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Pharmacology – II [PHL 322]

Pharmacology – II [PHL 322]. The Basic Principles of Central Synaptic Neurotransmission. Dr. Mohammad Nazam Ansari. Introduction. SYNAPTIC TRANSMISSION

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Pharmacology – II [PHL 322]

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  1. Pharmacology – II [PHL 322] • The Basic Principles of Central Synaptic Neurotransmission Dr. Mohammad Nazam Ansari

  2. Introduction • SYNAPTIC TRANSMISSION • The definition of synaptic transmission is simply the communication between two nerve cells. Communication believed to involve specialized structures termed "synapses". • Charles Sherrington (1897) : named ‘Synapse’

  3. Types of Synapses • Axoaxonic: Axon to axon • Dendrodendritic: Dendrite to dendrite • CNS Synapses • Axodendritic: Axon to dendrite • Axosomatic: Axon to cell body

  4. Principles of Synaptic Transmission • Basic Steps • Neurotransmitter synthesis • Load neurotransmitter into synaptic vesicles • Vesicles fuse to presynaptic terminal • Neurotransmitter spills into synaptic cleft • Binds to postsynaptic receptors • Biochemical/Electrical response elicited in postsynaptic cell • Removal of neurotransmitter from synaptic cleft • Must happen RAPIDLY!

  5. Principles of Synaptic Transmission • Neurotransmitters: “Substance that is released at a synapse by one neuron and that affects a postsynaptic cell, in a specific manner” • Amino acids • Amines • Peptides

  6. Principles of Synaptic Transmission • Neurotransmitters • Small molecules synthesized in the terminal button and packaged in synaptic vesicles. E.g. Amino acids and amines are stored in synaptic vesicles • Large molecules assembled in the cell body, packaged in vesicles, and then transported to the axon terminal. E.g. Peptides are stored in and released from secretory granules • Often coexist in the same axon terminals

  7. Principles of Synaptic Transmission • Neurotransmitter Synthesis and Storage

  8. Principles of Synaptic Transmission • Release of Neurotransmitter (NT) Molecules :  • Exocytosis – the process of NT release • A nerve impulse reaches the terminal knob of a neuron, causing the pre-synaptic membrane to depolarize. • The depolarization of the pre-synaptic membrane causes voltage gated-calcium-channels to open. • The entry of Ca2+ causes vesicles to fuse with the terminal membrane and release their contents

  9. Principles of Synaptic Transmission • Neurotransmitter Release • Secretory granules • Released from membranes that are away from the active zones • Requires high-frequency trains of action potentials to be released

  10. Principles of Synaptic Transmission • Neurotransmitter receptors: There are multiple receptor types for a given NT • Ionotropic: Transmitter-gated ion channels • Ligand-binding causes a slight conformational change that leads to the opening of channels • Depending on the ions that can pass through, channels are excitatory or inhibitory • NT binds and an associated ion channel opens or closes, causing a PSP. If Na+ channels are opened, an EPSP occurs. If K+ channels are opened, an IPSP occurs Excitatory and Inhibitory Postsynaptic Potentials: • EPSP: Transient postsynaptic membrane depolarization by presynaptic release of neurotransmitter. E.g. Ach- and glutamate-gated channels cause EPSPs • IPSP: Transient hyperpolarization of postsynaptic membrane potential caused by presynaptic release of neurotransmitter. E.g. Glycine- and GABA-gated channels cause IPSPs

  11. OUT Cl- Na+ Glu GABA Cl- Na+ GABAA receptor Glutamate/AMPA receptor Inhibition Excitation IN

  12. Principles of Synaptic Transmission • Metabotropic: G-protein-coupled receptors • Trigger slower, longer-lasting and more diverse postsynaptic actions • Same neurotransmitter could exert different actions depending on what receptors it bind to • (1) NT 1st messenger binds. (2) G protein subunit breaks away. (3) Ion channel opened/closed OR a 2nd messenger is synthesized. (3) 2nd messengers may have a wide variety of effects. • Autoreceptors: present on the presynaptic terminal • Typically, G-protein coupled receptors • Commonly, inhibit the release or synthesis of neurotransmitter • Negative feedback Effector proteins

  13. Principles of Synaptic Transmission • Neurotransmitter Reuptake, Enzymatic Degradation, and Recycling • As long as NT is in the synapse, it is active – activity must somehow be turned off • Clearing of neurotransmitter is necessary for the next round of synaptic transmission • Simple Diffusion • Reuptake aids the diffusion • Neurotransmitter re-enters presynaptic axon terminal or enters glial cells through transporter proteins • The transporters are to be distinguished from the vesicular forms • Enzymatic destruction • In the synaptic cleft • Acetylcholinesterase (AchE)

  14. Principles of Synaptic Transmission • Neuropharmacology • The study of effect of drugs on nervous system tissue • Receptor agonists: Mimic actions of naturally occurring neurotransmitters • E.g. Nicotine binds and activates the Ach receptors of skeletal muscle (nicotinic Ach receptors) • Receptor antagonists: Inhibitors of neurotransmitter receptors • e.g. Curare binds tightly to Ach receptors of skeletal muscle • Toxins and venoms • Defective neurotransmission: Root cause of neurological and psychiatric disorders

  15. DOPAMINE • D1, D2, D3, D4, D5 receptors; all metabotropic • D1, D5: all postsynaptic, and increase adenylatecyclase (AC) • D2, D3, D4: presynaptic and postsynaptic, and decrease AC • Dopamine pathwaysdo many things: • Control flow of blood through the brain • Motor control (nigrostriatal) system • Behavioural control: Dopamine is the brain’s motivational chemical. The primary role of dopamine is pleasure and motivation. • A shortage of brain dopamine causes an indecisive • personality, unable to initiate even the body’s own movement. Parkinson’s disease. • Excess dopamine, more arousal. Attention deficit disorder. May cause schizophrenia.

  16. Neurotransmitters and Neuromodulators • catecholamines synthesized from tyrosine • indoleamines synthesized from tryptophan Catecholamine biosynthesis indoleamine biosynthesis

  17. SEROTONIN - at least 14 different receptor subtypes - 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, 5-HT1F; all metabotropic - 5-HT2A, 5-HT2B, 5-HT2C; all metabotropic - 5-HT3; ionotropic, Cl- channel, inhibitory input - 5-HT1B and 5-HT1D are presynapticautoreceptors

  18. A synapse that uses serotonin/5-HT

  19. Fluoxetine/Prozac blocks the SERT Treatment of depression. anxiety disorders, obsessive-compulsive disorders Re-uptake of 5-HT/serotonin

  20. 5–hydroxytryptamine (Serotonin) Functions : • Addiction, aggression, anxiety, impulsivity • Learning, memory, mood • Emesis, nausea, appetite • Penile erection, sexual behavior • Sleep, • Thermoregulation • Respiration • Vasoconstriction • Locomotion Deficiencies in the Function of Serotonin Anxiety, depression, obsessive-compulsive disorder, schizophrenia, stroke, obesity, pain, hypertension, vascular disorders, migraine, and nausea to disruptions and particularly deficiencies of serotonin.

  21. 5–hydroxytryptamine (Serotonin) Clinical uses : • Antidepressants & anxiolytics • Atypical antipsychotics: • Anorectics (decreases appetite): releases 5HT • Antiemetics : • Gastroprokinetic agents: • Antimigraine agents 7.Increases appetite: 5-HT2A blocker

  22. Glutamate • Excitatory neurotransmitter • Located – throughout CNS • Receptor types a) Ionotropic receptors i) NMDA – long duration of action (Ca+ Channel) ii) AMPA – fast action (Na+ Channel) iii) Kainic acid – fast action (Na+ Channel) b) Metabotropic (GPCR) receptors: autoreceptor

  23. Glutamate – clinical use • Alzheimers disease, influenza • Cough suppressant • Anesthesia • Stroke • Epilepsy • Diabetic neuropathic pain • Senile dementia • Suppress withdrawal symptoms from morphine

  24. Gama Amino Butyric Acid (GABA) :  • synthesized from glutamic acid by GAD • Actions - Major inhibitory neurotransmitter (NT) • Location – Widely distributed in brain & spinal cord • Receptor types & actions – • GABAA - Ionotropic, Cl- influx, postsynaptic receptor • - fast IPSP • b) GABAB - Metabotropic, GPCR, • - K+ activate channel , reduce Ca2+ conductance, inhibit adenylcyclase • - slow & long lasting IPSP • c) GABAC - Cl- influx

  25. Clinical uses – GABA related drugs :  As antiepileptics As anesthetics Sedative hypnotics ( BZD, barbiturates) - anxiety - insomnia - sedation & amnesia - component of anesthesia - control of ethanol or sedative-hypnotic withdrawal state - muscle relaxants Migraine headache prophylaxis – - valproate, topiramate Spasmolytics :stroke, cerebral palsy, multiple sclerosis - baclofen, diazepam

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