GABAaR & Addiction

Question 1

Describe the sturcture of a GABAa Receptor

Answer 1

Pentameric, 5 subunits

Alpha subunots

Beta subunits

Gamma, delta, epsilon, theta, pi subunits

Question 2

Receptors containing which subunits are diazepam (BDZ) sensitive?

Answer 2

y2

a1, 2, 3, 5

Question 3

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

Answer 3

y2

a4, 6

Question 4

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

Answer 4

a1 H -> R becomes insensitive

a6 R -> H becomes sensitive

Question 5

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

Answer 5

a1-3, 5 have a histine residue

a4, 6 have argine residue in the equivalent position

Question 6

Where on the GABAa receptor is the BDZ binding site?

Answer 6

Between a and y subunit interface

Question 7

What conditions can BDZ be used to treat?

Answer 7

Sleep disorders

Anxiety disorders

Epilepsy

Muscle spasms

Question 8

What are the main side effects of BDZ?

Answer 8

Sedation

Amnesia

Dependence

Addiction

Question 9

What are the symptoms of BDZ dependence/withdrawal ?

Answer 9

Sleep disturbances

irritability

Anxiety

Panic attacks

Question 10

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

Answer 10

Ethanol

Question 11

What antagonist for BDZ can be used in OD?

Answer 11

Flumazenil

Question 12

What particular mutation of a1 blocks the effects of Midazolam?

Answer 12

a1 H 101 R

Question 13

Where can GABAaR a1 sbunits be found?

Answer 13

GABA neurones express the a1 subunit

Dopamine neurones do not

Question 14

BDZ cause disinhibition of dopamine neurones in the VTA

Describe the two mechanisms by which this occurs

Answer 14

(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

Question 15

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

Answer 15

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)

Question 16

In a choice between sucrose, and sucrose+water

How do WT and a1H101R mice compare?

Answer 16

WT preferentially administer midazolam

a1H101R do not

Question 17

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

Answer 17

BDZ that are inert at a1-GABAaR

Such as L-838,417

Question 18

How is L-838,417 not addictive?

Answer 18

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

Question 19

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

(REF)

Answer 19

Both a1 and a2 required for self-admin

a2 knock-out abolishes self-admin

Engin 2014

Question 20

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

Answer 20

Limited expression in VTA

However, high expression in Nucleus accumbens

Question 21

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

Answer 21

Decrease release of GABA onto dopamine neurones

via mu opioid receptors

opening of K channels

decreasing opening of Ca channels

Question 22

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

Answer 22

Decrease release of GABA via cannabinoid CB1 receptors

Decrease opening probability of voltage-gated Ca channels

Question 23

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

Answer 23

act on a1-GABAaRs on GABA-ergic interneurones

Decrease release of GABA onto dopamine neurones

Question 24

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

Answer 24

Activates nAChRs (a4B2) on dopamine neurones

Causes their depolarisation

Increased dopamine release

Question 25

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

Answer 25

Influence dopamine transporter/release Thereby increase extracellualr dopamine

Question 26

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

Answer 26

Depression Anxiety Cognitive impairment Addiction

Question 27

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

Answer 27

a2 subunit

Question 28

What two functions is the NAcc generally associated with?

Answer 28

Reward Stress

Question 29

The majority of NAcc neurones are what form of neurone?

Answer 29

95% GABAergic

Question 30

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

Answer 30

Days 2-9

Question 31

ELS paradigm causes what change in mother-pup interaction?

Answer 31

Reduced frequency of mother-pup interaction

Question 32

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

Answer 32

Enhanced acute effects Supresses behavioural sensitisation

Question 33

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

Answer 33

Enhanced acute locomotion Reduced sensitisation

Question 34

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

Answer 34

Core medium spiny neurone | (MSNs)

Question 35

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

Answer 35

a2 subunit No change in a1

Question 36

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

Answer 36

Express extrasynaptic a4Bd GABAaRs that mediate a tonic current

Question 37

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

Answer 37

THIP | (gaboxadol)

Question 38

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

Answer 38

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

Question 39

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

Answer 39

B1 L-285-R

Question 40

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

Answer 40

B1 P-228-H

Question 41

Where is B1 loacted and why is it important?

Answer 41

B1 mutations located in trnasmembrane regions Result in spontaneously active GABAaRs Cause large tonic current in accumbens