GABA Flashcards
Where is GABA synthesised from?
Glutamate - presynpatically
How is GABA stored?
By a vesicular GABA transporter
How is GABA released?
By calcium influx
Where does GABA act?
At ionotropic GABAa and metabotropic GABAb receptors
How is GABA cleared from synapse?
By reuptake using transporters on glia and neurons
What does too much GABA lead too?
Sedation/coma - because it produces inhibition
What can drugs which increase GABA transmission be used to treat - if at right dose?
Epilepsy - calm them down
Example of a GABA drug
GHB - date rape drug
a GABA metabolite than can be converted back to GABA by transamination, increases amount of GABA available, moderate dose like alcohol, but too much leads to unconscious and death
What does alcohol cause?
Unconsiousness, coma and death
the margin of safety is low, can get drunk from 0.2-0.3 but death is caused from 0.35-0.5 - luckily, people pass out before they reach this stage
What are the two GABA receptors?
GABAa - inotropic - lingad gated Cl- channels, fast IPSP’s
GABAb metabotropic receptors - G protein coupled receptors, indirectly coupled to K or Ca2+ channel through second messengers, opens k channel, closes Ca2+ channel. Slow IPSPS
What is the main difference between GABAa and GABAb?
GABAa = fast IPSPs GABAb = slow IPSPs
What are GABAa receptors made of?
6 possible subunits
What happens when GABA is released to GABAa?
Cl channel gated by the binding of GABA
GABA increases chloride and hyperpolarises the neuron
Decreasing the depolarising effects of an excitatory neuron - counteracts excitation
Why is GABA complex?
Because it has multiple binding sites
What drugs bind at GABA binding site?
Muscimol (comes from mushroom: evolution purpose to protect themselves) - agonist - eat the fungi, get signs of drunk
Bicuculine - antagonist - get disinhibition, don’t have breaks, get excitation
What drugs bind elsewhere on the receptor? (no competition with gaba)
Benzodiazepine Barbiturates Ethanal Neurosteroids all cause IPSPs
What do drugs which increase GABA activity do?
Reduce anxiety - anxiolytic
for example:
agonists: alcohol and barbiturates
indirect agonist: benzodiazepines
What do drugs which decrease GABA activity do?
Increase anxiety - antigenic
for example,
antagonist: flumazenil
Is there evidence for GABA dysfunction in anxiety disorders?
Yes, patients with panic disorders have less benzodiazepine binding sites
They lack inhibitory control in corticol and limbic regions to suppress inappropriate fear responses and have a panic attack - because they have no GABAa receptors
The frontal cortex is hyperactive during periods of anxiety
What are the actions of drugs at the GABAa receptor?
Barbiturate (agonist) - produces a full effect alone
Benzodiazepine (indirect agonist) - no effect alone, but in the presence of GABA has an effect
Flumazenil (antagonist) - no effect alone, if mixed with GABA, reduces the effect of GABAa receptor - blocking it
What are the problems with barbiturates?
General depression of neuronal activity - causes functions to slow down
poor therapeutic ratio - small difference between dose and overdose - high suicide risk
long term treatment = withdrawal and dependence
only used for severe insomnia and seizures
What is benzodiazepine?
Discovered in the 60’s, first one as librium. Then diazepam was the major treatment
acts as: anxiolytic, anticonvulsant, sedative, muscle relaxant, amnestic (memory)
good, fat acting, large therapeutic window
may cause dependence, if mixed with alcohol = depression
