug use, despite the known harmful consequences to the individual addict and to those around them.
  • Voluntary vs. Involuntary: Although the initial decision to take drugs may be voluntary, the disease of addiction involves profound brain changes that occur over time. These changes challenge an individual's self-control and severely impair their ability to resist intense impulses, or cravings, to take drugs.
  • Source: NIDA InfoFacts: Understanding Drug Abuse and Addiction.

Page 67: Addiction: Key Terms

  • Tolerance: A decreased sensitivity to a drug that develops as a result of repeated exposure to it. Higher doses are then required to achieve the same effect.
  • Sensitization: An increased sensitivity to a drug after repeated exposure. This is less common for pleasurable effects but can occur for some undesirable effects or craving.
  • Physical Dependence: Occurs when the body adapts to the presence of a drug, leading to withdrawal symptoms if drug use is stopped. Importantly, the slide notes that physical dependence, while a factor, is generally not the primary reason people continue to take most drugs; psychological dependence and craving are often stronger drivers.
  • Psychological Dependence: Characterized by compulsive and repetitive drug use, intense craving for the drug, and a strong emotional reliance on its effects.

Page 68: Addiction and Withdrawal: Further Definitions

  • Addiction Defined:
    • Preoccupation: An intense focus on obtaining the drug.
    • Compulsive Use: The inability to control drug-seeking and drug-taking behaviors, despite experiencing adverse consequences.
    • Relapse Risk: A high probability of returning to drug use after a period of abstinence.
  • Withdrawal Defined:
    • A negative and often intensely uncomfortable physiological and psychological reaction that occurs when drug use is stopped or significantly reduced after dependence has developed.

Page 69: The Basis for Addiction is Reward

  • Reward Definition: Reward is the positive subjective effect that any agent (e.g., a drug, food, social interaction) has on the user, leading to a desire to repeat the experience.
  • Mesolimbocortical Dopamine System: This pathway is identified as the major reward system in the brain.
    • It originates in the Ventral Tegmental Area (VTA) and projects to the nucleus accumbens, amygdala, prefrontal cortex, and hippocampus.
  • Role in Addiction: Abused drugs consistently increase dopamine release in the VTA and nucleus accumbens part of this system.
  • Universal Reward Pathway: This dopamine system underlies the addictive (or reinforcing) effects of a wide range of activities and substances, including:
    • Illicit drugs
    • Food
    • Sex
    • Gambling
    • "Warm fuzzies" (positive emotional experiences)
    • Social media validation (e.g., Reddit upvotes, TikTok likes), highlighting its role in behavioral addictions.

Page 70: A Neural Pathway in Addiction: Patient B-19 Case

  • Patient Profile: Patient B-19, a 24-year-old man, suffered from severe depression and obsession-compulsion.
  • Experimental Intervention (Deep Brain Stimulation): Electrodes were surgically implanted at 9 deep brain sites.
  • Reward Response: The electrode implanted near the Median Forebrain Bundle (MFB) consistently produced intense pleasure.
  • Self-Stimulation: When given free access to a stimulator, Patient B-19 compulsively pressed the button, described as "mashing the button 'like an 8-year-old playing Donkey Kong.'"
  • Intense Euphoria: During these self-stimulation sessions, B-19 stimulated himself to the point of experiencing "an almost overwhelming euphoria and elation" and had to be disconnected by force despite his vigorous protests.
  • Clinical Demonstration: This famous case vividly illustrates the powerful role of the mesolimbocortical dopamine system, particularly the MFB, in mediating profound reward and its potential for compulsive self-stimulation, mirroring the compulsive nature of addiction.

Page 71 and 72: Why Drug Rehab Usually Fails: Craving and delta FosB

  • The Problem of Craving: Intense craving is a major factor contributing to the high failure rate of drug rehabilitation.
  • delta FosB's Role:
    • Accumulation: In addicts, a transcription factor called delta FosB (\Delta\text{FosB}) builds up in neurons, particularly in the nucleus accumbens, with each exposure to the drug.
    • Long-Lasting Activation: Crucially, delta FosB remains activated for years even after the last drug exposure.
    • Nucleus Accumbens Remodeling: This persistent delta FosB expression remodels the nucleus accumbens, a key brain region in the reward pathway. This remodeling is thought to perpetuate craving and contributes significantly to the high rates of relapse observed in treated addicts.
  • Molecular Mechanism (BIOCARTA Diagram): The diagram illustrates the cellular pathway:
    • Drugs (cocaine, morphine, amphetamine, alcohol, nicotine, phencyclidine) activate receptors.
    • This triggers downstream signaling, involving phosphorylation events (e.g., Darpp-32 phosphorylation), often involving kinases like Cdk5.
    • This ultimately leads to the nuclear accumulation of delta FosB (e.g., \Delta\text{FosB } 35kd isoform).
    • Delta FosB forms a stable complex with JunD, forming an AP-1 transcription factor complex.
    • This complex alters gene expression in the nucleus, affecting targets such as Cdk5, Glur2 (a glutamate receptor subunit), dynorphin, and other proteins, leading to long-lasting changes in neuronal structure and function that promote addictive behaviors and craving.

Page 73: Addiction: Pharmacologic Treatment Strategies (1. Agonistic Treatments)

  • Principle: Agonistic treatments work by mimicking the effects of the addictive drug, but in a milder, more controlled manner.
  • Examples:
    • Opiate Addiction: Buprenorphine is used as a partial opioid agonist.
    • Nicotine Addiction: Nicotine patches deliver a steady, low dose of nicotine.
    • Chantix (Varenicline): This drug specifically stimulates nicotine receptors, but more weakly than nicotine itself (it's a partial agonist). This helps reduce cravings and withdrawal symptoms without providing the full "rush."
  • Mechanism: These treatments replace the drug, which helps manage withdrawal symptoms and reduces craving, thereby helping with motivation to quit.
  • Controversy: A frequently debated ethical question is whether it is appropriate to treat an addiction with another addictive drug. The quote from Aristotle, "I count him braver who overcomes his desires than he who overcomes his enemies," highlights the internal struggle of addiction.

Page 74: Addiction: Pharmacologic Treatment Strategies (2. Antagonistic & 3. Aversive Treatments)

  • 2. Antagonistic Treatments:
    • Principle: These drugs block the effects of the addictive substance by occupying or deactivating its receptors, preventing the drug from producing its desired effects (e.g., euphoria).
    • Examples:
      • Opiate Addiction: Naltrexone is an opioid receptor antagonist.
      • Alcohol Addiction: Baclofen, a GABA_B agonist, can interfere with the dopamine reward pathway, helping to block craving for alcohol.
    • Challenge: Unlike agonistic treatments, antagonists do not replace the drug's effects. Therefore, their success heavily depends on the addict's motivation to quit, as there is no rewarding sensation from taking the medication itself.
  • 3. Aversive Treatments:
    • Principle: These treatments aim to create an unpleasant, even violent, reaction if the addictive drug is consumed.
    • Example:
      • Alcohol Addiction: Antabuse (disulfiram) is a drug that, when taken, inhibits enzymes involved in alcohol metabolism. If alcohol is consumed while on Antabuse, it leads to a build-up of acetaldehyde, causing severe symptoms like nausea, vomiting, headaches, and flushing.
    • Usage: Aversive treatments are rarely used in current practice due to significant side effects and issues with patient compliance (many simply stop taking the medication).

Page 75: The Strength We Should Also Admire

  • This concluding slide presents an inspirational message using a visual metaphor:
    • It contrasts the commonly admired strength of achieving a goal (e.g., winning a race, represented by "I DID IT!").
    • With the equally, if not more, admirable strength of overcoming an addiction or personal struggle (represented by "I DID IT!" in the context of resisting temptation or staying sober).
  • Core Message: It implies that the internal battle against addiction and personal desires requires immense strength and perseverance, which should be recognized and admired just as much as external achievements. This reinforces the idea of addiction as a formidable challenge requiring profound internal strength to overcome. More accurately, perhaps the strength we gain in recovery. The internal strength. The spiritual strength that helps us overcome our base desires. My own opinion. I’m giving my own opinion. So I hope you’re writing that down for notes (internal thought of professor).