Drugs and the Brain

By | January 22, 2014

Notes adapted from the Coursera course titled "Drugs and the Brain" taught by Dr. Lester from Caltech.

1-4: Drug Entry into the Nervous System

  • Nicotine passes through 3 cell types and 6 cell membranes in under a few seconds. After being puffed in, it passes through alveolar epithelium cells, then it passes through two types of capillary cells in the brain.
  • Once in the brain, nicotine can be protonated. The positively charged form interacts with the receptors. But this protonation can also take place in the lungs or mouth, especially if the cigarettes have ammonium hydroxide, which maintains a neutral pH environment (nicotine is protonated in neutral pH, as its pKa (pH when half of chemical is protonated) is 8).
  • Levodopa, the main drug in Parkinson's treatment, crosses the blood brain barrier and is decarboxylized to form dopamine. Dopamine itself does not cross the blood brain barrier. This is an example of a prodrug because it gets modified to enter the body.
  • Blood brain barrier - Outside the capillaries, there are endothelial cells that allow various types of molecules to diffuse outside the capliaries into the cells. However, in the brain, there are no spaces between the endothelial cells (tight junctions connect them). Proteins and polar molecules can not cross, whereas in other organs, they can. Only nonpolar molecules can cross the blood brain barrier.

1-5: Introduction to Drug Receptors

  • Proteins are made of amino acids formed together through amide bonds in a dehydration reaction.
  • Proteins are designated from the N terminus to the C carboxyl terminus
  • Proteins contain a few structural motifs – alpha helices and beta sheets (held in place by hydrogen bonds between carboxyl O on one group to the nitrogen H on the other

1-6: More about receptors as proteins

  • Receptors typically have a cytosolic region within the cell, a membrane region that spans the membrane, and a binding region outside the membrane
  • Ligand (the drug) binding sites are sometimes located between two subunits on the receptor protein, but normally they have stabilizing components. The binding must be thermodynamically and kinetically preferred.
  • Nicotinic acetylcholine receptor – each subunit has four alpha helix intermembrane units and in total there are five subunits
  • Conformational changes typically occur after binding, which alters the channel (e.g., opens the channel).
  • Most receptors are allosteric proteins; a ligand binding at one site affects the function of a ligand that binds at another site

1-8: Techniques for Studying the Brain

  • There exist methods for studying the brain at various spatial resolutions (from about the synapse level to the entire brain level) and temporal resolutions (millisecond to years).

1-9: Botulinum toxin

  • Botulinum toxin is made by an aerobic bacterium
  • A german physician ate an uncooked sausage in 1793 and noticed paralysis
  • Botulinum toxin is fatal in low qualities; it paralyzes muscles
  • The bacterium synthesizes the toxin as a single protein chain and then cleaves the protease towards the beginning of the protein. The two chains (light and heavy chain) are held together by a disulfide bond. The light chain enters the cells and acts as an enzyme that prevents neurotransmitter from being released at synapse.
  • It most common use relaxes the activity of overactive muscles

1-10: Origin of the Resting Potential

  • Cells evolved in the ocean. The outside of neurons has high levels of sodium ions and chloride ions and inside there is a high concentration of potassium ions.
  • Potassium ions diffuse outside the cells, leads to a loss in positive charge (leads to a negative charge) in the inside of the cell. Using Nernst equation and assuming equilibrium (delta G = 0), you can calculate the resting potential solely from potassium. However, neurons are not equilibrium systems so we look at electrical perspectives.
  • An individual sodium channel acts as a conductor (conductance is the inverse of resistance).

1-11: Electrical aspects of Ion Channels

  • Each channel in a circuit model of a cell is placed in a parallel circuit and is given a conductor and a switch (to indicate if the channel is open or closed) and a battery, which is the Nernst potential of that ion.
  • We consider Kirchoff's Current Law (conservation of charge) as we sum up the potential of our equivalent circuit
  • Two major roles for ion channels in drugs and the brain: (1) drugs at synapses open or close the channel and (2) drugs at axons and cell bodies alter equilibrium of voltage gated channels
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