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Neuropharmacology - Translational Psychiatry > GABAaR & Addiction > Flashcards

GABAaR & Addiction Flashcards

1
Q

Describe the sturcture of a GABAa Receptor

A

Pentameric, 5 subunits

Alpha subunots

Beta subunits

Gamma, delta, epsilon, theta, pi subunits

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2
Q

Receptors containing which subunits are diazepam (BDZ) sensitive?

A

y2

a1, 2, 3, 5

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3
Q

GABAa receptors containing which subunits are diazepam (BDZ) insensitive?

A

y2

a4, 6

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4
Q

The sensitivities of a1 and a6 GABAa subunits can be changed by what mutations?

A

a1 H -> R becomes insensitive

a6 R -> H becomes sensitive

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5
Q

What is the structural difference between a1-3, a5 and a4, 6? With regards to their sensitivity to diazepam

A

a1-3, 5 have a histine residue

a4, 6 have argine residue in the equivalent position

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6
Q

Where on the GABAa receptor is the BDZ binding site?

A

Between a and y subunit interface

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7
Q

What conditions can BDZ be used to treat?

A

Sleep disorders

Anxiety disorders

Epilepsy

Muscle spasms

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8
Q

What are the main side effects of BDZ?

A

Sedation

Amnesia

Dependence

Addiction

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9
Q

What are the symptoms of BDZ dependence/withdrawal ?

A

Sleep disturbances

irritability

Anxiety

Panic attacks

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10
Q

BDZ risk of overdose is greatly enhanced in the presence of which other common drug?

A

Ethanol

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11
Q

What antagonist for BDZ can be used in OD?

A

Flumazenil

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12
Q

What particular mutation of a1 blocks the effects of Midazolam?

A

a1 H 101 R

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13
Q

Where can GABAaR a1 sbunits be found?

A

GABA neurones express the a1 subunit

Dopamine neurones do not

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14
Q

BDZ cause disinhibition of dopamine neurones in the VTA

Describe the two mechanisms by which this occurs

A

(1)

BDZ enhance pahsic inhibition on the GABA-ergic interneurone

Causes a decreased GABA release onto dopamine neurone

(2)

Decreased inhibition of dopamine neurone

Causes increased excitation of dopamine neurone

Increased dopamine release in the Nucleus Accumbens

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15
Q

Knowing the mechanism of BDZ on the VTA, describe how midazolam and flumazenil act

A

Midazolam increases the firing rate of dopamine neurone

Reversed by Flumazenil

Midazolam decreases the firign rate of GABA neurones

Reversed by Flumazenil

(Effects do not occur in a1H101R mice)

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16
Q

In a choice between sucrose, and sucrose+water

How do WT and a1H101R mice compare?

A

WT preferentially administer midazolam

a1H101R do not

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17
Q

With regards to the a1 GABAaR subunit, how could new BDZ be anxiolytic but without abuse potential?

A

BDZ that are inert at a1-GABAaR

Such as L-838,417

18
Q

How is L-838,417 not addictive?

A

This drug has no effect on dopamine release via VTA GABA interneurones

Instead acts on a3-GABAaRs on dopamine neurones

Decreases excitability

Decreases dopamine release

19
Q

What is the role of a2-GABAaRs in midazolam self-admin?

(REF)

A

Both a1 and a2 required for self-admin

a2 knock-out abolishes self-admin

Engin 2014

20
Q

Where is the expression of a2 GABAaR subunits found, why is it important?

A

Limited expression in VTA

However, high expression in Nucleus accumbens

21
Q

Many drugs act via the VTA-accumbens pathway to increase accumbal dopamine. How do opioids do this?

A

Decrease release of GABA onto dopamine neurones

via mu opioid receptors

opening of K channels

decreasing opening of Ca channels

22
Q

Many drugs act via the VTA-accumbens pathway to increase accumbal dopamine. How do cannabinoids do this?

A

Decrease release of GABA via cannabinoid CB1 receptors

Decrease opening probability of voltage-gated Ca channels

23
Q

Many drugs act via the VTA-accumbens pathway to increase accumbal dopamine. How do BDZ do this?

A

act on a1-GABAaRs on GABA-ergic interneurones

Decrease release of GABA onto dopamine neurones

24
Q

Many drugs act via the VTA-accumbens pathway to increase accumbal dopamine. How does nicotine do this?

A

Activates nAChRs (a4B2) on dopamine neurones

Causes their depolarisation

Increased dopamine release

25
Q

Many drugs act via the VTA-accumbens pathway to increase accumbal dopamine. How do cocaine / amphetamine do this?

A

Influence dopamine transporter/release

Thereby increase extracellualr dopamine

26
Q

Early life stress (ELS) is associated with which behavioural disorders?

A

Depression

Anxiety

Cognitive impairment

Addiction

27
Q

Wich GABAaR subunit is linked to addiciton throguh studies on its polymorphisms?

A

a2 subunit

28
Q

What two functions is the NAcc generally associated with?

A

Reward

Stress

29
Q

The majority of NAcc neurones are what form of neurone?

A

95% GABAergic

30
Q

In the ELS paradigm using mice, during which days are the stress in place (fine mesh cage bottom)

A

Days 2-9

31
Q

ELS paradigm causes what change in mother-pup interaction?

A

Reduced frequency of mother-pup interaction

32
Q

Loss of the a2-GABAaR subunit causes what changes to the effects of cocaine?

A

Enhanced acute effects

Supresses behavioural sensitisation

33
Q

Both ELS and a2-knockout mice exhibit what common behavioural changes with cocaine exposure?

A

Enhanced acute locomotion

Reduced sensitisation

34
Q

What particular cell in the NAcc is investigated for its GABAa receptor expresson?

A

Core medium spiny neurone

(MSNs)

35
Q

ELS causes a decrease in NAcc expression of which GABAaR subunit?

A

a2 subunit

No change in a1

36
Q

Maguire 2014 showed that MSNs express what? why is it important?

A

Express extrasynaptic a4Bd GABAaRs that mediate a tonic current

37
Q

Selective activation of extrasynaptic a4Bd GABAaRs can be achieved by what?

A

THIP

(gaboxadol)

38
Q

Descrbe the evidence for the effect of ethanol on GABAaRs, with regard to the delta receptor.

(addiction)

A

d-knockouts drink less but same sedative and anxiolytic effects

GABAaR antagonist perfusion into accumbens reduces self-admin

Causing reduced d/a4 subunit expression in vivo reduces self-admin

39
Q

What specific genotype of GABAaR b1 subunit mutation causes a profound alcohol prefference in mice?

A

B1 L-285-R

40
Q

In humans what genotype of GABAaR is associated with profound preference for ethanol?

A

B1 P-228-H

41
Q

Where is B1 loacted and why is it important?

A

B1 mutations located in trnasmembrane regions

Result in spontaneously active GABAaRs

Cause large tonic current in accumbens

Neuropharmacology - Translational Psychiatry (12 decks)

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