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THE SYNAPSE Sir Charles Sherrington (1897). presynaptic. postsynaptic. Chemical Transmission. In 1921 Otto Loewi had a dream…….. Perfused frog heart, and stimulated vagus nerve Heartbeat slowed (parasympathetic inhibition) Perfusate transferred to an unstimulated heart

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The synapse sir charles sherrington 1897
THE SYNAPSESir Charles Sherrington (1897)

presynaptic

postsynaptic


Chemical transmission
Chemical Transmission

  • In 1921 Otto Loewi had a dream……..

  • Perfused frog heart, and stimulated vagus nerve

  • Heartbeat slowed (parasympathetic inhibition)

  • Perfusate transferred to an unstimulated heart

  • It too beat more slowly

  • Inferred inhibitory substance (“Vagusstoff”)

  • Identified as Acetyl Choline


Silly idea
Silly Idea……..

  • “It was an unlikely assumption that the vagus should secrete an inhibitory substance”

  • “Even more unlikely that a substance supposed to be effective at close range….be secreted in large amounts that it would spill over, and after being diluted……still be able to inhibit another heart”


The synapse sir charles sherrington 18971
THE SYNAPSESir Charles Sherrington (1897)

presynaptic

postsynaptic


What happens
What happens…..

  • Wave of depolarisation reaches axon terminal

  • Voltage operated Ca2+ channels open

  • Calcium influx cause transmitter-filled vesicles to fuse with presynaptic membrane

  • Neurotransmitter is released into synaptic cleft via exocytosis

  • Neurotransmitter bind to receptors in postsynaptic membrane

  • Opening of postsynaptic ion channels


And then
And then……..

  • Post-synaptic current causes excitatory or inhibitory postsynaptic potential that changes the excitability of the postsynaptic cell

  • Vesicle membrane retrieved from plasma membrane

  • Neurotransmitters re-synthesised and stored in vesicles


The synapse unidirectional
The Synapse: unidirectional

20 x 10-9m

Axodendritic: most common


Types of synaptic connections
Types of synaptic connections

Presynaptic Inhibition or Facilitation



Stimulate same opioid receptors as heroin and other opiate drugs of abuse

(3 –40 AAs)

(Role in anxiety)

Similar effect to cannabis (9- (4.H2O)cannabinol



Dale s law one neuron one neurotransmitter but
Dale’s Law: one neuron, one neurotransmitter drugs of abusebut……

  • Neuropeptides and amines can co-exist

  • Neuropeptides modulate release of amine

  • eg neurotensin inhibits release of dopamine from some forebrain neurones


Synthesis of neurotransmitters
Synthesis of neurotransmitters drugs of abuse

  • Most neurotransmitters synthesised at “point of use”

  • Biosynthetic enzymes in terminal bouton

  • eg choline-O-acetyl transferase  Ach

  • eg tyrosine-3-hydroxylase, dopa decarboxylase, dopamine--oxidase  noradrenaline

  • Neuropeptides synthesised in soma and transported to synaptic bouton


Control of transmitter release
Control of Transmitter Release drugs of abuse

  • Rate of Firing

  • “Probability of Release”

    • Variable depending on CNS location

    • P from 0.1 to 0.9

  • Presence of autoreceptors on axon terminals or cell bodies

  • Presence of heteroreceptors at axo-axonal terminals


Autoreceptors
Autoreceptors drugs of abuse

  • Terminal

  • Inhibit transmitter release

  • Important in rapid firing

  • Somato-dendritic

  • Found on cell body or dendrites

  • Slow rate of firing

  • Fewer action potentials reach axon terminal


Heteroreceptors
Heteroreceptors drugs of abuse

  • Receptors for a different transmitter at axo-axonal terminals

    • eg 2 receptor on presynaptic membrane of a noradrenaline-containing neurone is an autoreceptor

    • If 2 receptor on5-HT neuron, then it is a heteroreceptor

  • Often inhibit NT release by reducing opening of calcium channels


Production of a sharply timed signal
Production of a “sharply timed” signal drugs of abuse

  • Enzymic breakdown

  • Re-uptake by presynaptic terminal

  • Uptake by nearby glial cells


MOA; catechol-O-methyltransferase (COMT) drugs of abuse

GABA inactivated by reuptake into presynaptic neuron and into astrocytes

DAT; 5-HTT (or SERT), NAT, NET

eg acetylcholin-

esterase


Two receptor superfamilies
Two Receptor Superfamilies drugs of abuse

  • Class 1

    • Ligand-gated ion channel (LGICR)

    • = ionotropic

  • G-protein coupled (GPCR)

    • = metabotropic

  • Both are proteins with 3 domains

    • 1) extracellular

    • 2) lipophilic membrane-spanning

    • 3) cytoplasmic


Class 1 ionotropic receptor
Class 1 ionotropic receptor drugs of abuse

Rapid response <1ms

eg nAChR,GABAA Receptor,

Glutamate NMDA (N-methyl-D-aspartate) receptor (Ca2+)


Class 2 metabotropic receptors
Class 2, metabotropic receptors drugs of abuse

  • Less immediate, longer lasting

  • NT binds to receptor

  • Conformational change activates G (= guanine nucleotide) protein

    • Open ion channels

    • Activates second messenger system


Class 2 gpcr
Class 2, GPCR drugs of abuse

  • G protein opens ion channel

  • or

  • G protein activates effector enzymes

  • 2nd messengers

  • Phosphorylate key proteins (kinases)

  • Cellular effects

effector enzyme

2nd messenger system



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