Lecture 6b

Friday, August 31, 2018 21:07

Synaptic Transmission and pharmacology

Neuron processes a signal, how to transmit to another neuron
Reach Axon terminal, how does the electrical signal somehow continue over this gap or syn

Synaptic transmission
- Action potential cannot 'jump' across the synapse
- Neurons need to used another form of communication
- Chemical messengers (AKA neurotransmitters) are released from the axon terminal.
- These messengers travel across the synapse to signal the next neuron.
- Defuse across the synaptic space to interact with the post-synaptic neuron, on the ot
side that is how the signal pass to the other neuron
Type of synapse
- Where the synapse is forming between two neurons, really depend on the names
- Multiple synapse
- Axodendritic (axon to dendrite-most common) with post-synaptic neuron
- Axosomatic (axon to cell body)
- Axoaxonix (axon to axon) axon terminal synapse with the post-synaptic neuron
- Pre-synaptic neuron: the neuron that sends the message
- Post-synaptic neuron: the neuron that receives the message
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Axon terminal
- Contains synaptic vesicles which carry neurotransmitters
Synaptic vesicles
- Called exocytosis: Vesicles to 'fuse' with the cell membrane and releases the contents
the synapse
- Action potential signal that process to start
- Neurotransmitters contain in this vesicle will not be released if the action potential is
initiate process
Neurotransmitters(NT)
- Chemical messenger molecules that are released by the neurons axon terminal
- Used to communicate with surrounding neurons
- Locate inside vesicle
- Ultimately use to continue the signal in different form from the one neuron to the ne
- NT release into the synapse, they will defuse the synaptic space and connect with cer
receptors on membrane of the synaptic neuron
- NT connect/bind with the receptors on the post-synaptic neuron
Types of NT
- There are many types of NT
- Dales principle: a typical neuron will release only one type of NT at all axon terminals
- Different types of NT cause different effects on the post-synaptic neuron
- 2 main NT in the body: GABA and Glutamate
- One neuron only release one type NT, rare to see one neuron of multiple NT
Receptors
- Ligand-gated ion channels located on the membrane of the post-synaptic neuron
- Conduct ions cross the membrane when open these channels and need to wait for th
right NT to activate the receptor or if not, the receptors will never open
Receptors type
Lock and Key model
- NT will be the key and the receptor will the lock
- Need to find the right 'fit' to make the channel open
- NMDA Receptor----in order to activate this receptor, two NT gly and glutamate, need
to open channels
- AMPA---conduct sodium and potassium, but only need glutamate to bind in order to
activate that channel
- GABA--conduct negative ions, require the GABA of NT to allow chloride to enter
Synaptic transmission
- When the action potential(AP) gets to the end of the axon, it spreads to the axon
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- AMPA---conduct sodium and potassium, but only need glutamate to bind in order to
activate that channel
- GABA--conduct negative ions, require the GABA of NT to allow chloride to enter
Synaptic transmission
- When the action potential(AP) gets to the end of the axon, it spreads to the axon
terminals
- Axon terminals contain synaptic vesicles which carry neurotransmitters.
- The AP triggers the synaptic vesicles to undergo exocytosis-releasing NT into the syna
- Neurotransmitters diffuse across the synapse and bind to specific receptors on the po
synaptic neuron membrane.
The post-synaptic Neuron
- This can have an excitatory or inhibitory effect.
- Excitatory Post-Synaptic Potential (EPSP)
▪ Small local depolarization
▪ Typically opens channels for Na+ and / or Ca2+
- Inhibitory Post-Synaptic Potential (IPSP)
▪ Small local hyperpolarization
▪ Typically opens channels for Cl-
- Many EPSPs work together to reach the threshold and produce an AP
- Receptor opening will cause depolarization, shifting the resting membrane to the less
negative value
- When we get enough excitatory input, that is essentially reach the threshold then we
conduct action potential, at the same time, we will get inhibitory input, so ultimately
to the threshold is a competition between the excitatory and inhibitory, if the excitat
can win, we can get to the threshold and the action potential can happen.
Glutamate and GABA
- Glutamate is a Common excited NT in the body, if there is no glutamate, we will not a
to function GABA, balance between to.
- 2+ charge, positive charge, stronger than sodium, calcium moving into the cell the
effective will be much larger
- Positive ion entering neuron, making the inside less negative, depolarization effect
- GABA, conducting chloride, negative charge, more negative, hyperpolarization effect
moving the membrane potential further away
Post-Synaptic potentials
- Neurons integrate EPSPs and IPSPs
- The process of
- Two inhibitory post-synaptic potentials and three excitatory post-synaptic potential a
other inhibitory post-synaptic potential, three for each and cancel out
- If you got more excitatory, it will move membrane close to the threshold; if you got m
inhibitory, it will move membrane away from the threshold
Type of summation
- Spatial summation: summing potentials that arrive at different synapses
- Temporal summation: summing potentials that arrive at different times at the same
synapse
- If there are excitatory post-synoptics potential happen in each of those location, the
of those sodium ion will cause a large depolarization effect
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Type of summation
- Spatial summation: summing potentials that arrive at different synapses
- Temporal summation: summing potentials that arrive at different times at the same
synapse
- If there are excitatory post-synoptics potential happen in each of those location, the
of those sodium ion will cause a large depolarization effect
- Contraction the muscle allow the movement, the information hit the muscle at the sa
time.
- To perform voluntary behaviours like walking or talking, the timing of our action pote
generation must be quite precise.
- If we cannot generate action potentials when needed, we would not be able to funct
such a coordinated way.

Synaptic Pharmacology
- Chemicals and drugs affect the synapse and function
Deactivation of neurotransmitters
- Clean the synapse, break down the NT by enzymes and also re-uptake

- Direct agonist:
- Indirect agonist: produce/increase the same effect that is already happening, block
enzymes from breaking down NT in the synapse---NT will have more time and opport
to produce that effect
- Direct Antagonist: glutamate from the pre-synaptic neuron, allow sodium to enter, th
drug block up this happening that the sodium cannot enter the cell, because the
glutamate cannot bind with the receptors that pretty much cove
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- Ketamine is using on animal more than on people today.

Acetylcholine (ACh)
- Inhibitory NT when it binds to Muscarinic receptors-the heart(smooth muscle) stop m
from contracting
- Excitatory NT when it binds to Nicotinic receptors
▪ Skeletal muscles (arms and leg)
▪ Cortical neurons (brain)
- Primary role:
▪ PNS: motor neurons mainly release ACh to cause muscles to contract!
▪ CNS: ACh will stimulate neurons in the brain that helps with attention and focus
- ACh won't undergo re-uptake. It is a unit can't take back up
ACh synapses + drugs
- Nicotine--direct agonist of ACh at Nicotinic receptors;
▪ In people (smokers): Excitatory effect makes smokers feel more alert and focused;
▪ As an insecticide: overdose of nicotine causes muscles to seize--leads to death by car
arrest
- Curare
▪ Direct antagonist of nicotinic receptors--blocks Ach from binding to receptors, stoppi
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 ▪ In people (smokers): Excitatory effect makes smokers feel more alert and focused;
▪ As an insecticide: overdose of nicotine causes muscles to seize--leads to death by car
arrest
- Curare
▪ Direct antagonist of nicotinic receptors--blocks Ach from binding to receptors, stoppi
Ach from binding to allow it opens
▪ Leads to paralysis-no muscle contraction
▪ Amazonian Indians use curare on the tips of their arrows and darts for hunting, lose a
to contract
▪ Come from the plants
- Botulinum toxin (botox)
▪ Indirect antagonist of nicotinic receptors-block Ach release from pre-synaptic neuron
the first place. Cannot call muscle contraction
▪ By paralyzing facial muscles, prevent wrinkles
Serotonin (5-hydroxytryptamine; 5 HT)
- Primarily an excitatory NT in the brain
- Receptors: At least 12 different receptor types
- Role: regulates mood, behaviour, hunger, sleep, memory
▪ Strong link to depression! It though that people with depression don't produce enoug
HT.
- Removal from synapse:
▪ Re-uptake
▪ Monoamine Oxidase (MAO): Enzyme used to breakdown dopamine in the synapse.
Degrade, taking back up by itself
- In the brain, regulate the mood, hunger, memory, serotonin makes us happy
- Changes the molecule, things get added, removed, melatonin, drugs out sleep cycle
- Change the neurotransmitters with changing some of the molecules

- As NT occur in the body, need molecule and diet able to form the NT, mainly re-uptak
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Serotonin synapse + Drugs

Psychedelic Drugs: LSD, Psilocin ('magic' mushrooms), Mescaline(peyote)
▪ Direct 5 HT receptor agonists--they perform in the exact same way as 5HT binding to
receptors
▪ Effects: hallucinations, loss of reality, time dilation (minutes seem like hours), extrem
emotional reaction ranging from panic to spiritual ecstasy
MDMA (aka ecstasy)
▪ Indirect 5HT agonist-triggers the release of 5HT; blocks re-uptake
▪ Effects: mild psychedelic and stimulation; increased blood pressure, body temperatur
heart rate, nausea, sweating, chills
Selective serotonin Re-Uptake Inhibitors (SSRI's)
▪ Used to treat depression
▪ Indirect agonist-blocks transporters trying to remove 5 HT from the synapse
▪ Effects: anti-depressant effects are delayed by 4 weeks for unknown reasons
▪ See no changes in the behaviour in 5 weeks, instant effect when people take MDMA,
a long time to keep in and show the difference when take this drug
Doesn't allow the same effect to happen, interact with the serotonin system in the body, bo
temperature, heart rate. Depression, serotonin may then release, block in the re-uptake an
emphasize the effect the serotonin the synaptic neuron.

Dopamine 多巴胺
- Inhibitory and excitatory NT
▪ Primary receptors: D1 & D2 receptors
▪ Other receptors: D3, D4, D5 receptors
- 2 primary roles:
▪ Movement
▪ Reward and reinforcement (happiness, addiction)
▪ Best neurotransmitters, be happy if this system is working
- Removed from synapse by monoamine Oxidase (MAO)
▪ Enzyme used to breakdown dopamine in the synapse
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Dopamine synapses + Parkinson's Disease
- A movement disorder characterized by tremors and rigid movement
- Not enough dopamine being produce by neurons in certain region in the brain. The
neurons don't work in that specific region, is not efficiency.
- Dopaminergic neurons located in a brain area crucial for movement start dying. Not
working as they should, kill the neuron which produce dopamine
- Treatment: L-dopa----a drug that can be converted to dopamine in the neuron---used
temporary dopamine replacement
- Quite large, molecule, it can't directly move into the brain area, reject some dopamin
and become evident in the brain, inject the dopamine (drug). No cure for this disease
Dopamine synapses+ Drug abuse/dependence
- Drugs that increase abusive behavior and cause physical dependence
- Feel good and be happy will do that behavious more and more, increase the dopamin
the system such as alcohol, heroin, cocaine, nicotine
- Normal synapses, NT has been released, they had already broken down
- Cocaine blocks re-uptake, NT in the synapses for longer time, more effects on this po
synaptic receptors, increase post-synaptic potential, generate more action potential.
system equip to handle, amount of receptors, depending on how many channels,
overstimulation

- Minimal receptors

Abuse
Drug abuse: a behavioural disorder characterized by impulsive drug-seeking, pre-occupatio
with drug use, and impaired self control over drug use.
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Abuse
Drug abuse: a behavioural disorder characterized by impulsive drug-seeking, pre-occupatio
with drug use, and impaired self control over drug use.
- caused by drug -induced changes in a dopamine system in the brain that is responsib
rewards
- Abuse behaviours are an acquired drive---that is, it is a learned behaviour
- Harder to achieve high reward feelings---increases cravings and addiction behaviour
- Abuse is different to physical dependence
- Drugs like cocaine and amphetamines do not produce clear signs of physical depende
- Impaired self-controlled, ultimately we can unlearn that behaviour which is very hard
Physical dependence
- Preventing to take the drugs, a physiological syndrome produced by chronic or heavy
use.
- Take pain killer, excitatory effect,
- Increase inhibition: up-regulate excitatory receptors (glutamate)
- Down-regulate inhibitory receptors (GABA)
- Tolerance: larger and larger doses required to achieve the same effect
- Increase the drug and have bigger effect of receptors, completely tolerant, overdose
one of those drugs
- Withdrawal: when the drug wears off, the CNS becomes hyper-excitable --characteriz
by shakes, anxiety, delirium tremens (confusion and hallucinations), and convulsions
- Physical dependence on alcohol, systems had adapted, driving test, attention
task/memory task, people who have dependence will behave better than the one wh
doesn't have the alcohol in the system
Abuse versus Physical dependence
- Physical dependence often accompanies abuse-but these are not the same.
- Not all abusers will experience withdrawal symptoms or tolerance.
- Detoxification: getting through the withdrawal stages (typically about 1 week)
Does eliminating physical dependence mean the abuser is cured of their addictive behaviou
No. most abusers continue to crave their drug, and relapse following detoxification resultin
the re-development of physical dependence.
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