General Anaesthetics and GABA Flashcards
Why do we think GABAa is the main target for general anaesthetics?
Compared the action of 4 diff structurally diff GAs on 6 diff receptor types and seen they all work on GABAa
Which form of etomidate is more potent?
R form (over S form)
What subunit is etomidate action dependent on?
Beta2
Hill-Venning et al 1997
What on the beta subunit determines the etomidate binding?
N position 265
S265N on beta1 greatly increased the action of etomidate binding
Bellini et al 1997
What are the roles of the GABAa subunit isoforms?
Alpha1 - sedation
2,3 - anxiolytic
5 - impaired cognition
Give examples of PAMs of GABA
Diazepam, flutrinazepam
What is the effect of PAMs of GABA?
Sedation, muscle relaxant, anxiolytic
Give example of a NAM of GABA?
DMCM (beta carboline)
Where is the benzodiazepine binding site?
The alpha/gamma subunit interface
Which subunits are insensitive to diazepam?
alpha4 and alpha6
What is the mutation which makes the alpha subunits insensitive to diazepam?
H101R
Why are benzodiazepines not ideal as long term medication?
Sedative
Tolerance quickly
Addictive
Benzodiazepines have some value for nociceptive pain
T/F
F
Benzodiazpeines may be useful in inflammatory pain via alpha4 mediated effects
T/F
F
May relieve inflammatory pain via alpha 1
Why is L838, 427 preferred over morphine?
No decrease in efficacy
Harrison 2008
Why do we think that alpha1 is needed for benzo activity?
Alpha1 KO mice don’t show any classic benzo effects (sedation)
McKernan et al 2000
Less time in light portion of light/dark box compared to wild type
Why do we think that alpha2 is needed for benzo activity?
KO mice show less time in the open arms of the EPM compared to WT
What is the action of L-838, 417 on alpha1?
Antagonises
What is the action of L-838, 417 on alpha2?
PAM
Anxiolytic without sedation
What does the ventrobasal nucleus receive GABA input from?
Nucleus reticularis
Where does the nucleus reticularis receive excitatory input from?
Cortex
What is the action of THIP?
Agonist at alpha4-beta2-delta GABA receptors
They effect of THIP is dependent on which subunit?
Delta
How do we know that gaboxadol effect is dependent on delta subunits?
WT mice given it fall right off on the rota rod test
Delta KO mice are fine
Where are alpha-5 subunits found?
Hippocampus
What does etomidate do to cognitive performance?
Decrease
How are the impaired cognition effects of etomidate shown?
Dose-dependent, reversible negative effect on mice performance in NOR task
With reduction in LTP
Zurek et al 2014
How do we know that etomidate works on alpha-5?
No cognitive impairment seen in NOR in alpha-5 KO mice
