GABA-A receptor pharmacology

Question 1

Inhibitory GABA transmission

Answer 1

AS8

Question 2

what blocks GAT 1-3 GABA transporter?

Answer 2

Tiagabine

An anticonvulsant

Question 3

What are the 7 things thata bind to GABA_A receptor?

Answer 3

1. Propofol
2. Bariturates
3. Steroids
4. GABA
5. Etomidate
6. Benzodiazepines
7. Volatile anesthetics

Question 4

PAMs?

PAMs of the GABA_Ar

Answer 4

Positive allosteric modulators

Enhance function

Ligands that act at the benzodiazepine binding site

eg. diazepam

Question 5

NAMs definition?

NAMs of the GABA_AR

Answer 5

Neative allosteric modulators

Decrease function

Does nothing itself but when GABA is present it decreases the response

Question 6

What stops PAMs and NAMs from binding at the GABA_AR?

Answer 6

Antagonist of the benzodiazepine site.

eg. flumazenil.

Prevents PAM and NAMs as it occupies the site they bind to

Question 7

GABA_A receptor structure?

Answer 7

5 subunits

2x alpha1

2x beta 2

1 x gamma2.

GABA site: 2 of them. between the alpha-beta.

BZ: between the alpha-gamma

Question 8

How many different GABAA receptor isoforms are there?

Answer 8

19 different subunits.

Rules that govern the binding between particular subunits.

Question 9

Benzodiazepines?

Answer 9

Widely used to treat anxiety and insomnia.

Induce muscle relaxation

Control epileptic seizures and can produce amnesia.

Tolerance quickly

Question 10

Valium?

Answer 10

Used for treatment of anixety during the day sedation

Tolerance takes longer for valium than benzodiazepines

Question 11

What does diazepam do?

Answer 11

Enhances the function of a1,a2,a3,a5 GABA_AR.

Does not enhance a4 or a6 GABA_AR

Question 12

Why does diazepam effect some GABAAR but not all?

Answer 12

At 101 AA the residue has to be H and not R (which it is for alpha 4 and 6)

Question 13

alpha1 mutation

Answer 13

causes loss of 3H-flumazenil binding.

Prevents the prolongation of thalamic mIPSCs by selective drug zolpidem.

Sedative effect of diazepam is still there

Question 14

Benzodiazepine addiction?

Answer 14

Initially, feel sleepy and uncoordinated.

After a few weeks, physical dependence may occur.

Addiction is associated with chronic use.

BZ abuse in conjunction with other substance such as alcohol

Question 15

What mediates the pleasurable effects of diazepam?

Answer 15

Mediated by the alpha1 GABAA receptor

Question 16

Alpha 2 GABAA receptor mediates?

Answer 16

The anxiolytic effects of diazepam

ie. relieves anxiety

Question 17

Name the 3 ways to measure analgesia in moud models of inflammatory pain and neuropathic pain?

Answer 17

Heat hyperalgesa (paw withdrawal)

Mechanical sensitisation: Von-Frey filaments

Cold allodynia: time spent trying to physically heat paw up

Question 18

What subunit is important in the pain pathway?

Answer 18

alpha 2.

Question 19

Alpha2 GABAA receptor?

Answer 19

Densely expressed in dorsal horn neurones.

Diazepam suppresses the sensitised response to heat and mechanical stimulation.

Question 20

alpha5 GABAA receptors and cognition

Answer 20

Expressed extrasynaptically in hippocampal CA1 neurones.

Surpression of alpha5: improve performance

Question 21

The role each GABAA receptor have on benzodiazepines effects?

Answer 21

AS9

Question 22

How to design a drug discover programme to indentify GABAAR subtypes?

Answer 22

Design a compound

Undergo displacement test with 3H-flunitrazepam to see its affinity.

Test binding selectivity using fluroscents