Lecture 10 Flashcards
Criteria for neurotransmitters:
- present in presynaptic terminals
- released in response to stimulation
- able to interact with postsynaptic receptors
- rapidly removed from the synapse
Neurotransmitters need mechanisms for:
- synthesis and/or storage
- release
- transmitter action i.e. specific receptors
- transmitter removal
It does not count as neurotransmitters if:
has continuous stimulation
cannot be removed from the synapse
What are the three main types of transmitters/modulators?
ACh
Amino acids
Biogenic amines
Name four amino acid neurotransmitters
Glutamate (excitatory)
GABA (inhibitory)
glycine (inhibitory)
aspartic acid
Name biogenic amine neurotransmitters
Catecholamines (adrenaline, noradrenaline, dopamine; go through different steps to synthesize specific amine)
Serotonin (also called 5-HT)
Histamine
Name four neuropeptides
Enkephalin (natural opiate)
Substance P
Cholecytokinin
beta - endorphin (hugely different in size but works in same system)
Amino acid and amine neurotransmitters are:
small molecules
stored and released from synaptic vesicles
capable of many binding to and activating (ligand-gated channel receptors, G-protein coupled receptors)
Can do short-term and long-term signalling
The peptide neurotransmitters are:
large molecules
stored in secretory granules
only activate G-protein coupled receptors
made in soma
Glutamate is:
Most common, excitatory transmitter in CNS
Amino acid, found in all neurons
3 glutamate receptor subtypes based on the drugs which act as selective agonists
Action is terminated by selective uptake into presynaptic terminals and glia
Glutamate cannoe be used as a what? and why?
Marker
- Found everywhere but in neurons which use glutamate as a neurotransmitter, the concentration is much higher
How much more glutamate do glutamatergic neurons have compared to neurons that use glutamate for protein synthesis?
2-3 times
Name the three receptor subtypes::
- AMPA receptor
- NMDA receptor
- Kainate receptor
Where is AMPA receptor found and how is it activated?
Most widely distributed
Only activated by AMPA drug
How is NMDA receptor activated?
Only activated by NMDA drug
What are glia?
Supporting cells (2 neuron + 1 glia hypothesis formed now)
What do AMPA receptors do?
Mediate fast excitatory transmission
Glutamate binding to AMPA receptors trigger Na and K currents resulting in an EPSP
AMPA is not very permeable to Ca
What are NMDA receptors?
NMDA receptors often co-exist with AMPA receptors
- AMPA receptors can be on their own but hard to find
NMDA receptors on their own
NMDA receptors have a voltage-dependent Mg block
- Mg pops out during depolarization
- NMDA receptors become more permeable to Ca
- NMDA receptors need to be indirectly activated by
another transmitter
NMDA receptors are permeable to Ca as well as Na and K
- Their activation can have more widespread, lasting changes in the postsynaptic cell
- Involved in strengthening of synapses
What is an enzyme that converts glutamate to gamma-amino butyric acid (GABA)?
Glutamic acid decarboxylase (GAD)
GAD 65 and 67 are markers for GABAergic neurons
How does the conversion from glutamate to GABA terminate?
There is a transporter protein that finds GABA and selective uptake into presynaptic terminals and glia
What is GABA?
Most common inhibitory transmitter in CNS
In what cases can GABA become an excitatory transmitter?
During development when other Cl transporters make sure there is more Cl inside at rest, Cl moves out of cell through GABA-gated Cl channels
- causes depolarization
Where in the CNS are GABA especially found?
Cortex and striatum
What happens when there is too much or too little inhibition via GABA?
Too much: Coma or loss of consciousness
Too little: Seizures
What is autoinhibition?
When the GABAergic neuron inhibits itself
- keeps signal specific to that timing
What is disinhibition?
inhibitory synapses can act as a shunt and make membrane potential more negative at one point.
When there is disinhibition, how much change in voltage is there at the soma?
none
What is double inhibition?
If the neuron is GABAergic, it can be inhibited by another GABAergic neuron, causing excitation
How are GABA-A receptors modulated?
Other chemicals can bind to the GABA-A receptor and modulate the response to GABA binding
These chemicals have no effect without GABA binding
Name the chemicals needed for GABA-A receptor modulation and their effects.
Ethanol - behavioral effects (is addictive)
Benzodiazepines (e.g. diazepan) - used to treat anxiety by increasing frequency of channel opening
Barbiturates - sedatives and anti-depressants - increases duration of channel opening
Neurosteroids (metabolites of steroid hormones) - e.g. Progesterone
- Can break down into two neurotransmitters
- metabolites of progesterone can affect GABA-A receptors (PMT…)
What difference can be found between normal people and people suffering from anxiety attacks when it comes to GABA-A receptor distribution?
PET scan from a patient suffering anxiety attacks
- Labelled with a benzodiazepine (engn diazepam)
- Shows loss of GABA-A receptors
What are opiates?
Drugs derived from the opioid poppy
What are examples of opiates?
Heroin, morphine
What are opioids?
A broad class of natural and synthetic compounds
What are examples of opioids?
Endorphins
What do opioids and opiates do?
Elicit effect by activating opioid receptors
What are endorphins?
Naturally occurring small proteins or peptides
ENDogenous proteins with mORPHINE like properties
Name a few examples of endorphins?
Endorphin, enkephalin, dynorphin
How are endorphins synthesized?
Formed in the RER
Packaged into secretory granules by Golgi apparatus
How are opioid receptors distributed?
Widely distributed in the CNS but concentrated in nociceptive areas
How many types of opioid receptors are there?
three ; mu, kappa, sigma
What do opioid receptors in the spine contribute to?
Blocks pain signal (analgaesia)
What do opioid receptors in the periaqueductal grey do?
Regulates sensation of “pain”
What do opioid receptors in the amygdala do?
Regulates emotional component
What do opioid receptors in the frontal cortex do?
Cognitive aspects
What do opioid receptors in the brain stem (medulla oblongata) do?
Depress respiration and cough reflex (may induce vomiting)
What do opiate receptors do?
Can prevent voltage-gated Ca channels
Opening or increase opening of K channels, both hyperpolarize the cell
Decreases cAMP production via Galphai
What are the three types of G-proteins?
- Gs: Stimulatory G-proteins
- Gi: Inhibitory G-proteins
- Gq: Phosphorylatory G-proteins
Name three therapeutic uses of opiates:
- Analgesia - reduces perception of and emotional response to pain (perception - receptors, emotional - amygdala)
- Intestinal disorders: reduces diarrhea (decreases dehydration)
- Antitussine - cough suppressant (codeine - less addictive than heroin)
What are the four problems that restrict therapeutic use?
- Serious side effects
- Tolerance
- Dependence
- Relieve dull visceral pain bettern than sharp pain
What are the serious side effects from the use of opiates?
Respiratory depression - breathing rate decreases when opiates are too high
Sedation
Constipation
What happens when tolerance develops?
Reduced clinical effect
Higher dosage needed for same effect
What happens when dependence develops?
Leads to withdrawal symptoms
An emotional need to take drugs
Depends on dosage and time period
