GABA Basics

Question 1

Alco-Mouse mutations

Answer 1

Beta1 L285R (TM3)
Beta1 P228H (TM1)

Showed preference for ethanol
Result in spontaneously active GABAARs - large tonic currents in NAc

Question 2

NAMs of GABA

Answer 2

beta-carbolines like DCMC

Question 3

Properties of NAMs

Answer 3

Proconvulsant, anxiogenic

Question 4

Properties of PAMs

Answer 4

Anticonvulsant, anxiolytic, sedative, analgesic, amnestic

Question 5

PAMs of GABA

Answer 5

Benzodiazepines (ie diazepam), flunitrazepam, barbiturates, muscle relaxants, alcohol, propofol, etomidate

Question 6

What subunits required for effect of barbiturates?

Answer 6

Alpha1 and beta1

Question 7

What subunit required for effect of diazepam?

Answer 7

Gamma2

Question 8

Diazepam enhances function of which subunits?

Answer 8

Alpha 1, 2, 3, 5 + beta gamma2
Have H at position 101

Question 9

Diazepam does not enhance function of which subunits?

Answer 9

Alpha 4, 6 + beta gamma2
Have R at position 101

Question 10

Benzodiazepine side effects

Answer 10

Sedation
Dependence - may manifest as withdrawal
Amnesia
Addiction

Antagonist flumazenil may help in case of overdoses

Question 11

Benzodiazepines treat

Answer 11

Sleep disorders
Epilepsy
Anxiety disorders
Muscle spasms

Question 12

Alpha 1

Answer 12

Sedation
Anti-convulsive
Amnesia
Addicition

Question 13

Alpha 2

Answer 13

Anxiolysis
Muscle relaxation

Question 14

Alpha 3

Answer 14

Muscle relaxation

Question 15

Alpha 5

Answer 15

Muscle relaxation
Amnesia
BZ sensitive

Question 16

GABAARs alpha 2 Q241W Mouse

Answer 16

Prevents neurosterod modulation of alpha 2 GABAAR
Reduced alcohol preference

Question 17

Effect of alcohol on neurosteroid synthesis

Answer 17

Decreases synthesis
25 mM not so much, but 50+ mM yeh

Question 18

Alpha4 beta2/3 delta GABAARs

Answer 18

Delta knockout drinks less
Ethanol causes increased tonic current - some studies say at 30mM some say only at 100mM

Bicuculline into NAc reduces self-administration

Question 19

GABA in the VTA

Answer 19

In VTA -> GABAergic interneurons release GABA onto dopaminergic neurons -> increases DA release in NAc (reward, depression, stress)

GABA interneurons: express alpha 1, midazolam (BZ) prolongs effect (blocked by H101R)
DA neurons: no alpha 1, midazolam prolongs effect slightly (not blocked by H101R)

Question 20

Benzodiazepines and DA neurons in the VTA

Answer 20

BZs enhance phasic inhibition on GABA-interneurons -> decreased GABA onto DA neurons
Decreased inhibition of DA -> increased excitation of DA neurons -> increased DA release in NAc

Midazolam increased firing rate of DA neurons, decreases firing rate of GABA neurons (not in H101R mice)
WT, not alpha 1/2 H101R mice, self-administer midazolam
Alpha 2 mainly expressed in NAc

Question 21

GABA Transporters

Answer 21

GAT 1-3
On pre-synaptic membrane (blocked by tiagabine, anti-convulsant)

VGAT
Vesicular GABA amino acid transporter
On vesicle membrane carrying GABA

Question 22

Drugs and GABA

Answer 22

Opioids - decrease GABA release onto DA neurons via MOPrs
Cannabinoids - decrease release of GABA onto DA neurons via CB1
BZs - acts on alpha1 GABARs in GABA interneurons decrease GABA release onto DA neurons, increasing DA excitability
-> disinhibition

Nicotine - activates NAChRs on DA neurons, causes depolarisation, increased DA release
Cocaine + amphetamine - influence DA transporters/release, increases extracellular conc of DA

Question 23

What subunits does ELA affect?

Answer 23

alpha2 beta gamma2
Synaptic alpha2 GABARs expressed in NAc MSN

ELA mice show higher levels of corticotrophin releasing factor (CRF) - peptide hormone involved in stress response

ELA or loss of alpha2 enhances effects of cocaine (10mg/kg) as in enhanced locomoter effects, and reduced sensitisation of cocaine

ELA selectively decreases alpha2 subunit immunoreactivity in adult mouse NAc, also less gabaergic synapses, decreased mIPSC amplitude, decreased frequency of NAc MSNs