The Blood-Brain Barrier:

• Molecules can’t slip b/w the cells and go in/out of the capillaries (only in the nervous system)

  • Very few things actually get into the brain

• Some lipid solubility - pretty much everything has to have an active transport system (glucose, amino acids, vitamins, hormones)

• 1st internal mechanism of protection for the brain

• Circumventricular organs::not protected by the BBB

  • Area postrema::neg. molecules coming into brain and brain stem - the first poison detection center, causes vomiting/diarrhea

Nourishing Vertebrate Neurons:

• Glucose, lactate, acetate - brain uses more sugar than any cells/organs

  • Sperm and cancer also really attracted to sugar

  • Using glucose requires oxygen, crosses in using a transport system

• Korsakoff’s Syndrome::”alcoholic’s disease” - thiamine deficiency; neurons in the midline structures start to die (also seen in anorexic patients)

History:

• 1st NT discovered by Otto Loewi (1921) - acetylcholine using frog hearts

  • Acetylcholine works on skeletal muscles, tissue, internal organs

  • Activating vagus nerve lowers heart rate

Two Classes of Receptors:

1. Ionotropic receptors::open ion channels

   1. Quick activity; a few ms

   2. GABA receptors open chloride channels (hyperpolarization)

   3. Glutamate receptors open sodium and calcium channels (depolarization)

2. Metabotropic receptors::2nd mess, metabolic change occurs

   1. Slow, long lasting (30ms - s, m, etc.)

   2. G-protein coupled

   3. Can open surrounding ion channels or alter prod. of proteins

Basic Rules of Neurotransmitters:

1. Must by synthesized by a presynaptic neuron and stored in vesicles

2. Must be released in response to an action potential reaching the terminal

3. Receptor must recognize the NT somewhere

4. Must be some kind of a change to the cell when received by receptor

5. Blocking release interferes w/ability of presynaptic cell to affect postsynaptic cell

Neurotransmission in 4 Steps:

1. Synthesis (axon terminal or cell body)

2. Release

3. Receptor action

4. Inactivation

Activation and Deactivation:

• Receptor-site activation

  • Post-synaptic effects

    • Depolarization, hyperpolarization, modulating effects

  • Pre-synaptic effects

    • Autoreceptors::a way of giving feedback to the neuron about the status of the external environment; guides overall production in Cell A

• NT deactivation

  • Diffusion - they float away where they have no effect (automatic)

  • Degradation - degrade/fall apart over time (automatic)

  • Transporters (reuptake)::presynaptic, reabsorb the NT and recycle it so it can be used again

  • Glial cell help - astrocytes pull excess NTs and safely give to cell A

Types of Synapses:

• Type I::excitatory

• Type II::inhibitory

• PSD::pre or post synaptic density

How Drugs Work:

• Agonists::increase effectiveness of the NT targeted

• Antagonists::decrease effectiveness of the NT targeted

• Pharmacologists need to know Effective Dose of potential drugs - start w/animal models

• Need to know Toxic Dose (TD50) or Lethal Dose (LD50)

• Therapeutic Index (TI)::difference between ED and LD can have wide or narrow variability

Amino Acid NTs:

• GABA::gamma-aminobutyric acid

  • Primary inhibitory NT (opens chloride channels and causes hyperpolarization; oval shaped vesicles on cell body)

  • Valium, Xanax → Benzodiazepenes (opens chloride channels for longer periods of time)

  • Alcohol (agonist) - loss of coordination and balance (cerebellum)

  • As you turn up GABA, glutamate is negatively effected (“brain mush”)

Glutamate:

• Makes GABA - in every cell in our body, but very specialized in neurons

• Primary excitatory NT (round vesicles, Type I synapses)

• Learning and memory

• Alcohol (antagonist) - loss of memories (hippocampus), poor decisions (PFC)

• If turned up too high, can become neurotoxic::kills other neurons

Quaternary Amine NTs:

• Acetylcholine (ACh)::highly tied to learning and memory (hippocampus and basal ganglia); fast acting at the neurotransmitter junction and degrades very quickly

  • Synthesized from Acetyl Coenzyme A and Coline (thru diet)

  • Acetylcholinesterase (AChE)::enzyme, breaks down ACh

  • Cholingeric Drugs:

    • Curare, Botex, Sarin/Soman/Tabun - neuromuscular junction

      • Curare and Botox are paralytics bc they block the ability of ACh to bind to the muscle - antagonists

      • Sarin/Soman/Tabun - nerve gases and AChE-I agonists

      • Nicotine - agonist, causing brain fog because ACh receptors are being removed

  • Alzheimer’s Disease - shrinkage in the hippocampus, tau protein chains start to disintegrate and break, neurons die or retract; plaque forming in synapse makes it hard for ACh and glutamate

Neuromuscular Junction:

• Axons of motor neurons synapse onto receptor proteins that form clusters on various muscles throughout the body

Monoamine NTs - Catecholamines:

• Dopamine

  • Motion and control, reward (feelings of pleasure)

  • Drugs

    • Cocaine, methylphenidate - dopamine agonists and block reuptake

    • Adderall, amphetamines - dopamine agonists and increase release of DA

    • MDMA - at low doses releases DA

    • Wellbutrin - dopamine reuptake inhibitor, helps people w/depression

  • Diseases (Parkinson’s on left end of continuum, schizophrenia at right end)

    • Parkinson’s - tremors, inability to initiate movement, DA neurons in substantia nigra are dying and can’t stimulate the basal ganglia in the mesostriatal pathway - treat w/a dopamine agonist (L-Dopa)

    • Schizophrenia - delusions and hallucinations, flight of ideas, disorganized behavior, overstimulation of dopamine in mesolimbocortical pathway - treat w/a dopamine antagonist (anti-psychotics)

• Norepinephrine (NE)

  • Attention, vigilance, arousal, alertness

  • SNRIs (Effexor, Remeron, Cymbalta, Meridia) - good for mild/mod depression

  • NRIs (Atomoxetine - Strattera) - ADHD nonstimulant

• Epinephrine (Epi)

  • Mainly in body, small amounts in brain - aka “adrenaline rush”

  • Cardiac meds (beta blockers)

• Catecholamine Synthesis

  • Phenylanine and tyrosine part of our diet - essential amino acid, foods high in protein (soy based products, eggs, nuts/seeds, seafood, meat)

  • Turning up phenylanine/tyrosine can increase dopamine, and maybe increase NE and Epi

Monoamine NTs - Indoleamines:

• Serotonin (5-HT)

  • Synthesized from tryptophan

  • Emotional states, impulse control, dreaming, OCD, anxiety, dep, over-eating, aggression

  • SSRIs - Prozac, Paxil, Lexapro, Celexa, Zoloft

  • Psychedelics - LSD, psilocybin - interaction b/w 5-HT and DA

  • Ecstasy - MDMA

• Serotonin Synthesis

  • Tryptophan::essential amino acid (foods high in protein - wild game, seeds/nuts, cheeses, seafood/fish, meat)

Peptide NTs:

• Opiate Drugs

  • Opioid receptor activation::inhabit VTA GABA neurons and increase DA activity

  • Blocks locus coeruleus activity in brain which thereby decreases response to stress, impairs memory, decreases arousal

• Cannabis

  • Delta-a-tetrahydrocannabinol (THC) and cannabidol (CBD)

    • THC - pain relief, lower BP, relief of nausea, decreased eye pressure in glaucoma, immunosuppressive actions (Schedule I drug)

  • Many, many cannabinoid receptors in the brain

  • Decrease glutamate activity in brain regions

  • Disrupts attention, STM impairments, altered sensory awareness

  • Not lethal, very few receptors in brain stem