Chapter 6 Neurotransmitter Systems

Introduction

• Three classes of neurotransmitters– Amino acids, amines, and peptides

• Ways of defining particular transmitter systems:– By the molecule, synthetic machinery, packaging,

reuptake and degradation, etc.

• Acetylcholine (Ach)– First identified neurotransmitter

• Nomenclature (-ergic) – Cholinergic and noradrenergic

Henry Dale – received the Nobel Prize for Medicine in 1926 for his work on synaptic transmission.

He is also well known for his coining of the term “cholinergic.”

• Studying Transmitter Localization

• Immunocytochemistry – localize molecules to cells

• In situ hybridization– Localize synthesis of protein or peptide to a

cell (detect mRNA)

Muscarine – a type of poison found in some mushrooms

Moto-Taxi Driver (1999) at a coffee shop in Bangalore, IndiaHe is stimulating his nicotinic receptors.

A farmer harvesting opium poppies.

Studying Neurotransmitter Systems

• Neurotransmitter - three criteria– Synthesis and storage in presynaptic neuron– Released by presynaptic axon terminal– Produces response in postsynaptic cell

• Mimics response produced by release of neurotransmitter from the presynaptic neuron

• Studying Transmitter Release

– Transmitter candidate: Synthesized and localized in terminal and released upon stimulation

– CNS contains a diverse mixture of synapses that use different neurotransmitters

– Brain slice as a model• Kept alive in vitro Stimulate synapses,

collect and measure released chemicals

• Studying Synaptic Mimicry

– Qualifying condition: Molecules evoking same response as neurotransmitters

– Microionophoresis: Assess the postsynaptic actions– Microelectrode: Measures effects on membrane

potential

• Studying Receptor Subtypes– Neuropharmacology

• Agonists and antagonists

• e.g., ACh receptors – Nicotinic,

Muscarinic• Glutamate receptors

– AMPA, NMDA, and kainite

– Ligand-binding methods• Identify natural receptors using

radioactive ligands •Can be: Agonist, antagonist, or

chemical neurotransmitter

– Molecular analysis- receptor protein classes– Transmitter-gated ion channels

» GABA receptors» 5 subunits, each made with 6 different

subunit polypeptides– G-protein-coupled receptors

Neurotransmitter Chemistry

• Evolution of neurotransmitters– Neurotransmitter molecules

• Amino acids, amines, and peptides • Dale’s Principle

– One neuron, one neurotransmitter• Co-transmitters

– Two or more transmitters released from one nerve terminal

– An amino acid or amine plus a peptide

Neurotransmitter Chemistry

• Cholinergic (ACh) Neurons

Neurotransmitter Chemistry

• Cholinergic (ACh) Neurons

• Catecholaminergic Neurons– Involved in movement,

mood, attention, and visceral function

– Tyrosine: Precursor for three amine neurotransmitters that contain catechol group• Dopamine (DA)• Norepinephrine (NE)• Epinephrine (E,

adrenaline)

• Serotonergic (5-HT) Neurons– Amine neurotransmitter

• Derived from tryptophan– Regulates mood, emotional behavior, sleep

• Selective serotonin reuptake inhibitors (SSRIs) - Antidepressants

– Synthesis of serotonin

• Amino Acidergic Neurons– Differences among amino acidergic neurons

quantitative NOT qualitative – Glutamic acid decarboxylase (GAD)

• Key enzyme in GABA synthesis• Good marker for GABAergic neurons• GABAergic neurons are major of synaptic

inhibition in the CNS

• Other Neurotransmitter Candidates and Intercellular Messengers– ATP: Excites

neurons; Binds to purinergic receptors

– Endocannabinoids– Retrograde

messengers

Consumption of Cannabis:

Effect is due to its ability to alter neural activity in the brain in ways similar to several different neurotransmitters

Transmitter-Gated Channels

• Introduction– Fast synaptic transmission– Sensitive detectors of chemicals and voltage– Regulate flow of large currents– Differentiate between similar ions

• The Basic Structure of Transmitter-Gated Channels– Pentamer: Five protein subunits

Transmitter-Gated Channels

• Amino Acid-Gated Channels– Glutamate-Gated Channels

• AMPA, NMDA, kainite

Transmitter-Gated Channels

• Amino Acid-Gated Channels– GABA-Gated and Glycine-Gated Channels

• GABA mediates inhibitory transmission • Glycine mediates non-GABA inhibitory

transmission• Bind ethanol, benzodiazepines, barbiturates

• GPCR Effector Systems– The Shortcut Pathway

• From receptor to G-protein to ion channel; Fast and local

• GPCR Effector Systems– Second Messenger Cascades

• G-protein: Couples neurotransmitter with downstream enzyme activation

• GPCR Effector Systems (Cont’d)• Push-pull method (e.g., different G proteins or

stimulate and inhibit adenylyl cyclase)

• Divergence– One transmitter

activates more than one receptor subtype greater postsynaptic response

• Convergence– Different

transmitters converge to affect same effector system

Divergence and Convergencein Neurotransmitter Systems

Concluding Remarks

• Neurotransmitters– Transmit information between neurons– Essential link between neurons and effector

cells• Signaling pathways

– Signaling network within a neuron somewhat resembles brain’s neural network

– Inputs vary temporally and spatially to increase and/or decrease drive

– Delicately balanced– Signals regulate signals- drugs can shift the

balance of signaling power