Lecture 4 Chemicals In The Brain PDF

Lecture 4 Chemicals in the Brain The presentation is for personal use only and must not be copied or used outside of BSMS Dr Natasha Sigala [email protected] Module 202 Neuroscience & Behaviour Outline  Chemical signals and synapses (location, structure)  Synaptic transmission Neurotransmitt...

Lecture 4 Chemicals in the Brain The presentation is for personal use only and must not be copied or used outside of BSMS Dr Natasha Sigala [email protected] Module 202 Neuroscience & Behaviour Outline  Chemical signals and synapses (location, structure)  Synaptic transmission Neurotransmitters: •synthesis •storage •release •recovery and break down Categories of Neurotransmitters: •Amino-acids (Glu, GABA, Gly) •Monoamines: Catecholamines (DA, NE, epinephrine) & Serotonin •ACh 2 •Neuropeptides Learning outcomes Name different categories of neurotransmitters, and describe their differences in terms of function, speed of action, effects on the postsynaptic terminals, synthesis, storage, release, recycling and degradation Explain excitotoxicity Explain why there are different types of neurotransmitters 3 Categories of neurotransmitters Amino acids Monoamines Acetylcholine Neuropeptides • Synthesized locally in presynaptic terminal • Stored in synaptic vesicles • Released in response to local increase in Ca2+ • Synthesized in the cell soma and transported to the terminal • Stored in secretory granules • Released in response to global increase in Ca2+ 4 Neurotransmitters in the CNS 1) Fast neurotransmitters, e.g. amino acids 2) Slow neurotransmitters, e.g. neuropeptides (From Rang and Dale, p.69) Differential release of neuropeptide and small molecule co-transmitters Neurotransmitters in the CNS Amino acid transmitters fast transmission 1) Excitatory – slightly depolarises the postsynaptic cell’s membrane • Glutamate (Glu) (CNS) 2) Inhibitory - slightly hyperpolarises the postsynaptic cell’s membrane • (γ-aminobutyric acid) GABA (brain) • Glycine (Gly) (spinal cord and brain stem) 7 Diffuse Modulatory Systems e.g. The Serotonergic system function in: mood sleep pain emotion appetite Common principles of organisation: • Core: small set of neurons, most arise from brain stem (from Bear, Connors & Paradiso 2nd ed) • Each neuron contacts >100,000 other neurons throughout the brain 8 Why have multiple neurotransmitters? Neurotransmitters and Neuromodulators thalamus Excitation (Glu) Inhibition (GABA) Source:http://www.genesis-sim.org/GENESIS/Tutorials/genesis-intro/genesis-intro.html 9 Glutamate (Glu) synthesized in presynaptic terminal from 2 sources: 1) from glucose via the Krebs cycle 2) from glutamine converted by glutaminase into Glutamate loaded and stored in vesicles by vesicular glutamate transporters (VGLUTs) reuptake by excitatory amino acid transporters (EAATs) in the plasma membrane of presynaptic cell and surrounding glia glial cells convert Glu to glutamine and this is transported from the glia (“ball boys”) back to nerve terminals where it is converted back into Glutamate. 10 GABA (γ-aminobutyric acid) synthesized from glutamate (Glu) in a reaction catalyzed by glutamic acid decarboxylase (GAD) loaded and stored into vesicles by a vesicular GABA transporter, GAT (Gly uses the same transporter) cleared from synapse by reuptake using transporters on glia and neurons including non-GABAergic neurons higher proportion of GABA is made de novo to refill vesicles rather than recycling 11 Regulation of amino acid transmitter release too much Glu / too little GABA : hyper-excitability – epilepsy excitotoxicity too much GABA: sedation/coma Cerebral ischemia  the metabolic events that retain the electrochemical gradient are abolished  reversal of the Na+ / K+ gradient  transporters release glutamate from cells by reverse operation  excitotoxic cell death (Ca2+ -> enzymes -> digestion) GHB γ-hydroxybutyrate (date rape drug)  a GABA metabolite that can be converted back to GABA  Increases amount of available GABA  too much leads to unconsciousness and coma 12 Categories of neurotransmitters  Amino acids Monoamines Acetylcholine Neuropeptides • Synthesized locally in presynaptic terminal • Stored in synaptic vesicles • Released in response to local increase in Ca2+ • Synthesized in the cell soma and transported to the terminal • Stored in secretory granules • Released in response to global increase in Ca2+ 13 The Monoamines Catecholamines Dopamine Epinephrine (adrenaline) Norepinephrine catechol Indolamines Serotonin (5-Hydroxytryptamine, 5-HT) serotonin 14 Catecholamine synthesis I Dopamine synthesis occurs in two steps administration of Levodopa for treating Parkinson’s disease (from Bear, Connors & Paradiso) 15 Catecholamine synthesis II DBH located in synaptic Vesicles only, and NE is the only transmitter synthesised within vesicles (from Bear, Connors & Paradiso) 16 Catecholamine storage Loaded into vesicles by Vesicular monoamine transporters (VMATs) (proton gradient like Glu and GABA transporters) Modulation of catecholamine synthesis by drugs: L-DOPA, Levodopa, the precursor of dopamine, is used as a treatment for Parkinson’s disease. Dopa decarboxylase converts it into dopamine increasing the pool of releasable transmitter. 17 Catecholamine release and reuptake released by Ca2+ - dependant exocytosis binds and activates receptor signal terminated by reuptake into the axon terminal by transporters powered by electrochemical gradient (Dopamine transporters (DATs), Norepinephrine transporters (NETs) etc.) in the cytoplasm the catecholamines are: - reloaded back into vesicles - enzymatically degraded by Monoamine oxidases (MAOs) or - inactivated by Catechol-O-methyl-transferase (COMT) 18 Modulation of catecholamine release & reuptake by drugs Amphetamine reverses transporter, so pumps out transmitter and blocks reuptake (DA & NE) Cocaine and Methylphenidate (Ritalin) block DA reuptake into terminals. More DA in synaptic cleft – extended action on postsynaptic neuron. Selegiline - MAO inhibitor found in dopaminergic nerve terminals. Prevents the break down of DA, allowing more to be released on subsequent activations ( treatment of early-stage PD, depression and dementia), and overall increasing the available amount of DA. Entacapone - COMT inhibitor (treatment of PD), increases the available amount of neurotransmitter. 19 Serotonin (5-HT) Serotonin Synthesis in two steps: (from Bear, Connors & Paradiso) 20 Serotonin storage, release and reuptake stored in vesicles signal terminated by reuptake by Serotonin transporters (SERTs) on presynaptic membrane - destroyed by MAOs in the cytoplasm 21 Drugs modulating serotonin release and reuptake Fluoxetine (Prozac) blocks reuptake of serotonin (SSRI – selective serotonin reuptake inhibitor) (treatment of depression, OCD) Fenfluramine stimulates the release of serotonin and inhibits its reuptake (has been used as an appetite suppressant in the treatment of obesity) MDMA, methylenedioxymethamphetamine (ecstasy) causes NE and serotonin transporters to run backwards, releasing neurotransmitter into synapse/extracellular space (assessed for therapeutic potential in PTSD) 22 Categories of neurotransmitters  Amino acids  Monoamines Acetylcholine Neuropeptides • Synthesized locally in presynaptic terminal • Stored in synaptic vesicles • Released in response to local increase in Ca2+ • Synthesized in the cell soma and transported to the terminal • Stored in secretory granules • Released in response to global increase in Ca2+ 23 Acetylcholine (ACh) Choline acetyltransferase (ChAT, CAT) converts choline+ Acetyl CoA (coenzyme A) into acetylcholine. is packaged into vesicles by vesicular acetylcholine transporter (VAChT). rapidly degraded in synaptic cleft by acetylcholinesterase (AChE) Choline is transported back into the presynaptic terminal and converted to acetylcholine 24 Drugs modulating acetylcholine degradation AChE (Acetylcholinesterase) inhibitors block the breakdown of ACh, prolonging its actions in the synaptic cleft e.g. Neostigmine (treatment of myasthenia gravis, MG) 25 Categories of neurotransmitters  Amino acids  Monoamines  Acetylcholine Neuropeptides • Synthesized locally in presynaptic terminal • Stored in synaptic vesicles • Released in response to local increase in Ca2+ • Synthesized in the cell soma and transported to the terminal • Stored in secretory granules • Released in response to global increase in Ca2+ 26 Major neurotransmitters in the CNS Neuropeptides slow transmission Vary in their methods of synthesis and release from small molecule transmitters Short polypeptide chains (3 to 36 amino acids) Over one hundred neuropeptides described e.g. endorphins, neuropeptide Y, substance P, endogenous opioids, vasopressin 27 2: < 400 mm/day 2: 0.5 - 5.0 mm/day Small clear-core vesicles Large dense-core vesicles 28 Neuropeptide release and degradation • Follow the secretory pathway and NOT released in the same manner as small molecule transmitters • dense core vesicle fusion and exocytosis occurs as a result of global elevations of Ca2+ (sustained or repeated depolarization or release of Ca2+ from intracellular stores) • neuropeptide vesicle membrane recycled but not refilled • bind to and activate receptor • neuropeptides signalling is terminated by diffusion from site of release and degradation by proteases in the extracellular environment • release is slower than small molecule release and signals may be maintained for longer 29 Other transmitters / Retrograde signalling • Soluble gases Nitric oxide (NO) and Carbon monoxide 1) Nitric oxide made in postsynaptic neuron by Nitric oxide synthase (activated by the binding of Ca2+ and calmodulin) 2) The gas is not stored but rapidly diffuses from its site of synthesis. Diffuses between cells (into presynaptic cell - retrograde transmitter) 3) Activates guanylyl cyclase which makes the second messenger cGMP 4) Within a few seconds of being produced NO is converted to biologically inactive compound (switching off the signal) 5) Potentially useful for coordinating activities of multiple cells in a small region (tens of micrometers) (how big is a neuron?) 30 Other transmitters / Retrograde signalling •Endocannabinoids Small lipids which mostly cause reduced GABA release at certain inhibitory terminals. A cannabinoid is also the active component of marijuana (Cannabis sativa). 31 Summary  several categories of neurotransmitter e.g. small molecules vs. neuropeptides  can be regulated at all stages of their life cycle: • Synthesis • Storage • Release • Reuptake or degradation 32 Which neurotransmitters are released in response to global increase in Ca2+ concentration in the presynaptic terminal? Select the single best answer from the list below. A. B. C. D. E. Acetylcholine Amino acids Catecholamines Monoamines Neuropeptides Reading materials Bear, Connors & Paradiso, Neuroscience: Exploring the Brain 2nd, 3rd or 4th ed Chapter 5 & 6 Carlson, Physiology of Behaviour 9th or 11th ed , Chapter 2 & 4 http://www.williams.edu/imput/synapse/index.html Purves et al, 4th or 5th ed, Neuroscience Kandel, Schwartz & Jessell, 4th ed, Principles of neural science Chapters 10-16 34