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Lecture 6 from a college level neuropharmacology course taught in the spring 2012 semester by Brian J. Piper, Ph.D. ([email protected]) at Willamette University. Includes neurotransmitter release, reuptake, and inactivation
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Neurocommunication
Brian J. Piper, Ph.D.
Terminology
• Neurotransmitter: chemical that is released in the brain and has an effect on a local target
• Hormone: chemical that is released into bloodstream that has an effect on a distant target
Goals
• Neurotransmission– History– Onset: Neurotransmitter release (classical and
non-classical)– Offset: autoreceptors, transporters, enzymes– Receptor Families
• Endocrine
History: Golgi vs. Cajal• Italian physician• Reticulum theory• Silver stain
Camillo Golgi (1843-1926)
Controversy: Golgi vs. Cajal
• Santiogo Ramon y Cajal– Neuroanatomist– Used Golgi’s technique– Neuron theory
1852-1934
Chicken cerebellum
Neural CommunicationThe body’s information system is built from
billions of interconnected cells called neurons. Communication between
neurons is both electrical and chemical.
Otto Loewi
• Discovered “Vagusstoff” later known as acetylcholine
• “father of neuroscience”• Nobel Prize 1936
What are amino acids?
• Amine (NH2) + Carboxyl ( -COOH)• 20 total, 9 essential
tyrosine Tryptophan
More terminology
• Peptides: short (<50) strings of amino acids, Valine-Glycine-Serine-Alanine… e.g. NPY
C terminal: COOHN terminal: NH2
Arginine, Proline, Lysine, Phenylalanine,
Methionine, Histidine, Aspartic Acid, Valine
More terminology
• Peptides: short (<50) strings of amino acids, Valine-Glycine-Serine-Alanine… e.g. NPY
More terminology
Proteins: longer strings of amino acids, have 3-D structure, form receptors, transporters
ComparisonPeptide Protein
Size (amino acids) < 40 >40
Dimensions 1-D 3-D
Complexity Low High
Hemoglobin
“Typical” Synapse
Electron Microscope
• Beams of electrons are presented to a thin section, 50 pm (10-12) resolution
• Reveals different types of Synapses
Dendritic Spine
Axodendritic Synapse
Axosomatic Synapse
Neurotransmitter Criteria
• 1) Found and made presynaptically.• 2) Mechanism for inactivation.• 3) Stimulating neuron releases it.• 4) Receptors found postsynaptically.• 5) Applying substance has biological effect.• 6) Antagonizing inhibits biological effect.
“neuromodulators”
Neurotransmitter ComparisonClassical Non-Classical
Discovery 1950’s 1980’s
Concentration High Low
# Few Many
Synthesis Anywhere Soma
Classical Neurotransmitters
• Monoamines: dopamine, norepinephrine, serotonin
• Acetylcholine (ACh)• Amino Acids: glycine, GABA, Glutamate
Non-classical Neurotransmitters
• Peptides: Corticotropin-releasing factor (CRF), endorphins
• Lipids: Anandamide• Gases: Nitric Oxide
Co-TransmittersAmine/Amino Acid Peptide
Dopamine Cholecystokinin (CCK)
Norepinephrine enkephalin
Epinephrine neurotensin
Serotonin substance P
Acetylcholine somatostatin
Gamma aminobutyric acid (GABA) motilin
Stahl, S. (2000). Essential Psychopharmacology, p. 20.
Axon Terminal
Brakes II
• Autoreceptors: this receptor (“auto” = “self”) can act to inhibit further neurotransmitter release– Terminal (axon) autoreceptors: inhibit
neurotransmitter release– Somatodendritic autoreceptors: reduce rate of
action potentials
Brakes I
• Enzyme: A + B __ENZ____> AB
• Enzyme: CD __ENZ____> C + D
Transporters• Proteins that move molecule from one place
to another, examples:– SERT: serotonin transporter– NET: norepinephrine transporter– DAT: dopamine transporter
Inside----------------------------------------------------------------------Outside
Post-synaptic
• Ligand: substance that binds to a receptor• Ion: atom where # electrons ≠ # protons
– Ca2+ Na+ K+
– Cl-
• First messenger: neurotransmitter• Second messenger: other molecule• Kinase: enzyme that adds phosphate (PO4)
Types of Receptors
So Many Receptors!
Serotonin (5-HT):1234567
Family 1: Ionotropic
• Binding to receptor opens channel to let ions in (aka: ligand gated ion receptors)
Family 1: Ionotropic
• Binding to receptor opens channel to let ions in (aka: ligand gated ion receptors)
0:40 – 6:20: http://www.youtube.com/watch?v=8jPH2pKzIDY
Family 2: Metabotropic (2nd messenger)
• Steps:• 1) Ligand binds receptor• 2) G protein acts on enzyme• 3) Enzyme regulates 2nd
messenger• 4) 2nd messenger acts on
protein kinase
6:30-9:00 http://www.youtube.com/watch?v=8jPH2pKzIDY
Family 2: Metabotropic (Channel)
• Steps:• 1) Ligand binds receptor• 2) G protein alters
channel • 3) ions flow out of
neuron
Receptor Families ComparedIonotropic Metabotropic
Subunits 4-5 1
Mechanism Simple: Channel opening Complex: G protein cascade
2nd messengers No Yes
Speed Fast Slow
Meyer & Quenzer (2005). p 73
Family 3: Tyrosine Kinase
• Steps: 1) Ligand (BDNF) binds to Trk receptor2) Trk receptors come together, and phosphorylate each other
So many drug targets!!!
Examples:1) Tryptophan6) Nicotine10) MAO-I11) SSRIs
Endocrine SystemGland Hormone (Function)
Pineal Melatonin (light-dark rhythm)
Thyroid T3/T4 (energy)
Adrenal Cortisol (stress)
Pancreas Insulin (glucose)
Ovaries Estrogens (2nd sex characteristics)
Testes Androgens (2nd sex characteristics)
Example
• Rats that received ecstasy (MDMA) during adolescence were more sensitive to a 5-HT2 agonist when adults
Biezonski et al. (2009). Brain Research, 1252, 87-93.
Reference