GABA and Addiction

Question 1

Define GABA

Answer 1

GABA plays a role in inhibition and opposes the actions of glutamate
It causes inhibition because of chlorine influx- hyperpolarization
GABAA- fast ligand gated ion channel
GABAB- slow G-protein coupled receptor

Question 2

Discuss the GABAAR

Answer 2

pentameric receptor

19 different sub-units and different sub-units have different locations

Question 3

Talk about the binding sites for GABAA

Answer 3

GABA site- alpha and B and GABA, muscimol, and gabaxadol- agonists

and bicuculline and antagonist gabazine are antagonists - competitive antagonists

Allosteric sites - benzos bind between alpha and gamma
Inverse agonist- B carboline also called an negative allosteric modulator
Antagonist- Flumenazil
Positive allosteric modulator- diazepam,

Question 4

What are the different alpha sub-unit types?

Answer 4

1- sedative
2- anxiolytic and analgesic
3-
4-
5- cognition

Question 5

Which alpha sub-units are benzo sensitive and not benzo sensitive?

Answer 5

1,2,3,5- sensitive because they have HISTIDINE

4,6- ARGININE

Question 6

What does Tan 2010 say?

Answer 6

miazolam not preferre over sucrose in alpha H101R mutatnt mice as they are insensitive to benzos

Question 7

What did mathieson 2005 say?

Answer 7

L838,417 - = BZ that was inert at alpha1 but active at alpha 2/3/5 – anxiolytic without sedative - GABAAR subtype-selective anti-anxiety drugs. - Could such drugs be anxiolytic without
causing addiction

Question 8

GABAAR alpha2 polymorphisms are linked to what?

Answer 8

alcohol abuse in population studies
edenburg 2004
enoch 2006
engin 2012

Question 9

What does Gunn 2013 say?

Answer 9

both ELS and alpha 2-/- exhibit an enhanced acute locomotor effect to cocaine an reuced sensitization

Question 10

Which receptors does ELS have an effect on?

Answer 10

decreased alpha 2 sub-unit in NAc

No change in alpha 1 subunit expression or alpha4Betaelta

Question 11

discuss the extrasynaotic receptors in the nucleus accumbens

Answer 11

alpha4betadelta receptors
responsible for tonic current
bicuculine is an antagonist that blocks this and THIP(gabaxadol) is an agonist

Question 12

Discuss the effects of alcohol on extra synaptic GABA receptors

Answer 12

the effects of acute ethanol on anxiety and sedation arent altered in beta knockout mice but these mice drink less alcohol and so a role for delta GABAARs in the rewarding/reinforcing effects of alcohol

Question 13

What does Nie 2011 say?

Answer 13

extrasynaptic delta containing sub-unit containing GABAA—reinforcing effects of oral ethanol
GABAAR antagonist bicuculine reduces the ethanol self aministration an so oe accumbal injection of siRNAto ecrease expression of either the delta or alpha4 subunit decreases the ethanol intake in rats

Question 14

What does Maguire 2014 say?

Answer 14

in the nucleus accumbens D1 and D2 receptor expressing MSN have both extrasynaptic and synaptic GABAARs

Question 15

What does Anstee 2013 say?

Answer 15

A B1 sub-unit mutation -single point mutation results in spontaneously active GABAAR via the extrasynaptic receptors causing increase in tonic inhibition and increase in ethanol preference