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:
==Ionotropic receptors==::open ion channels
- Quick activity; a few ms
- GABA receptors open chloride channels (hyperpolarization)
- Glutamate receptors open sodium and calcium channels (depolarization)
==Metabotropic receptors==::2nd mess, metabolic change occurs
- Slow, long lasting (30ms - s, m, etc.)
- G-protein coupled
- Can open surrounding ion channels or alter prod. of proteins
Basic Rules of Neurotransmitters:
- Must by synthesized by a presynaptic neuron and stored in vesicles
- Must be released in response to an action potential reaching the terminal
- Receptor must recognize the NT somewhere
- Must be some kind of a change to the cell when received by receptor
- Blocking release interferes w/ability of presynaptic cell to affect postsynaptic cell
Neurotransmission in 4 Steps:
- Synthesis (axon terminal or cell body)
- Release
- Receptor action
- 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
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