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BMSc - Psychiatry > Addiction and GABAa > Flashcards

Addiction and GABAa Flashcards

1
Q

What is a GABAa receptor?

A

Transmitigated ion channel used for fast info transfer between neurons

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2
Q

What is a GABAb receptor?

A

GCPR

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3
Q

What does GABAa conduct?

A

Anions

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4
Q

How many transmembrane subunits does GABAa have?

A

5

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5
Q

How does GABA act on GABAa?

A

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

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6
Q

Which drugs enhance GABAergic transmission?

A

Diazepam and Propofol

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7
Q

What are the effects of neurosteroids binding to GABA?

A

Anti-anxiety

Pain relief

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8
Q

Which GABAa type receptors are found in the hippocampus?

A

Alpha 5

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9
Q

Which GABAa type receptors are found in the cerebellum?

A

Delta

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10
Q

What are the different functions of the different receptor types?

A

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

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11
Q

Name a positive allosteric modulator of GABA

A

L-838,417

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12
Q

Where does L-838,417 act?

A

On alpha 2, 3, 5

Not 1 !!

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13
Q

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

A

Antagonism

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14
Q

Where do benzodiazepines bind?

A

between alpha and gamma2 subunits

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15
Q

What are the effects of diazepam?

A

Sedative, relaxant, anti-convulsant and decreased cognition

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16
Q

How do we know that diazepam is anxiolytic?

A

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

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17
Q

Which receptor type is the effect of diazepam reliant on?

A

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

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18
Q

Which mutation in the subunit can prevent diazepam action?

A

H101R

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19
Q

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

A

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

20
Q

Name a negative allosteric modulators of GABAa

A

Beta-carboline

21
Q

What is the effect of beta carboline?

A

Anxiety induction

Seizures

22
Q

What is flumazenil?

A

Antagonist of GABA

23
Q

What is the action of flumazenil?

A

Binds to GABA

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

24
Q

Which subunit type is insensitive to benzodiazepine action?

A

Alpha 6

25
Q

What occurs in benzodiazepine withdrawal?

A

Sleep disturbance, irritability, panic

26
Q

Which adverse experience is associated with GABA mutation and alcoholism?

A

ELS

27
Q

How can we model ELS in mice?

A

Give reduced bedding

Mother than spends less time with pups, maternal separation causes early life stress

28
Q

How does cocaine affect ELS mice vs WT?

A

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

29
Q

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

A

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

30
Q

How does ELS decrease the immunoreactivity of alpha2-GABAa?

A

Decreases the density and size of clusters of a2GABAa in the NAc

Mitchel et al 2018

31
Q

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

A

GABAergic transmission

32
Q

Where is a2GABAa expressed in the NAc?

A

Synapses

33
Q

Which structure projects DA to the NAc?

A

VTA

34
Q

How do benzodiazepines affect DA in the NAc?

A

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

35
Q

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

A

Reduces it

36
Q

How do opioids decrease GABA release onto DA neurons?

A 
Potentially by opening K channels 
OR
Decreasing the opening of VGCCs
Stops GABA release
(Overall more DA release!)
37
Q

How does cannabinoids decrease GABA release onto DA neurons?

A

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

38
Q

How does GHB release GABA effect onto DA neurons?

A

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

39
Q

How does cocaine increase DA?

A

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

40
Q

How do amphetamines act to increase DA?

A

Influence the uptake system

But also act directly to displace DA from the vesicles and increase circulation levels

41
Q

Which NAc receptors mediate a tonic inhibitory current?

A

alpha4-delta-GABAa

42
Q

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

A

Gaboxadol

Maguire et al 2014

43
Q

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

A

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)

44
Q

Which mutation causes mice to have increased alcohol preference?

A

beta1 L285R on the beta1 GABAa receptor subunit

Anstee et al 2013

45
Q

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

A

Increases incidence of spontaneous activation shown through patch recordings of HEK293 cells

Anstee et al 2013

BMSc - Psychiatry (12 decks)

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