Addiction and GABAa

Question 1

What is a GABAa receptor?

Answer 1

Transmitigated ion channel used for fast info transfer between neurons

Question 2

What is a GABAb receptor?

Answer 2

GCPR

Question 3

What does GABAa conduct?

Answer 3

Anions

Question 4

How many transmembrane subunits does GABAa have?

Answer 4

5

Question 5

How does GABA act on GABAa?

Answer 5

GABA released form presynaptic nerve and binds to its site on the synapse
Causes conformational change to open channel
Cl- then rapidly conducted through

Question 6

Which drugs enhance GABAergic transmission?

Answer 6

Diazepam and Propofol

Question 7

What are the effects of neurosteroids binding to GABA?

Answer 7

Anti-anxiety

Pain relief

Question 8

Which GABAa type receptors are found in the hippocampus?

Answer 8

Alpha 5

Question 9

Which GABAa type receptors are found in the cerebellum?

Answer 9

Delta

Question 10

What are the different functions of the different receptor types?

Answer 10

Alpha 1 and Beta 2 - sedation
Alpha 2 and 3 - anxiolytic
Alpha 5 - cognitive

Question 11

Name a positive allosteric modulator of GABA

Answer 11

L-838,417

Question 12

Where does L-838,417 act?

Answer 12

On alpha 2, 3, 5

Not 1 !!

Question 13

What is the effect of L-838,417 on alpha 1 GABA receptors?

Answer 13

Antagonism

Question 14

Where do benzodiazepines bind?

Answer 14

between alpha and gamma2 subunits

Question 15

What are the effects of diazepam?

Answer 15

Sedative, relaxant, anti-convulsant and decreased cognition

Question 16

How do we know that diazepam is anxiolytic?

Answer 16

Mice treated with diazepam spend more time exploring the exposed arms of the elevated plus maze

Question 17

Which receptor type is the effect of diazepam reliant on?

Answer 17

Alpha 1 and 2
Thought prev to just be alpha 1, but H101R alpha 1 AND H101R alpha 2 prevent a decrease in midazolam preference indicting that both are required for this effect

Question 18

Which mutation in the subunit can prevent diazepam action?

Answer 18

H101R

Question 19

How do we know that a mutated subunit stops diazepam from working?

Answer 19

H101R mice treated with diazepam do not explore the open arms of the elevated plus maze like wild type does

Question 20

Name a negative allosteric modulators of GABAa

Answer 20

Beta-carboline

Question 21

What is the effect of beta carboline?

Answer 21

Anxiety induction

Seizures

Question 22

What is flumazenil?

Answer 22

Antagonist of GABA

Question 23

What is the action of flumazenil?

Answer 23

Binds to GABA

Has no effect by itself but it stops other molecules from binding

Question 24

Which subunit type is insensitive to benzodiazepine action?

Answer 24

Alpha 6

Question 25

What occurs in benzodiazepine withdrawal?

Answer 25

Sleep disturbance, irritability, panic

Question 26

Which adverse experience is associated with GABA mutation and alcoholism?

Answer 26

ELS

Question 27

How can we model ELS in mice?

Answer 27

Give reduced bedding | Mother than spends less time with pups, maternal separation causes early life stress

Question 28

How does cocaine affect ELS mice vs WT?

Answer 28

Cocaine increases locomotion WT on day 1 has a mild increase, on day 10 has a significant increase ELS mice show the same increase in locomotion on day 1 than WT do on day 10 This indicates a higher response to cocaine Mitchell et al 2018

Question 29

How does the ELS response to cocaine show the ELS effect on GABAa-alpha2?

Answer 29

Alpha 2 KO mice display the same locomotor effects as ELS mice This implies that ELS causes alpha2-GABAa loss or loss of function Mitchell et al 2018

Question 30

How does ELS decrease the immunoreactivity of alpha2-GABAa?

Answer 30

Decreases the density and size of clusters of a2GABAa in the NAc Mitchel et al 2018

Question 31

What is the main method of signal transmission in the NAc?

Answer 31

GABAergic transmission

Question 32

Where is a2GABAa expressed in the NAc?

Answer 32

Synapses

Question 33

Which structure projects DA to the NAc?

Answer 33

VTA

Question 34

How do benzodiazepines affect DA in the NAc?

Answer 34

Enhance phasic inhibition of GABA transmission at interneurons Less GABA is then released onto the DA neuron There is less inhibition of the DA neuron More DA is released into the NAc

Question 35

How does the H101R mutation affect DA in the NAc in response to benzos?

Answer 35

Reduces it

Question 36

How do opioids decrease GABA release onto DA neurons?

Answer 36

``` Potentially by opening K channels OR Decreasing the opening of VGCCs Stops GABA release (Overall more DA release!) ```

Question 37

How does cannabinoids decrease GABA release onto DA neurons?

Answer 37

Binds to presynaptic CB1 receptors These decrease VGCC mechanisms No inhibition of DA > More DA

Question 38

How does GHB release GABA effect onto DA neurons?

Answer 38

Actives K+ channel opening Causes hyperpolarisation No release of GABA, DA increase

Question 39

How does cocaine increase DA?

Answer 39

Acts directly Binds to DA transporters to slow down reuptake of DA More circulating DA

Question 40

How do amphetamines act to increase DA?

Answer 40

Influence the uptake system | But also act directly to displace DA from the vesicles and increase circulation levels

Question 41

Which NAc receptors mediate a tonic inhibitory current?

Answer 41

alpha4-delta-GABAa

Question 42

Name a drug which activates the tonic inhibitory current in the NAc?

Answer 42

Gaboxadol Maguire et al 2014

Question 43

Why do we think that delta-GABAa mediates positive effects of alcohol?

Answer 43

Delta KO mice drink less, but still get the sedation effect Also when given virus to selectively decrease delta expression, the decrease in alcohol intake was sustained for 12-18 days (Nie et al 2011)

Question 44

Which mutation causes mice to have increased alcohol preference?

Answer 44

beta1 L285R on the beta1 GABAa receptor subunit Anstee et al 2013

Question 45

How does the beta1 L285R mutation affect the activation of GABA?

Answer 45

Increases incidence of spontaneous activation shown through patch recordings of HEK293 cells Anstee et al 2013