GABAaR & Addiction Flashcards
Describe the sturcture of a GABAa Receptor
Pentameric, 5 subunits
Alpha subunots
Beta subunits
Gamma, delta, epsilon, theta, pi subunits
Receptors containing which subunits are diazepam (BDZ) sensitive?
y2
a1, 2, 3, 5
GABAa receptors containing which subunits are diazepam (BDZ) insensitive?
y2
a4, 6
The sensitivities of a1 and a6 GABAa subunits can be changed by what mutations?
a1 H -> R becomes insensitive
a6 R -> H becomes sensitive
What is the structural difference between a1-3, a5 and a4, 6? With regards to their sensitivity to diazepam
a1-3, 5 have a histine residue
a4, 6 have argine residue in the equivalent position
Where on the GABAa receptor is the BDZ binding site?
Between a and y subunit interface
What conditions can BDZ be used to treat?
Sleep disorders
Anxiety disorders
Epilepsy
Muscle spasms
What are the main side effects of BDZ?
Sedation
Amnesia
Dependence
Addiction
What are the symptoms of BDZ dependence/withdrawal ?
Sleep disturbances
irritability
Anxiety
Panic attacks
BDZ risk of overdose is greatly enhanced in the presence of which other common drug?
Ethanol
What antagonist for BDZ can be used in OD?
Flumazenil
What particular mutation of a1 blocks the effects of Midazolam?
a1 H 101 R
Where can GABAaR a1 sbunits be found?
GABA neurones express the a1 subunit
Dopamine neurones do not
BDZ cause disinhibition of dopamine neurones in the VTA
Describe the two mechanisms by which this occurs
(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
Knowing the mechanism of BDZ on the VTA, describe how midazolam and flumazenil act
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)
In a choice between sucrose, and sucrose+water
How do WT and a1H101R mice compare?
WT preferentially administer midazolam
a1H101R do not
With regards to the a1 GABAaR subunit, how could new BDZ be anxiolytic but without abuse potential?
BDZ that are inert at a1-GABAaR
Such as L-838,417
How is L-838,417 not addictive?
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
What is the role of a2-GABAaRs in midazolam self-admin?
(REF)
Both a1 and a2 required for self-admin
a2 knock-out abolishes self-admin
Engin 2014
Where is the expression of a2 GABAaR subunits found, why is it important?
Limited expression in VTA
However, high expression in Nucleus accumbens
Many drugs act via the VTA-accumbens pathway to increase accumbal dopamine. How do opioids do this?
Decrease release of GABA onto dopamine neurones
via mu opioid receptors
opening of K channels
decreasing opening of Ca channels
Many drugs act via the VTA-accumbens pathway to increase accumbal dopamine. How do cannabinoids do this?
Decrease release of GABA via cannabinoid CB1 receptors
Decrease opening probability of voltage-gated Ca channels
Many drugs act via the VTA-accumbens pathway to increase accumbal dopamine. How do BDZ do this?
act on a1-GABAaRs on GABA-ergic interneurones
Decrease release of GABA onto dopamine neurones
Many drugs act via the VTA-accumbens pathway to increase accumbal dopamine. How does nicotine do this?
Activates nAChRs (a4B2) on dopamine neurones
Causes their depolarisation
Increased dopamine release
Many drugs act via the VTA-accumbens pathway to increase accumbal dopamine. How do cocaine / amphetamine do this?
Influence dopamine transporter/release
Thereby increase extracellualr dopamine
Early life stress (ELS) is associated with which behavioural disorders?
Depression
Anxiety
Cognitive impairment
Addiction
Wich GABAaR subunit is linked to addiciton throguh studies on its polymorphisms?
a2 subunit
What two functions is the NAcc generally associated with?
Reward
Stress
The majority of NAcc neurones are what form of neurone?
95% GABAergic
In the ELS paradigm using mice, during which days are the stress in place (fine mesh cage bottom)
Days 2-9
ELS paradigm causes what change in mother-pup interaction?
Reduced frequency of mother-pup interaction
Loss of the a2-GABAaR subunit causes what changes to the effects of cocaine?
Enhanced acute effects
Supresses behavioural sensitisation
Both ELS and a2-knockout mice exhibit what common behavioural changes with cocaine exposure?
Enhanced acute locomotion
Reduced sensitisation
What particular cell in the NAcc is investigated for its GABAa receptor expresson?
Core medium spiny neurone
(MSNs)
ELS causes a decrease in NAcc expression of which GABAaR subunit?
a2 subunit
No change in a1
Maguire 2014 showed that MSNs express what? why is it important?
Express extrasynaptic a4Bd GABAaRs that mediate a tonic current
Selective activation of extrasynaptic a4Bd GABAaRs can be achieved by what?
THIP
(gaboxadol)
Descrbe the evidence for the effect of ethanol on GABAaRs, with regard to the delta receptor.
(addiction)
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
What specific genotype of GABAaR b1 subunit mutation causes a profound alcohol prefference in mice?
B1 L-285-R
In humans what genotype of GABAaR is associated with profound preference for ethanol?
B1 P-228-H
Where is B1 loacted and why is it important?
B1 mutations located in trnasmembrane regions
Result in spontaneously active GABAaRs
Cause large tonic current in accumbens
