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Pharmacology – II [PHL 322] The basic principles of central synaptic neurotransmission Dr. Abdulaziz Saad Bin Saeedan Introduction • SYNAPTIC TRANSMISSION • The communication between two nerve cells. Communication believed to involve specialized structures termed "synapses". • Charles Sherrington (1897) : named ‘Synapse’ Neuron structure All neurons have same basic structure, a cell body with a number of dendrites and one long axon. Neuron • Axons carry information from the cell body to the axon terminals. • Axon terminals communicate with their target cells at synapses. Types of Synapses • CNS Synapses • Axodendritic: Axon to dendrite • Axoaxonic: Axon to axon • Axosomatic: Axon to cell body • Dendrodendritic: Dendrite to dendrite Signal transmission in neurons 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! 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 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 Principles of Synaptic Transmission • Neurotransmitter Synthesis and Storage 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 presynaptic membrane to depolarize. • The depolarization of the pre-synaptic membrane causes voltage gatedcalcium-channels to open. • The entry of Ca2+ causes vesicles to fuse with the terminal membrane and release their contents 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 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 GABAgated channels cause IPSPs OUT Cl- Na+ Cl- Na+ GABAA receptor Inhibition IN Glutamate/AMPA receptor Excitation 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. Effector proteins • Autoreceptors: present on the presynaptic terminal Typically, G-protein coupled receptors Commonly, inhibit the release or synthesis of neurotransmitter Negative feedback 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 Enzymatic destruction In the synaptic cleft Acetylcholinesterase (AchE) 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, causing weakness of muscles DOPAMINE • D1, D2, D3, D4, D5 receptors; all metabotropic • D1, D5: all postsynaptic, and increase adenylate cyclase (AC) • D2, D3, D4: presynaptic and postsynaptic, and decrease AC Dopamine pathways do 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 excitement. Attention deficit disorder. May cause schizophrenia. Neurotransmitters and Neuromodulators • Catecholamines synthesized from tyrosine • Indoleamines synthesized from tryptophan Catecholamine biosynthesis indoleamine biosynthesis 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 presynaptic autoreceptors A synapse that uses serotonin/5-HT Fluoxetine/Prozac blocks the SERT Re-uptake of 5-HT/serotonin Treatment of depression. anxiety disorders, obsessive-compulsive disorders 5–hydroxytryptamine (Serotonin) Functions : 1. Addiction, aggression, anxiety, impulsivity 2. Learning, memory, mood 3. Emesis, nausea, appetite 4. Penile erection, sexual behavior 5. Sleep, 6. Thermoregulation 7. Respiration 8. Vasoconstriction 9. movement 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. 5–hydroxytryptamine (Serotonin) Clinical uses : 1. Antidepressants & anxiolytics 2. Atypical antipsychotics: 3. Anorectics (decreases appetite): releases 5HT 4. Antiemetics : 5. Gastroprokinetic agents: 6. Antimigraine agents 7. Increases appetite: 5-HT2A blocker 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 Glutamate – clinical use 1. Alzheimers disease, influenza 2. Cough suppressant 3. Anesthesia 4. Stroke 5. Epilepsy 6. Diabetic neuropathic pain 7. Senile dementia 8. Suppress withdrawal symptoms from morphine 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 – a) GABAA - Ionotropic, Cl- influx, postsynaptic receptor - fast IPSP b) GABAB - Metabotropic, GPCR, - K+ activate channel , reduce Ca2+ conductance, inhibit adenyl cyclase - slow & long lasting IPSP c) GABAC - Cl- influx Clinical uses – GABA related drugs 1. As antiepileptics 2. As anesthetics 3. Sedative hypnotics ( BZD, barbiturates) in case of: - anxiety - insomnia - sedation & amnesia - component of anesthesia - control of ethanol or sedative-hypnotic withdrawal state - muscle relaxants 4. Migraine headache prophylaxis – - valproate, topiramate 5. Spasmolytics :stroke, cerebral palsy, multiple sclerosis - baclofen, diazepam Thanks