Notes can be found as interactive webpage at

3: Pharmacology; Neurodevelopment

8: Poison, Medicine, and Pharmacology #

  • Pharmakon: medicine and poison at the same time

    Everything is a poison. The difference between a poison and a remedy depends on the dose.
    – Paracelsus

  • Botulinum Toxin
    • Strongest toxin known
    • Disrupts acetylcholine transmitters of neuromuscular junctions
    • Human LD$_{50}$ = lethal dose for 50%: 2 ng / kg
      • E.x. lethal dose for 50kg is 100ng
    • Therapeutic (Botox) dosage: ~5ng
      • Therapeutic Index (TI): lethal dose / therapeutic dose
        • E.x. 100/5 = 20 (unitlest)
  • Brain
    • The brain needs lots of energy; makes up ~25% of the body’s energy intake at rest
    • The brain receives robust blood flow via the circulatory system
    • Blood-brain barrier (BBB): Everywhere, except the brain and spinal cord, have pores in the blood vessel walls (allowing medium-large molecules system)
      • Walls are composed of phospholipid bilayer biological membrane – thus most of the thickness is hydrophobic
      • Ways to pass
        1. Transport proteins: glucose sugar, some amino acids (too big for channels)
        2. Diffusion: Sufficiently lipophilic / hydrophobic molecules – how non-endogenous molecules pass

Natural poisons #

Tetrodotoxin (TTX) #

  • Blocks voltage-gated sodium channels
    • Peripheral nerves unable to generate normal action potential
    • Leads to numbness, muscle weakness, paralysis
    • Can lead to death through respiratory paralysis
  • Does not get into the brain
  • No CNS effects!
  • In skin and organs of puffer/blow fish, octopus, newts, fugu
    • All unrelated animals; there are symbiotic bacteria that cause this resistance
  • TTX resistance: how do these animals (and their predators) not die?
    • Genetic variance can lead to an amino acid change in the sodium channel
    • Only 1/1800 amino acids are sufficient to be resistant

Saxitoxin #

  • Also called Paralytic Shellfish Poisoning (PSP)
  • Found in dinoflagellates and other protists
  • Causes numbness, muscular weakness, paralysis
  • Resistance results from mutations in the Sodium channel
    • Mutation changing a single amino acid from glutamic acid to aspartic acid (one carbon difference!) causes 1000x decrease in STX sensitivity

Batrachotoxins #

  • Discovered in skins of tiny amazonian frogs
    • Used for blow darts to hunt birds
    • Also found in birds which eat a certain beadle
      • Thought that inside the beadle live symbiotic organisms that produce the molecule
  • Paralytic effect
  • Rather than blocking VG sodium channels, these trigger the receptors (open) which causes a similar effect
    • Similar to local anesthetics (i.e cocaine, benzocaine, lidocaine, procaine)

2 Acetylcholine Receptors #

  1. Ionotropic (nicotinic ACh receptor)
    • Occurs in brain, neuromuscular junctions
    • Agonists: nicotine
    • Antagonist: tubocurarine
  2. GPCR (muscarinic ACh receptor)
    • Occurs in brain, parasympathetic NS
    • Agonists: Muscarine
    • Antagonist: Atropine (parasympatholytic)

9: Psychoactive Drugs #

Psychoactive drugs: top 5 #

  1. Caffeine: tea leaves, coffee, chocolate
    • Molecule blocks adenosine receptors (antagonist)
  2. Ethyl alcohol: beer, wine
    • From fermentation of sugar by yeast
    • Enhances GABA action at receptors
    • Antagonist at some glutamate receptors
    • Blocks presynaptic uptake of adenosine
    • Most popular sedative-hypnotic drugs; those that are calming at lower doses and can lead to death
      • TI is low; ~10 for ethanol
      • Also: Barbiturates (TI <10; used in lethal injection), benzodiazepines (Xanax, Valium), general anesthetics (gases; global loss of sensation for surgeries)
      • All enhance inhibitory action of Cl- GABA receptor in CNS
  3. Nicotine: tobacco plant
    • Agonist at nicotinic AChRs
    • Found in basal forebrain nuclei
    • CNS effects: stimulation and relaxation
    • PNS effects: partial sympathominetic via facilitation of norepinephrine release
  4. Arecoline: betel (areca) nut
    • Similar to nuts/dates
    • Popular in Asia
    • Commonly mixed with betel lea, slaked lime (Calcium hydroxide), spices, and, in India, tobacco
      • Slaked lime enhances psychoactive effects
    • Major psychoactive is Arecoline; muscarinic AChR (GPCR) agonist
    • PNS: Activates parasympathetic NS (parasympathomimetic)
    • CNS: stimulant/relaxant effects, like nicotine
  5. Cannabinoids: cannabis
    • Effects
      • Analgesic
      • Anti-inflammatory
      • Muscle relaxant
      • Appetite stimulant
      • Antiemetic
      • Reduces intraocular pressure
      • Anti-seizure
      • Sedative
      • Hypnotic
    • Unique botanical chemistry involving cannabinoids (THC, CBD)
    • Endogenous ligand; Endocannabinoids: Mediate retrograde signal (backwards!) 1. Anandamide 2. 2-AG
    • Can cause psychosis

  • Erythroxylum coca (cocaine)
    • From leaf to prevent insects from munching (similar to nicotine and caffeine)
    • Acts at norepinephrine (Locus coeruleus) / dopamine (ventral tegmentum, substantia nigra) receptors to prevent reuptake
    • PNS: Norepinephrine; sympathomimetic
    • CNS: stimulant; wakefulness, stamina, appetite suppressant, euphoria
    • Toxicities: sympathetic + CNS overstimulation, addiction
    • Local anesthetic
      • Only occurs at high concentration of substance
      • Disrupts Na+ reuptake
  • Amphetamine (adderall) and other stimulants (ritalin, provigil, etc)
    • Act on norepinephrine / dopamine, but make receptors ’leakey'
    • Similar effects to cocaine at high doses
    • Medical use: treatment of ADHD
  • Opium, opium poppy (Papaver somniferum), morphine, opioids
    • Acute effects
      • Analgesia: reduces pain
      • Anxiolytic: disrupts anxiety
      • Sedation: calming
      • Cough suppression
      • Decreased intestinal motility
      • Pupil constriction
    • Friedrich Wilhelm Sertürner was interested in learning what was inside pharmacy products
      • Extracted opium, founding morphine (~1803)
      • Later the other primary opiod, codeine, was extracted as well
    • Semi-synthetic opioids: synthetic modification of opiates from opium
      • Heroin from morphine; 2-3x more potent
    • Synthetic opioids: not directly related to morphine in chemical structure
      • Fentanyl; 100x more potent
      • Wildnil; 10,000x – used to kill large animals
    • Toxicity
      • Depression of respiratory control centers in brainstem
      • Potential OD potential (low TI)
      • High addictive potential
    • Opioid receptors
      • Agonists at opioid receptors (GPCRs: mu, delta, kappa)
      • Naloxone (Narcan) is an antagonist which blocks and reverses the effects of opioid agonists; used for ODs
      • Endorphins are the neurotransmitter involved
  • Psychedelics (‘mind manifesting’), hallucinogens
    • Leads to heightened awareness of internal/external perception
    • Acts on 5-HT$_{2A}$ serotonin receptor agonists; found all over brain
    • Impacts on brain functionality, synaptic neuroplasticity
    • Can be used to treat anxiety, depression, addiction, PTSD
    1. LSD
      • Discovered by Albert Hofmann
      • Most popular psychedelic
    2. Psilocybe mushrooms
      • Contains Psilocybin
      • Maria Sabina was the first shaman to spread the word to Gordon Wasson
    3. DMT
      • Naturally found; can be converted from tryptophan (amino acid)
      • Used in ayahuasca; used in tribal rituals
    4. Peyote cactus
      • Contains Mescaline molecule
      • Discovered by Arthur Heffter

10: Neural Development and Neuroplasticity #

  • Neuroplasticity:
    • Structure and function of synapses always is being modified
    • Occurs at all times, prevalent in prenatal development
    • Increases by…
      • Increase amount of NT released
        • Open gates for longer
      • Increase number of pre/post synaptic vesicles
      • Decrease reuptake transporters
  • Embryonic Development
    • Process
      • Starts with an egg full of embryonic stem cells
      • Grows into embryonic disc by 2 weeks
      • Neural tube (start of NS) starts to develop by week 3
    • Controlled by genes
  • Human genome
    • 23 chromosomes (from parents haploid cells)
    • 3 billion base pairs (ATCGs)
    • 21,000 distinct genes coding for proteins
    • < 2% of human genome code translated for function protein
      • 80% of the remaining 98% is transcribed into RNA
  • Cell differentiation is controlled by gene transcription: turning on/off of genes at different times
    • Done via transcription factors and regulatory RNA
    • E.x brain cells start as stem cells, grow into some nervous system neural progenitor cell, then can change into various types of neurons/gilial cells through axon and dendrite branching + forming connections (synaptogenesis)
  • Synaptogenesis involves the axon growing tip (growth cone) extending it’s ‘feelers’ (filopodia) outwards
    • Through staining we can see cell’s cytoskeleton (made of microtubules and microfilaments) which are very active in this process
    • Roger Sperry speculate there was some feedback so they knew where to go through chemical signals (Chemoaffinity hypothesis)
      • Now recognized as neurotrophins: proteins produced by the body important for cell growth and survival
    • Guidance Factors
      • Initiated by neurotrophin
      • ‘Steered’ by contact and soluble factors
        • Ephrin receptor interaction can cause either an attraction or repulsive
      • Microtubule is driven outwards while microfilaments communicate