What is the sequence of evens in synaptic transmission?
- Synthesis and packaging of neurotransmitter (usually) in presynaptic terminals
- Na+ action potential invades terminal which activates voltage gated Ca2+-channels
- Triggers Ca2+-dependent exocytosis of pre-packaged vesicles of transmitter
- Transmitter diffuses across cleft and binds to ionotropic and/or metabotropic receptors to evoke postsynaptic response
- Presynaptic autoreceptors inhibit further transmitter release
- Transmitter is (usually) inactivated by uptake into glia or neurones or transmitter is (unusually) inactivated by extracellular breakdown
- Transmitter is metabolised within cells
How can synaptic transmission be reduced by pharmacological manipulation?
- Block voltage gated Na channels
- Inhibit synthesis and packaging of NT
- Activate presynaptic inhibitory receptors
- Block postsynaptic receptors (eg. competitive antagonists, non competitive antagonists)
- Block voltage gated Ca channels
- Increase breakdown of transmitter
- Block release machinery
- Increase uptake of transmitter
- Block voltage gated Na channels
How can synaptic transmission be increased by pharmacological manipulation?
- Increase synthesis and packaging of NT (eg. by increasing availability of precursors)
- Activate postsynaptic receptors with an agonist
- Potentiate effects of transmitter on receptor (eg. increase channel open time)
- Block breakdown of transmitter
- Block uptake of transmitter
What types of neurotransmitters are there?
- Acetylcholine
- Monoamines
- Amino acids
- Purines
- Neuropeptides
- NO
Give examples of monoamine neurotransmitters
- Noradrenaline
- Dopamine
- Serotonin (5-HT)
Give examples of amino acid neurotransmitters
- Glutamate
- GABA
- Glycine
Give examples of purine neurotransmitters.
- ATP
- Adenosine
Give examples of neuropeptide neurotransmitters
- Endorphins
- CCK
- Substance P
Why is it no surprise that neurotransmitters have different functions in different regions?
There is a limited range of neurotransmitters
What does each neurotransmitter have?
- Its own anatomical distribution
- Its own range of receptors it acts on
- Its own range of functions in different regions (some separated by the blood brain barrier)
What is the anatomical distribution of dopamine in the brain?
- Brain stem
- Basal ganglia
- Limbic system an frontal cortex
What physiological functions are affected by dopamine?
- Vomiting
- Voluntary movement
- Emotions/reward
What is Parkinson’s caused by?
- Degeneration of DA cells in the substantia nigra (nigrostriatal)
- DA deficiency in the basal ganglia
How is dopamine synthesised?
- Glycine
- Alanine
- Phenylalanine
- Tyrosine
- DOPA
- Dopamine
Why can dopamine not evoke fast EPSPs or IPSPs?
No inotropic receptors
What are the names of the dopamine receptors?
5 subtypes of metabotropic (ie. g-protein coupled) receptors names D1-D5
How does the effect of dopamine differ through the brain?
It can produce many effects and different effects in different brain regions depending on the receptors expressed
What are the key enzymes in dopamine metabolic breakdown?
- MAO-B
- COMT
What does dopamine metabolic breakdown result in?
Homovanillic acid
How does Parkinson’s present?
Stiffness, slow movements, change in posture, tremor
What type of drugs can improve some symptoms of PD?
Dopaminergic drugs
What types of dopaminergic drugs are there?
- DA precursors
- DA agonists
Give an example of a DA precursor
Levodopa
Give examples of DA agonists ergots.
- Bromocriptine
- Pergolide
- Cabergoline
Give examples of DA agonist non-ergots
- Ropnirole
- Pramipexole
- Rotigotine
Why are DA agonist ergots no longer used?
5HT (2B) stimulation leads to fibrosis
Give an example of a DA agonist
Apomorphine
What enzyme inhibitors can be used in PD?
- Peripheral AAAD inhibitors
- MAOB inhibitors
- COMT inhibitors
Give examples of peripheral AAAD inhibitors
- Carbidopa
- Benserazide
Give examples of MAOB inhibitors
- Selegiline
- Rasagiline
- Safinamide
Give examples of COMT inhibitors
- Entacapone
- Tolcapone
What effect do enzyme inhibitors have in synthetic dopamine agonists?
No effect on synthetic dopamine agonists
What effect do peripheral AAAD inhibitors have on levodopa?
Decrease peripheral side effects of levodopa and allows a greater proportion of the oral dose to reach the CNS
What effect do COMT inhibitors have on levodopa?
Decrease metabolism of dopamine and so increase the effectiveness of levodopa
What do dopaminergic drugs improve?
Some improve motor features of Parkinson’s
-e.g. limb rigidity and bradykinesia, tremor
What do dopaminergic drugs worsen or cause?
- Nausea
- Vomiting
- Psychosis
- Impulsivity / abnormal behaviours
What do dopaminergic drugs fail to help?
Midline features
- Dysarthria
- Balance
- Cognition
What do dopamine antagonists improve?
- Nausea
- Vomiting
- Psychosis
What do dopamine antagonists worsen or cause?
Parkinson’s
What effect do DA antagonist antiemetic’s have on PD?
DA antagonist antiemetics will worsen PD and generally should not be used in people with PD
Where is area postrema (vomiting centre) located?
Area postrema (vomiting centre) in the medulla is functionally OUTSIDE the BBB
What feature would be required of a DA antagonist for it to not cause nausea?
A DA antagonist that didn’t cross the BBB
What is domperidone?
- DA antagonist that does not cross the BBB
- Is an anti-emetic and does not have antipsychotic properties
- Relatively safe in PD
What does domperidone not do?
Cross the BBB
What can be used with domperidone due to its anti-emetic property?
Apomoprhine
Dyskinesias
AIMS: abnormal involuntary movements
What type of drugs may cause dyskinesias?
Dopaminergic drugs
What type of drugs may cause parkinsonism?
DA antagonists
What type of dyskinesia is associated with long term DA antagonist use?
Tardive dyskineasias
What is the function of noradrenaline?
Reuptake blockers
What are tricyclic drugs used as?
Antidepressants
What are MAO inhibitors used as?
Antidepressants
What are selective serotonin reuptake inhibitors (SSRIs)?
Antidepressants
What are triptans (selective 5HT agonists) used for?
Used in the treatment of migraines
What are GABA agonists used for?
- GABA agonists are anti-epilepsy drugs.
- They also have anti-anxiety properties