Applied neuropharmacology Flashcards
Sequence of events that occur during synaptic transmission (9)
1) Synthesis and packaging of neurotransmitter (usually) into vesicles in presynaptic terminals
2) Na+ action potential invades terminal
3) Activates voltage gated Ca2+-channels
4) Triggers Ca2+-dependent exocytosis of pre-packaged vesicles of transmitter
5) Transmitter diffuses across cleft and binds to ionotropic and/or metabotropic receptors to evoke postsynaptic response
6) Presynaptic autoreceptors inhibit further transmitter release (negative feedback)
7) Transmitter is (usually) inactivated by uptake into glia or neurones
8) Or transmitter is (unusually) inactivated by extracellular breakdown
9) Transmitter is metabolised within cells
What transmitter is the exception to the rule: transmitter is usually inactivated by uptake into glia or neurons
ACh because it is inactivated by extracellular breakdown (broken down by cholinesterase in the synaptic cleft)
Pharmacological manipulation to REDUCE synaptic transmission (7)
- Block the voltage gated Na+ channels – eg local anaesthetics, would block all action potentials, not too useful.
- Block the voltage gated Ca2+ channels – eg those clever spider toxins, would block all transmitter release, not too useful.
- Block the release machinery, eg botox, would block all transmitter release, not too useful.
- Block the postsynaptic receptors, eg receptor antagonists, competitive or non-competitive. Selectivity helps. Lots of examples of that.
- Activate those presynaptic inhibitory receptors. (the autoreceptors – to inhibit transmitter release by turning off Ca channels and stopping intracellular Ca release)
- Increase breakdown of transmitter
- Increase uptake of transmitter
Pharmacological manipulation to INCREASE synaptic transmission
- Increase synthesis by flooding the cells with the appropriate precursors to encourage neurotransmitter release
- Activate post-synaptic receptors with an agonist - though that is not so useful because they get activated all the time
- Better to use an allosteric drug that does activate the receptor on its own, but potentiates the effects of the endogenous transmitter, eg benzodiazepines and barbiturates on GABA receptors.
- Block breakdown of transmitter – e.g. anticholinesterases on ACh
- Block the uptake of transmitter
Name some neurotransmitters (6)
ACh Monoamines - noradrenaline, dopamine Amino acids - glutamate, GABA Purins - ATP Neuropeptides - endorphins Nitric oxide
Dopamine is anatomically distributed in what 3 places
Brain stem
Basal ganglia
Limbic system & frontal cortex
Main function of dopamine
Voluntary movement
What pathways are dopamine involved in (4)
Mesocortical
Nigrostriatal
Tubero-infundibular
Mesolimbic
Parkinson’s is caused by
Degeneration of dopamine/dopamine deficiency in the substantial nigra of the basal ganglia
What enzyme converts tyrosine –> dihydroxyphenyalanine (DOPA)
What enzyme then converts DOPA –> dopamine
Tyrosine hydroxylase
Aromatic amino acid decarboxylase (AAAD)
Can dopamine made outside the brain cross the BBB
No
Can tyrosine and DOPA cross the BBB to enter the brain
Yes
How can dopamine synthesis be modulated in vivo
Can pharmacologically block AAAD outside the brain to allow more DOPA to cross BBB and enter brain
What type of receptors does dopamine act on
Metabotropic (g-protein coupled)
Dopamine is broken down in how many different 2 pathways + but both commonly involve which 2 enzymes
2
Monoamine-oxidase-B (MAO-B)
Catechol-O-methlytransferase (COMT)
