neuropharmacology: neurotransmission

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