L1 Introduction to Fundamental Neuropharmacology 2024-25 PDF

Introduction to fundamental neuropharmacology @Arturas Volianskis Serra da Capivara National Park in northeast Brazil; Possibly ~ 25000 years old Welcome to fundamental neuropharmacology Learning outcomes: introduction to fundamental neuro...

Introduction to fundamental neuropharmacology @Arturas Volianskis Serra da Capivara National Park in northeast Brazil; Possibly ~ 25000 years old Welcome to fundamental neuropharmacology Learning outcomes: introduction to fundamental neuropharmacology 1. Define neuropharmacology. 2. Revisit axonal conduction, neurotransmitters and synaptic transmission using neuropharmacological approach (3 case stories). 3. Review different types of neurotransmitters and neurotransmitter receptors. 4. Define neurotransmitter pharmacology and discuss the rest of the schedule for this unit. BI2432: Fundamental neuropharmacology Pharmacology and advancement of science Therapeutics, tools 3000 BC and weapons ~1600 AD ~1800 ~1900 ~1970 ~2000 BI2432: Fundamental neuropharmacology Pharmacology and its sub-disciplines BI2432: Fundamental neuropharmacology Pharmacology and its sub-disciplines Armed forces, Biological and chemical weapons BI2432: Fundamental neuropharmacology What is neuropharmacology? E S IN CE I C IEN ED SC M I VE IT N Neuropharmacology is a term G CO NEUROANATOMY describing the study of drugs that affect the nervous system, whether they affect sensory perception, motor NEUROPHYSIOLOGY function, seizure activity, mood, higher cognitive function, or other NEUROPHARMACOLOGY forms of nervous system functioning. NEUROTECHNIQUES BI2432: Fundamental neuropharmacology There are also many other, related terms, such as: Psychopharmacology (effects of drugs on psychologic parameters such as emotion and cognition). Neuropsychopharmacology (all sorts of drug effects on nervous system) Medical neuropharmacology (effects of medicines and their side-effects) In vitro neuropharmacology (effects of drugs on isolated tissues or neurones - determining concentration (in M) response relationships). In vivo neuropharmacology - (effects of drugs in organisms and animals;- determining dose (e.g. mg/kg) response relationships). “Molecular Neuropharmacology: A Foundation for Clinical Neuroscience” 2008 by Eric J. Nestler, Steven E. Hyman, Robert C. Malenka BI2432: Fundamental neuropharmacology Case story 1: let’s go fishing Anesthesiology 2013; 118: 1263 BI2432: Fundamental neuropharmacology Case story 1: let’s go fishing, and have a beer! Sometimes drinkers of beer, and spirits as well, were poisoned in the pub. This happened in North America and England in the 1820s, and was said to be a practice of publicans who were, in the words of Charles Dickens, “brewers and beer-sellers of low degree … who do not understand the wholesome policy of selling wholesome beverage.” The poison came from Cocculus indicus, a plant from Southeast Asia and India whose berry contains a poisonous compound regarded as a stimulant. Its crushed seeds were used traditionally to kill lice and stun fish. It was said to produce nausea, vomiting and stupor. (Nux vomica, the source of strychnine, was also popular.) https://www.thebeveragejournal.com/beer-column-april-2020/ BI2432: Fundamental neuropharmacology Case story 2: food poisoning An otherwise healthy 52-year-old man presented to the emergency room with nausea and vomiting accompanied by acute dyspnea. Two hours earlier the patient who was a recreational fisherman reported on consumption of liver and gonads extracted from a fish which he just captured at sea. Several minutes after consumption he complained of perioral paraesthesias with worsening limb muscle weakness. Shortly after admission to the ER, the patient developed an acute respiratory failure with bradypnea. This was accompanied by bradycardia which quickly deteriorated to cardiac arrest. After a short resuscitation, including tracheal Lagocephalus sceleratus (Pufferfish, fugu) intubation and mechanical ventilation, the patient cought by a local recreational fisherman off returned to sinus rhythm. On examination, shortly the cost of Tel Aviv. after patient was stabilized, signs of complete paralysis with absence of motor responses and lack of pupil reactions were noted. Patient was Kheifets J. et al., Case Rep Crit Care 2012 noted to be in deep coma with GCS of 3. At this doi: 10.1155/2012/782507 point, possible poisoning by paralyzing agent was suspected. Patient was transferred to the intensive care unit and treated by supportive measures. BI2432: Fundamental neuropharmacology Case story 1: food poisoning Several hours after his ICU admission, patient's family approached the medical stuff with a fish claimed to be consumed by the patient just two hours prior to his hospital admission. A diagnosis of tetrodotoxin (TTX) poisoning was suggested by typical clinical manifestations and temporal proximity to consumption of TTX-containing fish. The fish remnants were photographed and were immediately analyzed by a marine biologist and by the national center of poisoning. Consequently the fish was identified as the poisonous Lagocephalus sceleratus. At this point, the patient had a complete muscle paralysis with absent deep tendon reflexes and Lagocephalus sceleratus (Pufferfish, fugu) deep coma. cought by a local recreational fisherman off the cost of Tel Aviv. Kheifets J. et al., Case Rep Crit Care 2012 doi: 10.1155/2012/782507 BI2432: Fundamental neuropharmacology Fugu sashimi Voltage gated channels  Kazuyuki Hirooka, Dmitri E. Kourennyi, Steven Barnes Journal of Neurophysiology, 2000 Vol. 83 Tetrodotoxin (TTX) is a potent neurotoxin getting its name from Tetraodontiformes, an order that includes pufferfish and several other species that carry the toxin.  Alan Hodgkin Andrew Huxley (1914-1998) (1917-2012) Tetrodotoxin (TTX) is a potent neurotoxin getting its name from Tetraodontiformes, an order that includes pufferfish and several other species that carry the toxin.  Vitor Pinto, Victor A. Derkach, Boris V. Safronov Journal of Neurophysiology 2008 Vol. 99 Tetrodotoxin (TTX) is a potent neurotoxin getting its name from Tetraodontiformes, an order that includes pufferfish and several other species that carry the toxin.  IC50 ︎ ~ 6 nM moles of solute per liter of solution One mole (abbreviated mol) is equal to 6.022×1023 molecular entities Vitor Pinto, Victor A. Derkach, Boris V. Safronov Journal of Neurophysiology 2008 Vol. 99 Tetrodotoxin (TTX) is a potent neurotoxin getting its name from Tetraodontiformes, an order that includes pufferfish and several other species that carry the toxin.  Nieto, F.R. et al. Mar. Drugs 2012, 10, 281-305. Tetrodotoxin (TTX) is a potent neurotoxin getting its name from Tetraodontiformes, an order that includes pufferfish and several other species that carry the toxin. Case story 1: the outcomes for the patient Due to the severity of his illness, and after an extensive literature review, a decision was made to treat the patient with a cholinesterase inhibitor. During the first 24 hours the patient received 4 doses of intravenous neostigmine 2.5 mg. Immediately after the first dose of neostigmine deep tendon reflexes could be noted along with reversal of the comatose state. Over the next 24 hours, the patient completed a course of 4 doses of neostigmine. During that time a dramatic improvement was observed, which included complete recovery of muscle strength and return to full consciousness. 36 hours after his hospital admission the patient Lagocephalus sceleratus (Pufferfish, fugu) was extubated and had a complete and cought by a local recreational fisherman off uneventful recovery. the cost of Tel Aviv. Kheifets J. et al., Case Rep Crit Care 2012 doi: 10.1155/2012/782507 BI2432: Fundamental neuropharmacology Case story 3: let’s go hunting Case story 3: the disappearance of life BI2432: Fundamental neuropharmacology Curare vine, a liana, is used by the Indians in the Amazon to prepare arrow and dart poisons. The vine is a rich with alkaloids. The main alkaloid responsible for the paralysing actions is d-tubocurarine, which is an antagonist at Acetylcholine receptor. The ancient craft of neuropharmacology Curare vine, a liana, is used by the Indians in the Amazon to prepare arrow and dart poisons. The vine is a rich with alkaloids. The main alkaloid responsible for the paralysing actions is d-tubocurarine, which is an antagonist at Acetylcholine receptor. “Resistance to d-Tubocurarine of the Rat Diaphragm as Compared to a Limb Muscle: Influence of Quantal Transmitter Release and Nicotinic Acetylcholine Receptors” Tu Nguyen-Huu et al. Anesthesiology 5 2009, Vol.110 2009  IC50 ︎= 0.3 μM IC50 = 1.8 μM “Resistance to d-Tubocurarine of the Rat Diaphragm as Compared to a Limb Muscle: Influence of Quantal Transmitter Release and Nicotinic Acetylcholine Receptors” Tu Nguyen-Huu et al. Anesthesiology 5 2009, Vol.110 2009 “Neuromuscular blockade by d- tubocurarine on the acetylcholine- induced muscle twitch response in an isolated frog rectus abdominis muscle preparation.” Mirajkar. K. et al. J. Venom. Anim. Toxins incl. Trop. Dis. 2016 The antidote for curare poisoning is an acetylcholinesterase (AChE) inhibitor, such as physostigmine or neostigmine. (wikipedia)  Biological and chemical weapons Salisbury Cathedral and not Kremlin Novichok Poisoning A group of nerve agents. Inhibits acetylcholinesterase. Spasm / prevents relaxation of muscles (cardiac and respiratory). Cause of death asphyxiation or cardiac arrest. Fast acting. Remain poisonous for a long time period. Soups vs sparks Henry Dale Otto Loewi John Eccles (1875-1968) (1873-1961) (1903-1997) BI2432: Fundamental neuropharmacology The leach test and the discovery of acetylcholine The leech test was based on the use of eserine (physostigmine), a potent inhibitor of the enzyme acetylcholinesterase. The technique was based on the discovery by the German pharmacologist Fühner (1918), who showed that when eserine was added to an organ bath in which a leech muscle was suspended, the muscle became extremely sensitive to acetylcholine, and he suggested the preparation as an assay system for eserine. Wilhelm Feldberg merely reversed the procedure and used the eserinised muscle as a sensitive and simple assay for acetylcholine. The use of eserine in experiments by adding it to the perfusion fluid, reduced the circulating levels of acetylcholinesterase, increased the amounts of acetylcholine and thus made the accurate measurements possible (Kymograph). BI2432: Fundamental neuropharmacology Neurotransmitter criteria BI2432: Fundamental neuropharmacology Peripheral vs central excitatory transmission Neuromuscular junction: Central synapse: 1. Multi-vesicular release 1. Single release zones 2. Acetylcholine (Ach) 2. Glutamate (Glu) 3. Ach breakdown (cholinesterase) 3. Glu re-uptake (transporters) BI2432: Fundamental neuropharmacology The leach test and the discovery of acetylcholine BI2432: Fundamental neuropharmacology Neurotransmitter receptor types Two major classes of receptor: (1) ionotropic and (2) metabotropic or G-protein coupled (GPCR). BI2432: Fundamental neuropharmacology Classical neurotransmitters & their receptors Per Brodal “The central nervous system” 2010 BI2432: Fundamental neuropharmacology Neurotransmitters and other singling molecules A neurotransmitter is a chemical substance released from nerves upon electrical stimulation, that binds to a receptor or “receptive substance”. Classical Non-classical !"#$%&"'(&)*#+,!"'-+ 7#48(.(04&/$(81+,*#48(?#?$)0#1@+ !.)*(+/")012+ (?)/$#1@+A/11#1-+ + 3&4$/./$#+ + 3!5!+ 7#48($8(?')"+B/"$(81+,5>7C@+73C- + 3&%")*#+ 6(*(/.)*#12+ Fast (ms) + 7(8/08#*/&)*#++ + Neurotransmitter + /08#*/&)*#+ Slower (s-mins) Neuromodulator + 9#8($(*)*+,:;(?/.)*# Slowest (mins-hours) Neurotrophic factor e.g. BDNF, NGF BI2432: Fundamental neuropharmacology Fundamental neuropharmacology is neurotransmitter pharmacology! What are you going to learn during the rest of the fundamental neuropharmacology component? During fundamental neuropharmacology you will study neurotransmitter pharmacology; i.e. how different ligands, compounds and drugs interact with neurotransmitter receptors and how they induce or inhibit effects in nervous systems, tissues and cells. These effects may be neuronal or cellular, behavioural or cognitive, medicinal or illicit, wanted or unwanted, and you will learn to measure, quantify and interpret such effects. BI2432: Fundamental neuropharmacology Neurotransmitters & their function BI2432: Fundamental neuropharmacology Study materials: BI2432: Fundamental neuropharmacology Example question L1: What is the main molecular target for picrotoxin? (A) Acetylcholine receptor (B) Voltage gated Na+ channel (C) GABAA receptor (D) Voltage gated Ca2+ channel (E) 5-HT receptor BI2432: Fundamental neuropharmacology Weekly schedule of the fundamental neuropharmacology Friday 29.11.2024 (13:10-14:00 & 14:10-15:00); C/-1.04 Meyer & Quenzer Psychopharmacology, Nestler, Hyman & Malenka’s Molecular Neuropharmacology L1. Introduction to fundamental neuropharmacology Rang & Dale’s Pharmacology, L2. Basic principles of neuropharmacology I & lecture materials Friday 06.12.2024 (13:10-14:00 & 14:10-15:00); C/-1.04 Meyer & Quenzer Psychopharmacology, Nestler, Hyman & Malenka’s Molecular Neuropharmacology L3. Basic principles of neuropharmacology II Rang & Dale’s Pharmacology L4. Techniques in neuropharmacology & lecture materials Friday 10.12.2024 (13:10-14:00 & 14:10-15:00); C/-1.04 Meyer & Quenzer Psychopharmacology, Nestler, Hyman & Malenka’s Molecular Neuropharmacology L5. Acetylcholine and Glutamate (and a bit of Glycine) Rang & Dale’s Pharmacology L6. Pharmacological dissection of field responses The Hippocampus Book pages 27-30 & lecture materials Tuesday 07.01.2025 (13:10-14:00);C/-1.04 Meyer & Quenzer Psychopharmacology, Nestler, Hyman & Malenka’s Molecular Neuropharmacology L7. GABA and Glycine Rang & Dale’s Pharmacology & lecture materials Friday 10.01.2025 (13:10-14:00 & 14:10-15:00); C/-1.04 Meyer & Quenzer Psychopharmacology, Nestler, Hyman & Malenka’s Molecular Neuropharmacology L8. Catecholamines Rang & Dale’s Pharmacology L9. Serotonin & lecture materials Friday 27.01.2025 (13:00-13:45 & 14:00-14:45); C/-1.04 Meyer & Quenzer Psychopharmacology, Nestler, Hyman & Malenka’s Molecular Neuropharmacology L10. Neuropharmacology of drug dependence and addiction I Rang & Dale’s Pharmacology L11. Neuropharmacology of drug dependence and addiction II & lecture materials Tuesday 21.01.2025 (13:10-14:00); C/-1.04 Tuesday 23.01.2025 Neuroanatomy L12. Exam preparation 2 and Neuropharmacology ICA BI2432: Fundamental neuropharmacology