CAL 2 Flashcards
what is dopamine made out of
- carbon
- hydrogen
- oxygen
- nitrogen
which disorders is dopmaine involved in
- huntingtons
- parkinsons
- schziophrenia
- chronic pain syndrome
- Amyotrophic lateral sclerosis
what 5 things does dopaminergic transmission involve
- Synthesis
- Storage
- Release
- Interaction with dopamine receptors
- Inactivation
describe how dopamine is made
- tyrosine is uptaken into the presynaptic nerve terminal
- tyrosine is catalysed into DOPA by tyrosine hydroxylase
- DOPA is catalysed into dopamine by DOPA decarboxylase
what enzyme catalyses tyrosine into DOPA
tyrosine hydroxylase
what enzyme catalyses DOPA into Dopamine
DOPA decarboxylase
What is tyrosine
Tyrosine is a naturally occurring aromatic amino acid formed from the essential amino acid phenylalanine.
What is L dopa
L-DOPA is the precursor of dopamine and is formed from L- tyrosine.
why are levels of Ldopa in dopaminergic neurones low
Levels of L-DOPA in dopaminergic neurones are low because as soon as it is formed, it is decarboxylated and forms dopamine.
describe the structure of dopamine
Dopamine is a catecholamine. It has two adjacent phenolic hydroxyl groups on the benzene ring.
How is dopamine taken up and stored
- Dopamine is taken up by an active process and stored in presynaptic vesicles. This process depends on a supply of ATP as a source of energy.
- Storage depends on the vesicular monoamine transporter 2 (VMAT2).
what can be used as a marker of dopaminergic innervation
VMAT2 (vesicular monoamine transporter 2) - this is the transporter that is involved in storage of dopamine
- This transporter can be used as a marker of dopaminergic innervation
what happens to presynaptic vesicles
Presynaptic vesicles
Vesicles are recycled, so that once the transmitter has been released they can be refilled with newly synthesized transmitter (and also to some extent with transmitter which has been re-uptaken by the presynaptic terminal).
what calcium channels are on the nerve
N type calcium channels
What are the type of dopamine receptors
- D1 or D2
- Dopamine may also bind to and activate presynaptic
(D2) autoreceptors.
what happens when dopamine is reuptaken into the pre synaptic terminal
- Stored in vesicles
- Degraded into homovanillic acid (HVA) by catechol - O - methyl transferase (COMT), a largely extra neuronal enzyme and monoamine oxidase (MAO), and aldehyde dehydrogenase.
- Degraded into 3,4-dihydrophenylacetic acid (DOPAC) by MAO and aldehyde dehydrogenase
where is MAO stored
an enzyme associated with the mitochondria and located in the presynaptic nerve terminal
Is COMT extracellular or intracellular
extracellular
what does COMT do
- catalyses the transfer of a methyl group S- adenosylmethionine to a donor phenolic hydroxyl group on dopamine
what does MAO do
- deaminates a range of amine substrates
- primary produce is an aldehyde which is oxidised to the acid by aldehyde dehydrogenase
What is Homovanillic Acid (HVA)
HVA is the major metabolite of dopamine in the brain and its levels can be used to monitor dopamine turnover.
What is DOPAC (3,4-Dihydroxyphenyl acetic acid)
- DOPAC is a metabolite of dopamine formed following oxidative deamination by MAO.
- The aldehyde formed is then oxidised by aldehyde dehydrogenase to DOPAC.
Is the following statement true or false:
DOPA decarboxylase specifically decarboxylates L-DOPA
false
Is the following statement true or false:
Tyrosine hydroxylase is a vitamin B6 dependent enzyme
false
Is the following statement true or false:
Agonists of presynaptic dopamine autoreceptors inhibit dopamine synthesis
true
Is the following statement true or false:
Decarboxylation of L-DOPA by DOPA decarboxylase is rate-limiting in the synthesis of dopamine
false
what type of receptors are dopamine receptors
G protein receptors
What are the two different types of dopamine receptors family
D1
D2
what receptors are in each family of dopamine receptors
The D1 family includes
the D1 and D5 receptor subtypes.
The D2 family consists of
the D2, D3 and D4 receptor subtypes.
What does the D1 family of receptors do
These receptors are postsynaptic and activate adenylate cyclase.
where do you find the D1 receptor from the D1 receptor family type
D1 receptors are found mainly in the caudate-putamen, nucleus accumbens and olfactory tubercle, with lesser amounts in the cerebral cortex, limbic system and hypothalamus.
where do you find the D5 receptor from the D1 receptor family
D5 receptors are found in much lower concentrations than
D1, with the highest levels in the hippocampus and hypothalamus
which has a higher concentration D1 or D5
D1
What do the D2 family of receptors do
They exert the following effects:
1. Inhibit adenylate cyclase 2. Activate K+ channels 3. Decrease Ca2+ conductance 4. Potentiate ATP-mediated arachidonic acid release
where are D2 receptors found
- D2 subtype receptors are found in the caudate-putamen, nucleus accumbens and olfactory tubercle.
- D2 receptors are mainly postsynaptic, but there are also presynaptic D₂ receptors.
where are D3 receptors found and what do they do
D3 subtype receptors are
1. Less abundant than the D₂ subtype 2. Found mostly in limbic areas (nucleus accumbens and olfactory tubercle) where they may mediate control of emotional and cognitive functions
where are D4 receptors found
D4 subtype receptors are found in the frontal cortex, midbrain, amygdala and medulla.
Is the following statement true or false for the
D1 family of receptors:
activate adenylate cyclase
true
Is the following statement true or false for the
D1 family of receptors:
only modulate adenylate cyclase in human brain
false
Is the following statement true or false for the
D1 family of receptors:
are found both presynaptically and postsynaptically
false
- only postsynaptic
Is the following statement true or false for the
D1 family of receptors:
are present in the extrapyramidal motor system
true
Is the following statement true or false for
the D1 family of receptors:
The D5 subtype is found predominantly in the limbic areas
true
Is the following statement true or false for the
D1 family of receptors:
The D1 subtype is found predominantly in the limbic area
false
Is the following statement true or false for the
D2 family of receptors:
activate adenylate cyclase
false
Is the following statement true or false for the
D2 family of receptors:
do not need to interact with other receptors in order to modulate adenylate cyclase activity
true
Is the following statement true or false for the
D2 family of receptors:
are functionally coupled with receptors of
the D1 family
true
Is the following statement true or false for the
D1 family of receptors:
The D4 subtype is found predominantly in the neostriatum
false
Is the following statement true or false for the
D2 family of receptors:
The D2 receptor subtype is found both presynaptically and postsynaptically
true
what are the sites where drugs can influence dopamine transmission
synthesis, storage, release, inactivation of dopamine, interaction of dopamine with its receptors
What is an agonist
An agonist drug binds to and activates receptors. The endogenous agonist of dopamine receptors is the neurotransmitter dopamine.
What is an antagonist
An antagonist also binds to receptors but cannot activate them. Antagonists have no efficacy.
What does the drug alpha methyl P tyrosine do
- alpha methyl-p-tyrosine
The drug alpha methyl-p-tyrosine blocks dopamine synthesis by inhibiting the enzyme tyrosine hydroxylase
- this prevents tyrosine being converted to DOPA.
- competitive inhibitor
What is the rate limiting step of the production of dopamine
the hydroxylation of tyrosine to L dopa
what does tyrosine hydroxylase need as a cofactor
tetrahydrobiopterion
what is tyrosine hydroxylase inhibited by
- feedback inhibition from dopamine
- and dopamine acting on dopamine D2 autoreceptors
How is L dopa used in parkinsons disease
- L-DOPA is the natural precursor of dopamine and is used in the treatment of Parkinson’s disease.
- Dopaminergic nerve fibres take up L-DOPA and the enzyme DOPA decarboxylase converts it to dopamine
what vitmain is attached to DOPA decarxylase
Vitamin B6 dependent enzyme
Dopamine has a 5 to 10 fold higher affinity……
for presynaptic over postsynaptic receptors.
what drug is used in parkinsons
L dopa
How does reserpine work
- Compounds like reserpine, which is very rarely used in the clinic today,
- inhibit the vesicular storage of dopamine in dopaminergic nerve terminals.
- Reserpine exerts this effect by inhibiting irreversibly the vesicular monoamine transporter (VMAT2) which transports molecules of neurotransmitter from the cytoplasm into vesicles.
- The drug tetrabenazine acts in a similar manner, as it also inhibits VMAT2.
What drug is used in huntingtons disease
Tetrabenazine is used in the treatment of Huntington’s disease.
name some postsynaptic dopamine receptor agonists
Pergolide
quinpirole
Bromocriptine
Apomorphine
what do postsynaptic dopamine receptor agonists do
These drugs will mimic the effects of dopamine
name drugs that are used to treat parkinsons disease
Pergolide and quinpirole show little selectivity between
D1 and D2 receptors. Both are used to treat Parkinson’s disease.
Bromocriptine has much higher affinity for D2 than D1 receptors.
It is used in Parkinson’s disease and to treat certain types of infertility.
What does Apomorphine do
Apomorphine is a non-selective dopamine receptor agonist and is a potent emetic.
What do post synaptic dopamine receptor antagonists do
These drugs block the effects of dopamine at postsynaptic receptors.
what receptor do drugs that are used to treat schizophrenia have a higher affinity for
Most drugs used effectively in the treatment of schizophrenia (known as neuroleptics or antipsychotics) have a higher affinity for members of the D2 than D1 receptor families.
name some drugs used to treat scizophrenia
chlorpromazine, haloperidol, spiperone, sulpiride clozapine (mainly D4 affinity)
What other receptors do schizophrenia drugs have high affinities for
muscarinic acetycholine,
histamine (H1)
5-hydroxytryptamine (5-HT2) receptors.
what drugs are D2 selective
D2 selective: haloperidol, spiperone, S-sulpriride
name the affinity for dopamine receptors for
Raclopride:
Spiperone:
Clozapine:
Raclopride: D2=D3>D4
Spiperone: D2=D4>D3
Clozapine: D4>D2=D3
name some drugs that affect the storage of dopamine
Drugs such as D-amphetamine and amantadine release dopamine from dopaminergic presynaptic stores.
How can amantadine be used in parkinsons
Amantadine can be used in Parkinson’ s disease. One of its actions is to release dopamine from its stores and so partially to overcome the deficit in dopamine in dopaminergic synapses which is a characteristic of this disease.
what are 3 functions of D-amphetamine
- Inhibition of amine uptake
- Inhibition of monoamine oxidase activity (MAO)
- Release of dopamine (and noradrenaline) from monoaminergic nerve terminals
Many of its pharmacological actions (e.g appetite suppressant, hallucinogenic) are due to its effects on amine systems.
what are agonists of post synaptic dopamine receptors mainly used to treat
parkinsons
What are antagonist of post synaptic dopamine receptors mainly used to treat
schizophrenia
What is selegiline
Selegiline is a selective and irreversible inhibitor of MAOB.
what is a negative about selegiline
At higher doses it loses specificity and can also inhibit MAOA.
when is selegiline used
It is used at an early stage in Parkinson’s disease or as adjunct therapy, at a later stage in the disease.
what has a similar mechanism of action to selegiline
A more recent compound, rasagiline, has a similar mode of action.
name some inhibitors of COMT
Inhibitors of COMT such asentacapone and tolcapone are used in Parkinson’s disease.
name some antagonists of muscarinic acetylcholine receptors
Antagonists of muscarinic acetylcholine receptors (mAchRs), such as benzhexol (trihexyphenidyl) and benztropine, are used in Parkinson’s disease.
What do antimuscarnic drugs do
i) Increase dopamine release by blocking inhibitory mAchRs on nigrostriatal dopaminergic neurones
ii) Inhibit dopamine re-uptake
iii) Inhibit the overactivity of striatal cholinergic interneurones resulting from the loss of their inhibitory dopaminergic input
