Slide 1Principles of neurotransmitter systemsPrinciples of neurotransmitter systemsPrinciples of neurotransmitter systemsPrinciples of neurotransmitter systemsPrinciples of neurotransmitter systemsPrinciples of neurotransmitter systemsNeurotransmitter chemistryNeurotransmitter chemistryNeurotransmitter chemistryNeurotransmitter chemistryNeurotransmitter chemistryNeurotransmitter chemistryNeurotransmitter chemistryNeurotransmitter chemistryNeurotransmitter chemistryNeurotransmitter chemistryNeurotransmitter chemistryNeurotransmitter chemistryNeurotransmitter chemistryNeurotransmitter chemistryNeurotransmitter chemistryTransmitter-gated channelsTransmitter-gated channelsTransmitter-gated channelsTransmitter-gated channelsTransmitter-gated channelsTransmitter-gated channelsG-protein-coupled receptorsG-protein-coupled receptorsG-protein-coupled receptorsG-protein-coupled receptorsG-protein-coupled receptorsG-protein-coupled receptorsG-protein-coupled receptorsIntegration of neurotransmitter systemsSlide 37NEUROTRANSMITTER SYSTEMSNEUR 3000Dr. Joseph J. NormandinPRINCIPLES OF NEUROTRANSMITTER SYSTEMS•There are three classes of neurotransmitters•Amino acids•Amines•Peptides•(there’s probably more)•Within these classes there is a multitude of neurotransmitters•Each neurotransmitter is part of a system that includes:•The molecule itself•Synthesis of the neurotransmitter•Packaging•Reuptake & degradation•ActionPRINCIPLES OF NEUROTRANSMITTER SYSTEMS•There are three criteria that define a neurotransmitter•Synthesis and storage in presynaptic neurons•Released by a presynaptic axon terminal•Produces a response in a postsynaptic cell•Neurotransmitters bind to specific receptors•There are many receptor subtypes for a given neurotransmitter•Receptors can be transmitter-gated ion channels (ionotropic) or g-protein coupled receptors (metabotropic)•The receptor determines neurotransmitter action•A given neurotransmitter can have opposing actions depending on the receptorPRINCIPLES OF NEUROTRANSMITTER SYSTEMSPRINCIPLES OF NEUROTRANSMITTER SYSTEMS•Exogenous molecules also interact with neurotransmitter receptors•Any compound that binds to a receptor is a ligand•Exogenous ligands that mimic the effect of a neurotransmitter are called agonists•Exogenous ligands that block the effects of a neurotransmitter are called antagonistsPRINCIPLES OF NEUROTRANSMITTER SYSTEMSPRINCIPLES OF NEUROTRANSMITTER SYSTEMS•Neurotransmitter systems are defined by neurons that release a particular neurotransmitter•Dopaminergic neurons•GABAergic neurons•However, a given amine or amino acid neurotransmitter system may also co-release with peptide neurotransmittersNEUROTRANSMITTER CHEMISTRY•Acetylcholine (ACh)•Amine neurotransmitter•Cholinergic neurons•Found in:•Motor neurons of the neuromuscular junction•Central nervous system•Autonomic nervous systemNEUROTRANSMITTER CHEMISTRYNEUROTRANSMITTER CHEMISTRYNEUROTRANSMITTER CHEMISTRY•Acetylcholine (ACh)•In Alzheimer’s disease there is death of CNS ACh neurons•Drugs that inhibit AChE are effective in treating the memory deficits early on•How?NEUROTRANSMITTER CHEMISTRY•Catecholamines•Amine neurotransmitters•Dopamine (DA), Norepinephrine (NE), Epinephrine (E)•Catecholaminergic neurons•Dopaminergic, Noradrenergic, Adrenergic•Found in:•Central nervous system (DA, NE, E), mood, arousal, movement•Autonomic nervous system (NE), visceral responses•May also act as hormones (NE, E) visceral responsesNEUROTRANSMITTER CHEMISTRYNEUROTRANSMITTER CHEMISTRY•Catecholamines•Catecholamines are not degraded in the synaptic cleft•Termination of catecholaminergic signals is dependent on reuptake transporters•Back inside the axon terminal, monoamine oxidase (MAO) will degrade catecholamines•Dopaminergic cell death is a hallmark of Parkinson’s disease•Treatment in early Parkinson’s is with L-dopa•What does that do?NEUROTRANSMITTER CHEMISTRY•Serotonin, 5-hydroxytryptamine (5-HT)•Amine neurotransmitter•Serotonergic neurons•Found in:•Central nervous system, though few in number•Important in the regulation of mood, emotion, sleepNEUROTRANSMITTER CHEMISTRYNEUROTRANSMITTER CHEMISTRY•Serotonin, 5-hydroxytryptamine (5-HT)•Not degraded in the synaptic cleft•Termination of serotonergic signals is dependent on reuptake transporters•Back inside the axon terminal, monoamine oxidase (MAO) will degrade 5-HT•Blocking of the 5-HT transporter by SSRIs is the most common method of pharmacological intervention for depression•What does that do?NEUROTRANSMITTER CHEMISTRY•Amino acid neurotransmitters•Glutamate (Glu), Glycine (Gly), gama-Aminobutyric acid (GABA)•Amino acidergic neurons•Glutamatergic, Glycinergic, GABAergic•Found:•Ubiquitously in central nervous system•Glutamate is the major excitatory NT of the brain•GABA is the major inhibitory NT of the brainNEUROTRANSMITTER CHEMISTRYNEUROTRANSMITTER CHEMISTRY•Amino acid neurotransmitters•Not degraded in the synaptic cleft•Termination of amino acidergic signals is dependent on reuptake transporters on neurons and glia•Back inside the axon terminal or glia, GABA transaminase will degrade GABA; Glu & Gly are recycledNEUROTRANSMITTER CHEMISTRY•Other neurotransmitters•ATP•Found in presynaptic terminals in CNS & PNS•Released with calcium influx•Co-released with catecholamines at some synapses•Binds to purinergic receptors, ionotropic and metabotropicNEUROTRANSMITTER CHEMISTRY•Other neurotransmitters•Endocannabinoids•Small lipid molecules•Retrograde transmitter: from postsynaptic cell to presynaptic terminal•Regulates NT release at presynaptic terminal•Synthesized from membrane via a specific enzyme•Released w/o vesicle•Bind to CB1receptor, metabotropic, inhibits calcium channel opening•What would this do?TRANSMITTER-GATED CHANNELS•Transmitter-gated ion channels are a type of receptor•Binding of a ligand results in the opening of an ion channel•Also called ligand-gated ion channels, ionotropic receptors•Considered to be “fast” synaptic transmission•Channel selectivity for different ions determines the effect of ligand-bindingTRANSMITTER-GATED CHANNELS•Ionotropic glutamate receptors•AMPA, NMDA, Kainate receptors•Originally defined by the exogenous ligands that activated these receptors in experimental preparations•AMPA & NMDA receptors produce fast excitatory