Neurotransmitters PDF

Neurotransmitters Neurophysiology Review Sequence of synaptic transmission: 1. Dendrites receive signals (EPSPs, IPSPs) 2. Temporal and spatial summation determine if action potential is generated at axon hillock 3. Action potentials (i.e., rapid depolarization and hyperpolarization of cell m...

Neurotransmitters Neurophysiology Review Sequence of synaptic transmission: 1. Dendrites receive signals (EPSPs, IPSPs) 2. Temporal and spatial summation determine if action potential is generated at axon hillock 3. Action potentials (i.e., rapid depolarization and hyperpolarization of cell membrane) propagate 4. Action potential arrives at axon terminal 5. Voltage-gated calcium channels open, Ca2+ ions enter 6. Synaptic vesicles fuse with membrane, release transmitter into cleft 7. Transmitter crosses cleft and binds to postsynaptic receptors, opens ion channels 8. Ion flow creates a local EPSP or IPSP in postsynaptic neuron (see step 1) 9. Transmitter is inactivated/degraded by enzymes, removed by transporters, or diffuses 10.Transmitter may activate presynaptic autoreceptors Synaptic Transmission – Receptors Multiple types of ionotropic and metabotropic receptors for each neurotransmitter protein subunits determine the ligand and ion A given neurotransmitter can interact with several type of receptors 14 R types for serotonin 5 R types for dopamine 5 R types for norepinephrine Thus, neurotransmitters can send different messages (e.g., inhibitory, excitatory) by acting at different receptors Neurotransmitters co-localization / coexistence / co-release: some neurons contain more than one type of neurotransmitter; neurons have receptors for many types Neurotransmitters Small vesicles contain small molecule neurotransmitters Amines, amino acids, acetylcholine Synthesized by enzymes in cytoplasm (except norepinephrine), packaged into vesicles Rate limiting steps (usually an enzyme) that controls rate of synthesis Large dense-core vesicles contain peptides Made in soma Transported to terminal via microtubules (axonal transport) Neurotransmitters Classic neurotransmitters, endogenous substance that: exists in presynaptic axon terminal the presynaptic terminal contains enzymes to synthesize it is released in significant quantities when action potentials reach the terminal is recognized by specific receptors on postsynaptic membrane experimental application of it yields changes in the postsynaptic cell blocking its release prevents presynaptic activity from affecting postsynaptic cell Amines Amino acids Acetylcholine Neuropeptides Gasotransmitters NOTE: more than 100 neurotransmitters; we are only looking at a few! Neurotransmitters Neurotransmitters (organic cation) A few other tables – study tip: try to organize these all into one summary table! Neurotransmitters Neurotransmitter Type Signaling effect Major source Broad psychological functions Glutamate Amino acid Excitatory Excitatory neurons Mood, cognition, arousal, throughout the brain motivation, reward, learning GABA Amino acid (metabolite Inhibitory Inhibitory neurons Mood, cognition, arousal, of glutamate) throughout the brain motivation, reward, learning Dopamine Monoamine Neuromodulatory Substantia nigra, Motivation, reward, mood, (catecholamine) ventral tegmental area, cognition, movement, learning hypothalamus Norepinephrine Monoamine Neuromodulatory Locus coeruleus Arousal, stress (“fight or flight”) (catecholamine); metabolite of dopamine Serotonin Monoamine (indolamine) Neuromodulatory Raphe nuclei Mood, cognition, learning, physiological functions like digestion and vasoconstriction A few other tables – study tip: try to organize these all into one summary table! Neurotransmitters Amines Amino acids small molecule neurotransmitters Amino acids Acetylcholine Amine Neuropeptides Gases Amine Acid Neuropeptides You do not need to know the chemical formula/structures – this is just a visual Neurotransmitters Amines Amino acids small molecule neurotransmitters Acetylcholine Neuropeptides Gases You do not need to know the chemical formula/structures – this is just a visual Neurotransmitters – Amines Small-molecule neurotransmitters Monoamines Chemicals that contain an amine group (NH) in their chemical structure Since the chemical structure of all of these is similar, some enzymes & drugs affect all of them to some degree Most monoamines are made in small groups of neurons in brainstem and sent all over brain Monoamines Catecholamines Indolamines dopamine serotonin norepinepherine melatonin epinepherine Catecholamine Synthesis A few enzymes: hydroxylase: adds hydroxyl group (OH) decarboxylase: removes carboxyl group (COOH) methyltransferase: adds methyl group (CH3) final step of norepinepherine synthesis occurs in vesicles You do not need to know the chemical formula/structures, but know the precursors and the order of synthesis Dopamine (DA) Mesostriatal pathway Dopamine synthesized in substantia nigra (SN) important in motor control; neuronal loss is a cause of Parkinson’s disease Mesolimbocortical DA pathway Dopamine synthesized in ventral tegmental area (VTA) involved in reward, reinforcement, and learning; abnormalities associated with schizophrenia Mesolimbic (VTA to amygdala, hippocampus, nucleus accumbens); reinforcement/ reward Mesocortical (VTA to cortex); working memory, learning, attention, planning, strategies for problem solving Dopamine (DA) Ventral tegmental area site of Mesolimbocortical DA synthesis Dorsal site of Mesostriatal DA synthesis Ventral Dopamine (DA) Dopamine is strongly associated with reward All known drugs of abuse and other rewards - like food & sex, even video games - stimulate DA neurons, DA release, DA receptors in these pathways Mesolimbic pathway: VTA → Nucleus accumbens Mesocortical pathway: VTA → orbitofrontal cortex (prefrontal cortex) Dopamine (DA) DA Receptors Presynaptic (aka autoreceptors) Multiple types (D1-D5) All metabotropic D1 and D2 are most common D1 generally excitatory mostly post-synaptic D2-D5 generally inhibitory D2 pre- and post-synaptic Dopamine (DA) DA receptors and the Basal Ganglia Substantia nigra projects to caudate and putamen (aka striatum) Those are dopaminergic neurons Some striatal neurons have D1 receptors; others have D2 receptors… So dopamine can be excitatory to some neurons and inhibitory to others Dopamine (DA) Removal of dopamine from the synapse Dopamine transporters in presynaptic membrane takes dopamine from synapse back into terminal. Monoamine oxidase (MAO) breaks dopamine down inside terminal (MAO acts on ALL of the monoamines) (Dopamine transporter) Neurotransmitters – Amines Small-molecule neurotransmitters Monoamines Chemicals that contain an amine group (NH) in their chemical structure Since the chemical structure of all of these is similar, some enzymes & drugs affect all of them to some degree Most monoamines are made in small groups of neurons in brainstem and sent all over brain Monoamines Catecholamines Indolamines dopamine serotonin norepinepherine melatonin epinepherine Catecholamine Synthesis A few enzymes: hydroxylase: adds hydroxyl group (OH) decarboxylase: removes carboxyl group (COOH) methyltransferase: adds methyl group (CH3) final step of norepinepherine synthesis occurs in vesicles You do not need to know the chemical formula/structures, but know the precursors and the order of synthesis Norepinephrine (NE); noradrenaline Released from the locus coeruleus in the pons and lateral tegmental system in the midbrain Synthesized by small populations, but cell bodies project widely across several other areas also released as a hormone into the blood, where it causes blood vessels to contract and heart rate to increase Cells producing it are noradrenergic Behavioral effects are excitatory (increase vigilance, attentiveness to events in the environment) Also important in sexual behavior, mood, control of appetite Norepinephrine (NE); noradrenaline Dorsal Locus coeruleus: “blue spot” (brainstem) Pons Ventral Norepinephrine (NE); noradrenaline Can be released from axonal varicosities: swellings along the length of an axon that contain synaptic vesicles and released a neurotransmitter Nondirected synapses; string of beads Norepinephrine (NE); noradrenaline FIGHT OR FLIGHT Ganglia near spinal cord Everything activates together Acetylcholine and Norepinephrine Norepinephrine (NE); noradrenaline Norepinephrine Receptors 4 types of adrenergic receptors in the CNS: α1 α2 β1 β2 metabotropic found in other tissues of body sensitive to epinephrine as well Effects in brain are excitatory or inhibitory, depending on receptor Norepinephrine (NE) & Epinephrine (EPI) Epinephrine (adrenaline) Norepinephrine (noradrenaline) Yes, it’s the most common NT of your Neurotransmitter (NT) Yes sympathetic nervous system; mainly works as an NT Hormone Yes, mainly works as a hormone Yes Part of fight-or-flight response Yes Yes Made in/released from Mainly in and from your adrenal glands Mainly in and from your nerves Made from Norepinephrine Dopamine Mainly works to increase or maintain Works on/action Acts on almost all body tissues blood pressure When released into bloodstream During times of stress Continuously Severe asthma, anaphylaxis, low blood Emergency low blood pressure Common use in medicine pressure from severe conditions conditions Neurotransmitters – Amines Small-molecule neurotransmitters Monoamines Chemicals that contain an amine group (NH) in their chemical structure Since the chemical structure of all of these is similar, some enzymes & drugs affect all of them to some degree Most monoamines are made in small groups of neurons in brainstem and sent all over brain Monoamines Catecholamines Indolamines dopamine serotonin norepinepherine melatonin epinepherine Serotonin (5-HT) A few enzymes: hydroxylase: adds hydroxyl group (OH) decarboxylase: removes carboxyl group (COOH) methyltransferase: adds methyl group (CH3) Serotonin (5-HT) Most cell bodies are in raphe nuclei (midline of brainstem); serotonergic fibers project widely Serotonin is implicated in sleep states (arousal, dreaming), mood, sexual behavior, anxiety, eating, regulation of pain, nausea and vomiting Can be released from varicosities (like NE) Serotonin (5-HT) Dorsal Locus coeruleus: “blue spot” Pons Raphe nuclei (serotonin) Ventral Serotonin (5-HT) 14 different serotonergic receptors (known so far): Postsynaptic & presynaptic (autoreceptors) receptors All but one are metabotropic 5-HT3 is the one (known) ionotropic opens Cl- channel role in nausea and vomiting Some drugs can block this receptor (e.g., antiemetics like phenergan and Zofran); used to block side effects from chemo and radiation Neurotransmitters Amines Amino acids small molecule neurotransmitters Acetylcholine Neuropeptides Gases Acetylcholine (ACh) The first neurotransmitter to be identified (Loewi’s frog heart experiment) Neurons that use Ach are called cholinergic Three main systems within brain, originating in: 1. Pons (REM sleep) 2. Basal forebrain (activation of cortex, facilitation of learning) 3. Medial septum (theta rhythms of hippocampus, formation of some types of memories) ACh diminished in Alzheimer’s Disease Also found in PNS Acetylcholine (ACh) Two types of ACh receptors: Nicotinic (nACh) Most are ionotropic; mainly flux Na+ and K+ (excitatory) Includes 5 subunits; at least 17 known different subunits… so many different forms of the receptor Neurons in autonomic ganglia, brain Presynaptic facilitation at some axoaxonic synapses (e.g., hippocampus) Neuromuscular junctions (NMJ); antagonists such as curare cause paralysis Muscarinic (mACh) G protein-coupled (metabotropic), slower At least 5 known types Excitatory or inhibitory On innervated tissue of ANS Acetylcholine (ACh) ACh in the autonomic nervous system Parasympathetic Preganglionic neuron Ach Postganglionic neuron Ach Sympathetic Ach Preganglionic neuron Postganglionic neuron NE Acetylcholine (ACh) Parasympathetic nervous system: Two-neuron chain from CNS to target organ. One synapse between neurons in a ganglion. Both neurons use ACh, but it acts at different receptors. Muscarinic ACh receptors Nicotinic ACh receptors on neurons in ganglia on cardiac cells (postganglionic neurons) Acetylcholine (ACh) ACh in the somatic nervous system Skeletal muscle contraction accomplished by ACh (nACh-R) at neuromuscular junction (NMJ) Acetylcholine (ACh) Synthesis and breakdown of acetylcholine Acetyl- cholinesterase in synaptic cleft breaks ACh back down to acetate Comes from and choline breakdown of lipids ~ 50% of choline recycled ChAT transfers acetate from acetyl-CoA to choline → Acetylcholine Neurotransmitters Amines Amino acids small molecule neurotransmitters Acetylcholine Neuropeptides Gases Neurotransmitters – Amino Acids Main excitatory neurotransmitters in the brain are glutamate (Glu) and aspartate Gamma-aminobutyric acid (GABA) is inhibitory Glycine is usually inhibitory Glu and GABA likely among earliest neurotransmitters to evolve most neurons receive excitatory glut input and inhibitory GABA input rest of the NTs modulate responses GABA = Glu metabolite Glutamate (Glu) Ionotropic glutamate receptors AMPA receptor: controls a sodium channel NMDA receptor: controls a sodium & calcium channel; channel blocked by Mg + ions kainate receptor: controls a sodium channel f13-19-03007 f13-20-03007 AMPA R can help activate NMDA R More in learning and memory (Chapter 17) Glutamate (Glu) NMDA receptor At least 6 different binding sites (including in pore) Activation is more complex than simply whether the neurotransmitter binds Glutamate (Glu) Metabotropic glutamate receptors (mGluRs) At least 8 subtypes Some are autoreceptors Glutamate (Glu) Clearing glutamate from the synapse Excitatory amino acid transporters In astrocytes and in neurons (pre- and post-synaptic) Broken down by enzyme (glutamine synthase) Neurotransmitters – Amino Acids Main excitatory neurotransmitters in the brain are glutamate (Glu) and aspartate Gamma-aminobutyric acid (GABA) is inhibitory Glycine is usually inhibitory Glu and GABA likely among earliest neurotransmitters to evolve most neurons receive excitatory glut input and inhibitory GABA input rest of the NTs modulate responses GABA = Glu metabolite Gamma aminobutyric acid (GABA) Large GABA pathways in brain Many GABAergic interneurons Inhibition keeps brain under control…otherwise all cells would become excited (due to high connectivity) Glutamic acid decarboxlylase (GAD) Glutamic acid (glutamate) → GABA Gamma aminobutyric acid (GABA) GABA Receptors (several classes) GABA-A receptor: - Ionotropic - Cl- channel (influx) GABA-B receptor: - Metabotropic - activity opens a K+ channel (efflux) GABA-C receptor - Ionotropic - Cl- channel (influx) GABA-A receptor (ionotropic; at least 5 different binding sites) Gamma aminobutyric acid (GABA) Clearing GABA from the synapse GABA transporters In astrocytes and in neurons Broken down by enzyme (GABA aminotransferase) Glycine An important inhibitory neurotransmitter Receptor is ionotropic and controls Cl- channel Sometimes released w/ GABA (from same terminal) → rapid, long-lasting IPSPs Rapid via ionotropic glycine R Long-lasting via metabotropic GABA receptor Neurotransmitters Amines Amino acids Amino acids Acetylcholine Amine Neuropeptides Gases Amine Acid Neuropeptides You do not need to know the chemical formula/structures – this is just a visual Neurotransmitters – peptides Neuron produces larger precursor molecules, enzymes break them down into smaller peptides Synthesis and packaging into vesicles done in soma → sent to terminal Released from many parts of terminal, not just active zone, so affect all neurons (with appropriate receptors) in vicinity Used as neurotransmitters, neuromodulators, and hormones (periphery). Can have similar function in CNS and PNS E.g., angiotensin acts at kidneys when lose fluids; acts in brain to promote thirst Some terminals release classic neurotransmitters and peptides; peptide modulates activity of classic neurotransmitters Destroyed by enzymes outside of terminal; no reuptake or recycling Neurotransmitters – peptides Examples of peptide transmitter functions: Stress response (corticotropin releasing factor) Social bonding (pituitary hormones, e.g., oxytocin and vasopressin) Regulation of eating and drinking (e.g., orexin, vasopressin, angiotensin) Response to pleasure & pain (e.g., substance P, endogenous opioids) Endogenous Opioids Endorphins, Enkephalins, Dynorphins Different neural systems for different actions: Periaquaductal grey (PAG) and spinal cord: ↓ pain Reinforcement pathway: pleasure & reward PAG: species-typical defensive responses Receptors: Mu, delta, kappa All metabotropic Opioid drugs act on their receptors Endogenous Opioids Midbrain (mesencephalon) Neurotransmitters Amines Amino acids small molecule neurotransmitters Acetylcholine Neuropeptides Gases Nitric oxide (NO) A gas produced by cells in the nervous system Made on demand; not stored in vesicles Made in all parts of neurons Does not interact with membrane-bound receptor; diffuses out of cell and into others retrograde transmitter (postsynaptic neuron signals back to the presynaptic neuron) Activates enzymes (i.e., activates a 2nd messenger) NO is degraded within seconds of being made, but the 2nd messenger it activates can yield much longer lasting effects Involved in synaptic plasticity Vasodilator (brain & periphery) Neurotransmitters - summary Drugs can be developed to bind to just one or a few receptor subtypes Because receptor subtypes have different localizations and functions, drug actions can have widely varying effects Neurotransmitters - summary Amino acids Neuropeptides Fast-acting/point-to-point synapses Short chains of amino acids (largest NT) E.g., GABA, glutamate, aspartate, glycine Five categories of neuropeptides E.g., Endorphins (analgesia/reward systems) Monoamine neurotransmitters Unconventional neurotransmitters Slow, lingering and diffuse effects Soluble gases (nitric oxide/carbon monoxide) Arise from brainstem – Produced in neural cytoplasm Catecholamines/Indolamines – Short-acting (quickly broken down) Endogenous opioids, endocannabinoids Acetylcholine Neuromuscular junctions Autonomic nervous system Central nervous system Deactivated by enzymes in synapse (rather than reuptake)  Noradrenaline Anxiety Serotonin Irritability Energy expending Energy conserving vigilance impulse Cognitive function Mood Emotion Appetite Motivation Sex Aggression Dopamine Pleasure Drive Study tip: draw this, add as much detail as you can!