General Anaesthetics and GABA

Question 1

Why do we think GABAa is the main target for general anaesthetics?

Answer 1

Compared the action of 4 diff structurally diff GAs on 6 diff receptor types and seen they all work on GABAa

Question 2

Which form of etomidate is more potent?

Answer 2

R form (over S form)

Question 3

What subunit is etomidate action dependent on?

Answer 3

Beta2

Hill-Venning et al 1997

Question 4

What on the beta subunit determines the etomidate binding?

Answer 4

N position 265

S265N on beta1 greatly increased the action of etomidate binding
Bellini et al 1997

Question 5

What are the roles of the GABAa subunit isoforms?

Answer 5

Alpha1 - sedation
2,3 - anxiolytic
5 - impaired cognition

Question 6

Give examples of PAMs of GABA

Answer 6

Diazepam, flutrinazepam

Question 7

What is the effect of PAMs of GABA?

Answer 7

Sedation, muscle relaxant, anxiolytic

Question 8

Give example of a NAM of GABA?

Answer 8

DMCM (beta carboline)

Question 9

Where is the benzodiazepine binding site?

Answer 9

The alpha/gamma subunit interface

Question 10

Which subunits are insensitive to diazepam?

Answer 10

alpha4 and alpha6

Question 11

What is the mutation which makes the alpha subunits insensitive to diazepam?

Answer 11

H101R

Question 12

Why are benzodiazepines not ideal as long term medication?

Answer 12

Sedative
Tolerance quickly
Addictive

Question 13

Benzodiazepines have some value for nociceptive pain

T/F

Answer 13

F

Question 14

Benzodiazpeines may be useful in inflammatory pain via alpha4 mediated effects

T/F

Answer 14

F

May relieve inflammatory pain via alpha 1

Question 15

Why is L838, 427 preferred over morphine?

Answer 15

No decrease in efficacy

Harrison 2008

Question 16

Why do we think that alpha1 is needed for benzo activity?

Answer 16

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

Question 17

Why do we think that alpha2 is needed for benzo activity?

Answer 17

KO mice show less time in the open arms of the EPM compared to WT

Question 18

What is the action of L-838, 417 on alpha1?

Answer 18

Antagonises

Question 19

What is the action of L-838, 417 on alpha2?

Answer 19

PAM

Anxiolytic without sedation

Question 20

What does the ventrobasal nucleus receive GABA input from?

Answer 20

Nucleus reticularis

Question 21

Where does the nucleus reticularis receive excitatory input from?

Answer 21

Cortex

Question 22

What is the action of THIP?

Answer 22

Agonist at alpha4-beta2-delta GABA receptors

Question 23

They effect of THIP is dependent on which subunit?

Answer 23

Delta

Question 24

How do we know that gaboxadol effect is dependent on delta subunits?

Answer 24

WT mice given it fall right off on the rota rod test

Delta KO mice are fine

Question 25

Where are alpha-5 subunits found?

Answer 25

Hippocampus

Question 26

What does etomidate do to cognitive performance?

Answer 26

Decrease

Question 27

How are the impaired cognition effects of etomidate shown?

Answer 27

Dose-dependent, reversible negative effect on mice performance in NOR task
With reduction in LTP

Zurek et al 2014

Question 28

How do we know that etomidate works on alpha-5?

Answer 28

No cognitive impairment seen in NOR in alpha-5 KO mice