GABA and Anaesthetics

Question 1

Etomidate

Answer 1

Selective for GABAaRs

Enantiselective for R isoform of etomidate

Question 2

Etomidate is enantioselective

Answer 2

Bellili et al 2003

Question 3

Effects of Etomidate are b2 selective - chimeras

Answer 3

Bellili et al 1997

Question 4

N265S

Answer 4

mutation which infers etomidate effectiveness

Question 5

Etomidate does not produce sedation in b2N265S mouse

Answer 5

Bellili et al 2005

Question 6

b2 subunit

Answer 6

sedation
hypnosis
anaesthesia

Question 7

b2N265S mouse

Answer 7

low dose etomidate decreases locomotion in WT but not b2 mutant
does not produce slow wave sleep signals

Question 8

b2N265S and b3 N265M

Answer 8

don’t have LORR in presence of etomidate

b3N265M does not lose tail withdrawl - sign of immobility

Question 9

b3 subunit

Answer 9

hypnosis in part
immobility
respiratory depression

Question 10

tonic inhibition

Answer 10

extrasynaptic GABAa

Question 11

extrasynaptic GABAa

Answer 11

a4b2d

Question 12

synaptic GABA

Answer 12

phasic inhibition - a1

Question 13

86% of etomidate effects

Answer 13

extrasynaptic current

Question 14

Gaboxadol

Answer 14

supposed to promote a more natural sleep rhythm
poor gaba agonist
exerts effects via a4b2d

Question 15

d-/- mice

Answer 15

have lost effects of gaboxadol
decreased ataxia, sedation and analgesia
longer activity on rotarod test

Question 16

effects of different GABA a subunit as a result of BZD

Answer 16

a1 - sedation
a2 - anxiolytic and analgesic
a5 - impaired cognition

Question 17

a1H101R mouse

Answer 17

reduced 3-H flumazenil binding
prevents prolongation of thalamic mIPSCs
myorelaxant activity not mediated by a1

Question 18

a2H101R mouse

Answer 18

analgesia looked at using von frey and paw lick latency tests
reduced response to pain and algesia

Question 19

a2

Answer 19

highly expressed in lamina II and III of dorsal horn

analgesic responses are only maintained in a1H101R mutant

Question 20

Etomidate and memory

Answer 20

inhibits LTP in schaffer collateral CA1 pathway in WT but not -/-mice
effect reversed by L655,708 inverse agonist

Question 21

testing memory with etomidate

Answer 21

morris water maze a5-/- mice have no problem

Question 22

Zurek et al 2014

Answer 22

a5 GABAaR increase in function compromises memory performance
NOR reduced in both sedative 8mg/kg and anaesthetic doses 20mgkg
up to 1 week sedative
up to 2 weeks for anaesthetic
blocked by inverse agonist given 30 mins before training
a5-/- did not have issues
CA1 inhibitory current increased in mice with etomidate
LTP reduced 1 day post dose recovered in 1 week
tonic current increased for 1-3 days but no effect on phasic mIPSCs - 1 week

Question 23

a5 LTP

Answer 23

decreased LTP for 1 day post-sedative dose not seen in -/- mouse
increase tonic current for 1-3 days
no effect from synaptic GABAaRs

Question 24

Wang et al 2012

Answer 24

involvement of IL-1B with a5 memory
IL-1B increases the tonic current through p38 MAPK signalling
increased surface expression of a5
contextual fear memory - inverse agonists
a5 mediated impairment of LTP
IL-1B increases tonic current in CA1
IL-1B downregulates a1 and no effect on a2