neuropharmacology (Andrew Young)

Examples of endogenous chemicals

neurotransmitters

Examples of exogenous chemicals

drugs

Neurotransmitter synthesis, release, and clearance

1. arrival of action potential

2. calcium influx

3. vesicles Fues with presynaptic membrane and release transmitter

4. transmitter in synaptic cleft

5. transmitter binds to receptors in postsynaptic membrane

6. response in postsynaptic neurone

7. transmitter unbinds from receptors in postsynaptic membrane

8. active re-uptake into presynaptic terminal

9. re-packaging in vesicles

10. breakdown by enzymes

11. removal of inactive metabolites

The postsynaptic neurone is located

on the dendrite

The postsynaptic receptors are primarily responsible for

signal transmission

Explain what happens when a neurotransmitter binds to its receptor

1. neurotransmitter binds to receptors

2. receptor activated

3. signal transmitted to post-synaptic neurone

4. causes either excitation or inhibition

Where can presynaptic receptors be found

on neurone terminals where they modulate transmitter release

What are the two types of presynaptic receptors

• auto receptors - on the terminals of the same neurone as released the transmitter

  • Responds to the same neurotransmitter the neurone releases

  • Provides negative feedback (self-regulation)

• heteroreceptors - on terminals of a different neurone

  • Responds to a different neurotransmitter released by another neurone

  • Can increase or decrease neurotransmitter release

Heteroreceptors activation modulates release of

transmitters from the second terminal (also synthesis/storage)

• can be excitatory (enhances release) or inhibitory (reduces release) from the second terminal

What are the several mechanisms by heteroreceptors

• increases/decreases calcium channel opening

• increases/decreases vesicles binding to membrane and releasing transmitter

• may also affect synthesis by modulating enzyme function

What is considered to be an auto receptor a presynaptic or postsynaptic

only presynaptic neurones because they respond to the same neurotransmitter that this neurone releases, whereas postsynaptic neurones respond to the sender’s neurotransmitter, not their own, so they cannot be called “auto.”

Where can you find auto receptors

on neurone terminals

What happens during auto receptor activation

reduces release, synthesis and/or storage of transmitters from that terminal, either by blocking the calcium channels of the release

Auto receptors act as a 

negative feedback mechanism

What is a negative feedback mechanism

• reduces the release of the transmitter from the terminal

• makes the presynaptic neurone less excitable, which reduces the chance of neurotransmitter release in response to action potential

• decreases calcium channel opening (reduces calcium influx)

• prevents vesicles binding to membrane and releasing transmitter

• reduce synthesis by modulating enzyme function

If there is an agonist it acts as a…

key to turn on the receptors function, similar to the body’s natural signals

What does an antagonist do

it binds to the same receptor but blocks it from being activated, preventing a response

If there is a reduced release then

there is a reduced postsynaptic effect

Describe how the agonist work

1. agonist binds to receptor

2. receptor activated

3. causes the same change as the native transmitter in the post-synaptic neurone

How long does the agonist remain bound to the receptor

much longer than the native transmitter

When the agonist binds to the receptor it still creates…

an excitation or an inhibition

Describe how the antagonist works

1. antagonist binds to receptor

2. receptor occupied but no action

3. no change in post-synaptic neurone (block)

When the antagonist binds to the receptor there is… (about the effect and state of the neurone)

no effect and the neurone is stuck in a resting state

What are agonists used for

used to treat conditions involving under activity of neurotransmitters

• e.g. dopamine agonists in treatment of Parkinson’s disease

What are antagonists used for

used to treat conditions involving overactivity of neurotransmitters

• e.g. dopamine antagonists in treatment of schizophrenia

Where is nicotine from and what does it do (plant derivatives)

• from tobacco

• agonist at acetylcholine receptors

Where is muscarine from and what does it do (plant derivatives)

• from fungus

• agonist at acetylcholine receptors

Where is atropine from and what does it do (plant derivatives)

• belladonna: from deadly nightshade

• antagonist at acetylcholine receptors

• first pharmacological treatment for Parkinson’s disease

Where is curare from and what does it do (plant derivatives)

• from frogs

• antagonist at acetylcholine receptors

Where is bungarotoxin from and what does it do (venom toxins)

• from cobras

• antagonist at acetylcholine receptors

Where is batrachotoxin from and what does it do (venom toxins)

• from poison dart frogs

• prevents action potentials leads to paralysis

Where is tetrodotoxin from and what does it do (venom toxin)

• from puffer fish

• prevents action potentials leads to paralysis

What is allosteric modulators

its the response to the native transmitters (or an agonist) by a substance binding to a second binding site of the receptor which is separate from the main transmitter binding site

What effect does the allosteric modulator have on the postsynaptic signal

it has no effect

Describe the process of the allosteric modulator

1. modulator binds to allosteric binding site

2. receptor ‘potentiated’

3. no change in postsynaptic potential

Describe the process when both the modulator and transmitter are bound

1. modulator and transmitter both bound

2. action ‘potentiated’

3. enhanced postsynaptic resposnse

What happens when Barbiturates or Benzodiazepines bind to the modulator

enhances the action of GABA, through allosteric modulation of the GABA-A receptor

What are barbiturates used for now

mainly used only as anticonvulsants and anaesthetics

• could cause fatal respiratory depression high potential to produce dependence

Introduction of … reduced the use of barbiturates

benzodiazepines

What is benzodiazepines used in now

widely used in treatment of anxiety disorders, anaesthesia, insomnia

What are the drugs that affect clearance

• reuptake inhibitors

• breakdown enzyme inhibitors

How does reuptake inhibitors work

prevents the active uptake of transmitter from the synaptic cleft into the terminal, by blocking the uptake transporter molecules

• as a result, the transmitter remains in the synaptic cleft for longer, and is available to bind to receptors for longer

• therefore, enhances the effect of the transmitter

How do breakdown inhibitors work

prevent enzymes from breaking down the neurotransmitter

• leads to the transmitter remains in the synaptic cleft for longer, and is available to bind to receptors for longer

• therefore, enhances the effect of the transmitter

What is the aim of reuptake inhibitors and breakdown inhibitors

the drugs increase the amount of neurotransmitter in the synaptic cleft, therefore increasing binding of the transmitter to the receptors, and enhancing the signal

What do the drugs (reuptake inhibitor and breakdown inhibitor) do not bind to

to the postsynaptic receptors

What is a precursor

its a starting material/building block

Increasing the amount of precursors enables more…

transmitters to be synthesised

What do synthesis enzyme inhibitors do

blocks the conversion of precursors to transmitters in the terminals

• decreases the amount of transmitter available for release

What does the disruption of storage in vesicles do

prevents the storage of neurotransmitters in vesicles in the terminal

• decreases the amount of transmitter available for release, since only transmitter packaged in vesicles is available for release