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, India He 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 Convergence in 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