Neuropharmacology Exam 1

Study Guide for Exam: Neuropharmacology and Cellular Communication

Lecture 2: Basic Principles of Neuropharmacology

Pharmacokinetics

1. Key Definitions:

   • Clearance (CL): How the body eliminates a drug. Calculated as CL = Rate of elimination / Concentration of drug.

   • Volume of Distribution (Vd): Space required to contain a drug at blood concentration.

     • Formula: Vd = Amount of drug in body / Plasma drug concentration.

   • Half-Life (t½): Time required for drug concentration in plasma to decrease by 50%.

   • Therapeutic Window: Range between drug’s effective and toxic concentrations.

2. Kinetics:

   • First-Order Kinetics: Constant fraction of drug eliminated over time.

   • Zero-Order Kinetics: Constant amount eliminated, regardless of concentration (e.g., alcohol).

Pharmacodynamics

1. Drug Interactions with Targets:

   • Affinity (Kd): Strength of drug binding to target. Lower Kd = higher affinity.

   • Efficacy: Drug’s ability to produce a maximum effect.

   • Potency: Dose required to achieve a specific effect.

2. Receptor Types and Actions:

   • Agonist: Mimics endogenous ligands (e.g., morphine).

   • Antagonist: Blocks receptor activity (e.g., naloxone).

   • Partial Agonist: Produces a partial effect compared to full agonists (e.g., buprenorphine).

   • Inverse Agonist: Suppresses baseline receptor activity.

3. Tools:

   • Optogenetics: Uses light-activated ion channels for neuron-specific activation.

   • CRISPR: Genome-editing for disease modeling and therapeutic interventions.

Lecture 3: Cellular Basis of Communication

Neuron and Synapse Basics

1. Neuron Communication:

   • Electrical impulse (via sodium ion influx) triggers calcium-mediated neurotransmitter release into the synaptic cleft.

   • Neurotransmitters activate post-synaptic receptors (e.g., glutamate: excitatory; GABA: inhibitory).

2. Synaptic Plasticity:

   • Brain circuits are modifiable throughout life, adapting to environmental and developmental changes.

Glial Cells

1. Astrocytes:

   • Support neuronal migration and blood-brain barrier (BBB) formation.

   • Reactive gliosis in response to injury.

2. Oligodendrocytes and Schwann Cells:

   • Oligodendrocytes (CNS) and Schwann cells (PNS) produce myelin.

   • Enable saltatory conduction via Nodes of Ranvier.

3. Microglia:

   • CNS immune cells acting as scavengers, involved in neuroinflammation and repair.

Blood-Brain Barrier (BBB)

• Tight endothelial junctions regulate brain’s extracellular environment.

• Methods to bypass BBB:

  • Mannitol to open tight junctions.

  • Lipophilic prodrugs.

Lecture 4: Cellular Communication Mechanics

Neuronal Cytoskeleton

1. Microtubules:

   • Motor proteins transport cargo:

     • Kinesins: Anterograde (toward terminal).

     • Dyneins: Retrograde (toward soma).

2. Actin Cytoskeleton:

   • Found in dendritic spines, enabling structural changes essential for synaptic plasticity.

Action Potentials and Ion Channels

1. Electrical Potential:

   • Resting membrane potential: ~−70 mV (maintained by K+ ion permeability).

   • Action potential: Triggered by sodium influx and terminated by potassium efflux.

2. Voltage-Gated Ion Channels (VGLs):

   • Types: Na+, K+, Ca2+.

   • Selectivity:

     • NaV: 12x selective for Na+.

     • KV: 100-1000x selective for K+.

3. Nernst Equation:

   • Calculates equilibrium potential for ions.

   • Formula: Em = 58 log ([Ion]out / [Ion]in).

4. Membrane Permeability:

   • Ion flow altered by channel opening/closing, influencing membrane potential.

Synaptic Transmission

1. Steps:

   • Action potential arrives at terminal.

   • Ca2+ influx triggers vesicle fusion and neurotransmitter release.

   • Neurotransmitters bind to post-synaptic receptors, initiating signaling cascades.

Flashcards for Review

Pharmacokinetics

• Q: What does clearance (CL) measure? A: The rate at which the body eliminates a drug.

• Q: What is the therapeutic window? A: The range where a drug is effective but not toxic.

• Q: What is the formula for Volume of Distribution (Vd)? A: Vd = Amount of drug in body / Plasma drug concentration.

Pharmacodynamics

• Q: Define potency. A: The dose required to produce a specific effect.

• Q: What’s the difference between an agonist and an antagonist? A: Agonist mimics the endogenous ligand; antagonist blocks receptor activity.

• Q: What is an inverse agonist? A: A drug that elicits a response opposite to that of an agonist.

Neuron Communication

• Q: What ion initiates neurotransmitter release at the synaptic cleft? A: Calcium (Ca2+).

• Q: Name two excitatory and inhibitory neurotransmitters. A: Excitatory: Glutamate. Inhibitory: GABA.

Glial Cells

• Q: What role do astrocytes play in the BBB? A: Induce tight junctions in endothelial cells.

• Q: What’s the main function of oligodendrocytes? A: Myelination of CNS axons.

• Q: What do microglia do in the CNS? A: Act as scavengers and play roles in neuroinflammation and repair.

Ion Channels and Action Potentials

• Q: What maintains the resting membrane potential? A: Potassium ion permeability.

• Q: Which motor proteins are involved in microtubule transport? A: Kinesins (anterograde) and Dyneins (retrograde).

• Q: What is the Nernst Equation used for? A: To calculate the equilibrium potential of an ion.

Synaptic Transmission

• Q: What triggers vesicle fusion in the presynaptic terminal? A: Calcium ion (Ca2+) influx.

• Q: What are voltage-gated ion channels (VGLs)? A: Channels that open/close in response to voltage changes, enabling ion flow.

• Q: What is the role of neurotransmitters in synaptic transmission? A: To activate receptors on the post-synaptic neuron and initiate signaling cascades.

Flashcards for Signal Transduction and Pharmacology

1. What are the four processes of Pharmacokinetics (ADME)?

• Absorption, Distribution, Metabolism, Excretion.

2. What is the primary function of voltage-gated sodium (Na+) channels?

• Initiate and propagate action potentials in neurons.

3. What toxin blocks Na+ channels and where is it found?

• Tetrodotoxin (TTX), found in pufferfish.

4. What is the function of voltage-gated potassium (K+) channels?

• Help return the membrane potential to resting state after depolarization.

5. Name two diseases associated with K+ channel mutations.

• Episodic ataxia, Long QT syndrome.

6. What are the major classes of second messengers?

• cAMP, cGMP, Ca2+, IP3, DAG.

7. What are GPCRs and why are they important?

• G-protein coupled receptors; they mediate many cellular responses to hormones and neurotransmitters.

8. What are the three major G-protein subtypes and their effects?

• Gs (stimulates cAMP), Gi (inhibits cAMP), Gq (activates phospholipase C -> DAG/IP3).

9. What enzyme converts ATP to cAMP?

• Adenylyl cyclase.

10. What kinase is activated by cAMP?

• Protein kinase A (PKA).

11. What are the major roles of Ca2+ in neurons?

• Neurotransmitter release, synaptic plasticity, gene transcription.

12. What is the role of phospholipase C (PLC) in signaling?

• Cleaves PIP2 to produce DAG and IP3, leading to PKC activation and Ca2+ release.

13. What is the function of Protein Kinase C (PKC)?

• Modulates synaptic plasticity, cell survival, and receptor regulation.

14. Name two diseases treated with kinase inhibitors.

• Cancer (Gleevec inhibits tyrosine kinases), neurodegenerative diseases (PKC inhibitors).

15. What phosphatase is regulated by Ca2+/calmodulin?

• Calcineurin (PP2B).

16. Name two neurodevelopmental disorders linked to gene silencing.

• Rett Syndrome (MECP2 mutation), Angelman Syndrome (UBE3A mutation).

17. What is the primary action of NSAIDs?

• Inhibit cyclooxygenase (COX) enzymes to reduce inflammation and pain.

18. How does lithium affect bipolar disorder?

• Inhibits IP3 recycling, stabilizing mood.

19. What is the role of nitric oxide (NO) in the body?

• Acts as a vasodilator, regulates blood pressure.

20. What type of receptor does nitroglycerin target?

• Guanylyl cyclase, increasing cGMP levels for vasodilation.

21. What are receptor tyrosine kinases (RTKs) and their role?

• Membrane-bound receptors that activate intracellular signaling pathways in response to growth factors.

22. What neurotransmitter is primarily associated with the GABAergic system?

• Gamma-aminobutyric acid (GABA), which inhibits neuronal activity.

23. What is the function of CREB (cAMP response element-binding protein)?

• A transcription factor that regulates gene expression in response to cAMP signaling.

24. What is the function of dopamine in the central nervous system?

• Modulates reward, motivation, and motor control.

25. What is the significance of NMDA receptors in synaptic plasticity?

• NMDA receptors are critical for learning and memory by allowing Ca2+ influx during synaptic transmission.

26. What is the role of serotonin in mood regulation?

• Regulates mood, appetite, and sleep; targeted by antidepressants like SSRIs.

27. What enzyme breaks down acetylcholine in the synaptic cleft?

• Acetylcholinesterase.

28. What is the function of beta-blockers in pharmacology?

• Inhibit beta-adrenergic receptors to reduce heart rate and blood pressure.

29. What is the main inhibitory neurotransmitter in the brain?

• GABA (Gamma-Aminobutyric Acid).

30. What is the mechanism of action of benzodiazepines?

• Enhance GABA-A receptor activity, increasing inhibitory signaling in the brain.