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

2. 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’ Introduction

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

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!

6. 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

7. 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

8. Neurotransmitter Synthesis and Storage Principles of Synaptic Transmission

10. 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 Ca 2+ causes vesicles to fuse with the terminal membrane and release their contents Principles of Synaptic Transmission

11. 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

12. 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 Principles of Synaptic Transmission

13. OUT IN Cl - Na + GABA A receptorGlutamate/AMPA receptor GABAGABA G lu Inhibition Excitation

14. 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 Principles of Synaptic Transmission

16. 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) Principles of Synaptic Transmission

18. 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 Principles of Synaptic Transmission

19. 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 arousal. Attention deficit disorder. May cause schizophrenia.

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

21. SEROTONIN - at least 14 different receptor subtypes - 5-HT 1A, 5-HT 1B, 5-HT 1D, 5-HT 1E, 5-HT 1F ; all metabotropic - 5-HT 2A, 5-HT 2B, 5-HT 2C ; all metabotropic - 5-HT 3 ; ionotropic, Cl - channel, inhibitory input - 5-HT 1B and 5-HT 1D are presynaptic autoreceptors

22. A synapse that uses serotonin/5-HT

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

24. 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.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.

25. 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-HT 2A blocker

26. 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

27. 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

28. 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)GABA A - Ionotropic, Cl - influx, postsynaptic receptor - fast IPSP b) GABA B - Metabotropic, GPCR, - K+ activate channel, reduce Ca 2+ conductance, inhibit adenyl cyclase - slow & long lasting IPSP c) GABA C - Cl- influx

29. Clinical uses – GABA related drugs : 1.As antiepileptics 2.As anesthetics 3.Sedative hypnotics ( BZD, barbiturates) - 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