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

Pharmacology – II [PHL 322]

The Basic Principles of Central Synaptic Neurotransmission

Dr. Mohammad Nazam Ansari

• 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

• CNS Synapses

• Axodendritic: Axon to dendrite

• Axosomatic: Axon to cell body

Types of Synapses

• Axoaxonic: Axon to axon

• Dendrodendritic: Dendrite to dendrite

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!

• 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


• 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


• Neurotransmitter Synthesis and Storage


• 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


• Neurotransmitter Release

• Secretory granules- Released from membranes that are away from the active

zones

- Requires high-frequency trains of action potentials to be released


• 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


OUT

IN

Cl-

Cl-

Na+

Na+

GABAA receptor Glutamate/AMPAreceptor

GA

BA

Gl

u

Inhibition Excitation

• 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


• 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 DiffusionReuptake aids the diffusionNeurotransmitter re-enters presynaptic axon terminal or enters

glial cells through transporter proteinsThe transporters are to be distinguished from the vesicular forms

- Enzymatic destructionIn the synaptic cleftAcetylcholinesterase (AchE)


• 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


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 indecisivepersonality, unable to initiate even the body’s own movement. Parkinson’s disease.

Excess dopamine, more arousal. 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

Re-uptake of 5-HT/serotonin

Fluoxetine/Prozac blocks the SERT

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. Locomotion

Deficiencies in the Function of SerotoninAnxiety, 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 5HT4. 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)

- 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

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