Neurotransmitters 2: Noradrenaline, 5-hydroxtryptamine and dopamine Flashcards
What are monoamine neurotransmitters?
They were the first neurotransmitters to be identified in the CNS.
They are localised to small populations of neurons.
They have cell bodies in brain stem and basal forebrain.
They diffuse their projections and their neurons are modulatory.
Their processes and receptors are the same as in the periphery.
What are the 4 main monoamine neurotransmitters?
- Dopamine
- Noradrenaline
- Serotonin
- Histamine
What are the main principles of neurotransmitter action?
- Synthesis
- Storage
- Release
- Receptors
- Removal
- Degradation
Monoamines are formed in the pre-synaptic terminals from a precursors. The neurotransmitter is then taken up into a pre synaptic vesicle through vesicular transporters. On activation go an AP, the vesicle is moved towards the pre-synaptic membrane and releases its neurotransmitter by exocytosis into the synaptic cleft.
The NT stimulates the pre or post synaptic receptors and it removed by diffusion and uptake process into the pre-synaptic terminal into transporters or through glial cells through extra-neuronal transporters.
The NT is either metabolised or taken up into the vesicles for further release.
Give the basis of dopamine
Important in diseases including Schizophrenia and Parkinsons disease.
It is a precursor for noradrenaline.
More restricted distribution than noradrenaline.
What are the 4 in dopamine pathways in the brain?
Nigrostriatal pathway which runs from the substantia nigra up to the caudate nucleus. This pathways is important for movement and is lost in Parkinson disease.
Mesolimbic pathway which runs from the ventral tegmental area to the caudate nucleus. This pathways controls out responsiveness to external and stumble, motivation, motor activity, reward, drug addiction and some of the positive symptoms of schizophrenia
Mesocrotical pathway from the ventral tegmental area to the frontal cortex. This is involved in normal cognition, motivation, emotion, disfunctional in psychoses and schizophrenia
Tuberoinfundibular pathway running from the arcuate nucleus to the median eminence. It is important in the control of prolactin release
What are all monoamine neurotransmitters synthesised from?
Amino acids in the pre-synaptic terminal.
What is dopamine synthesised from?
Dopamine - presynaptic amino acid is tyrosine and this is metabolised by tyrosine hydorxyalse to from L-DOPA. This is then metabolised by aromatic amino acid decarboxylase to form dopamine.
Dopamine is then metabolised by either monoamine oxidase or catechol-O-methyl transferase.
Either:
- 3MT is metabolised to from the final metabolise which is homovanillic acid.
- Dopamine can also be metabolised directly by mono-amine oxidase to form DOPAC. DOPAC can then be metabolised to from homovanilic acid.
Homovanillic acid is the final product and can be immured in the CSF to determine dopamine activity in the brain.
What are the two main enzymes involved in the metabolism of dopamine?
MAO - mono amine oxidase. Found in the pre-synaptic terminal and glial cells. It is found in mitochondrial membranes. It can also metabolise NA and 5HT. MAOa and b for DA. MAOa for NT and 5HT.
COMT - Catechol methyltransferase.
An enzyme found intra cellular but not in the pre - synaptic neuron so is involved with extra neuronal metabolism. This is particularly important in brain areas with low expression of pre synaptic dopamine transporter which is important in removing dopamine from the synaptic cleft.
How is dopamine transmitted across the synapse?
Dopamine is formed from tyrosine in the pre-synaptic terminal.
Dopamine is then taken up in to vesicles by a special transporter called the vesicular monoamine transporter (VMAT). This is an expanded version of the vesicle. Entry of dopamine into the vesicle.
Dopamine enters the vesicle through the vescicular mono amine transporter and is stored in an acid environment in the vesicle.
This is important as dopamine is very susceptible to degradation.
On the arrival on an AP, the vesicles are then moved to the pre synaptic membrane and dopamine is released into the pre-synaptic cleft.
The dopamine stimulates the post synaptic receptors and pre synaptic receptors.
Dopamine is removed by diffusion and then by dopamine transporter called DAT which is an efficient transporter and is able tot remove the majority of dopamine form the synaptic cleft.
Any dopamine beyond the pre synaptic terminal is able to be removed by the extra neuronal transporter, partially found in glial cells where is can be metabolised by catechol methyltransferase to 3 methxy tyromine and then forms HVA by mono amine oxidase enzyme.
In the presynaptic terminal, the dopamine that has been taken up is then either stored in the vesicles ready for re-release or metabolised by mono amine oxidase b found on surface of the mitochondrial membrane to form dopac.
What are the two families of dopamine receptors? Explain each
Families = (D1 and D2)
We now know there are 5 different dopamine receptors (D1-D5) and they are allocated to their families due to their similarity to the original D1 and D2 receptor discovered.
D1 family contains the original D1 receptor and D2.
D2 family contains the original D2 receptor and also D3 and D4.
All these receptors are G protein coupled receptors.
The G1 receptor is coupled to Gs (stimulatory G protein). The stimulation of this receptor results in an increase in cyclic AMP so both D1 and D5 receptor increase cyclic AMP following stimulation. These receptors are mainly found post-synaptically.
D2 receptors are linked to inhibitory G proteins (Gi or Go) and stimulation of theses leads to a decrease in cyclic AMP and or the opening of potassium channels. These receptors are found both pre and post synaptically.
D1 and D2 receptor are the most abundant in the brain. D1 are found in high levels in the cortex, limbic regions and in the striatum but are not found in the tubero-hypophyseal region.
D2 receptors are found in high levels in all these regions, (D2 receptors therefore control prolactin secretion).
D5 receptors is found in much smaller levels in the brain, found in the limbic and striatum mostly. D3 and D4 are also found in lower levels in these areas too but D4 is more found in the cortex.
What is the only dopamine receptor family found in the tubers-hypophyseal pathway?
D2 family
What agonists and antagonists can bind to the receptors?
Dopamine can be considered an agonist at D1 and D2 family of receptors.
However, it is particular potent in D2 family but less so in D1 family.
Apomorphine is a drug used in parksinsons disease and mimics the action of dopamine very well. It is very potent for D2 receptors but low potency for D1 receptor.
This can be seen similarly with bromocriotime with lower potency at D1 receptor. This is also used in Parkinson’s disease.
Number of drugs that can block the affects of dopamine: antagonists
These include chlorpromaize, holoperidol, sulpriride and clozapine. These drugs are used in the treatment of schizophrenia where dopamine activity is thought to be increased with relation to the positive symptoms. Can see these antagonists have higher potency for D2 family than D1 family.
Although there are antagonists more potent at D1 family, these are not in general use in clinic.
Can use dopamine agonists to enhance the affect of dopamine and antagonists to reduce affect of dopamine in the brain.
How are the different dopamine pathways associated with disease?
Nigrostriatal pathway = degenerate in Parkinsons disease resilient in low of motor function leading to tremor and instability and rigidity.
Mesolimbic pathway = involved in addiction as this stimulates the reward pathway. This is over active in schizophrenia resulting in positive symptoms.
Mesocortiyal pathway = through to be underachieve in individuals with schizophrenia and is also thought to be dysfunctional in ADHD.
Tuberoinfunidbular pathway = not associated with disease states but it inhibits prolactin release and antagonists of D2 receptors are used in the treatment of schizophrenia.
These D2 receptors antagonists block this pathway and result in hyperprolactinaemia.
What are some examples of drugs that can affect dopamine transmission?
Cocaine inhibits uptake of dopamine by dopamine transporter into the pre synaptic terminal resulting in more dopamine in extra cellular space. This can then stimulate the post-synaptic receptors. This is addictive.
Amphetamine and methylphenidate are also addictive. They inhibit uptake of dopamine into pre-synaptic terminal by blocking the dopamine transporters but also increase the released of dopamine from the pre-synaptic terminal resulting in increase in dopamine in the cleft. Therefore these are stimulate drugs nut can have a calming effect in people with ADHD.
L-dopa is the precursor of dopamine and can be given to increase dopamine formation. This is given for treatment of Parkinsons disease where dopamine neurons are lost and there are less dopamine in the nitrostriatal pathway.
Inhibition of mono amine oxidase b with a dura called selegiline or inhibition of COMT with a drug called entacapone can reduce the metabolism of dopamine. These are used in Parkinson’s as we are trying to increase the level of dopamine in the CNS.
Dopamine agonists - mimic the affect of dopamine by activating mainly D2 receptors. Used to treat Parkinson’s and restless less syndrome.
Dopamine antagonists at D2 receptors mainly can be used in schizophrenia as they will reduce the cavity of dopamine at the dopamine receptors.
Give the basic explanation for noradrenaline
Mechanisms of synthesis, storage and release same as periphery.
Modulatory actions:
- Beta receptors mainly excitatory via increased cAMP
- Alpha receptors inhibitory or excitatory
It is important in:
- Arousal
- Blood pressure regulation
- Mood control
